1 00:00:05,880 --> 00:00:12,440 >> WE'LL START THE INAUGURAL 2 00:00:12,440 --> 00:00:20,800 SYMPOSIUM AND WE HAVE SOME 3 00:00:20,800 --> 00:00:23,320 WELCOMING WORDS AND HOUSEKEEPING 4 00:00:23,320 --> 00:00:23,640 ITEMS. 5 00:00:23,640 --> 00:00:28,200 THE CONFERENCE IS SPONSORED BY 6 00:00:28,200 --> 00:00:33,520 THE NIH INTERMURAL PROGRAM AND 7 00:00:33,520 --> 00:00:35,400 THE NATIONAL GENOME INSTITUTE 8 00:00:35,400 --> 00:00:37,040 OFFICE OF THE CLINICAL DIRECTOR 9 00:00:37,040 --> 00:00:37,560 AND UNDIAGNOSED DISEASES 10 00:00:37,560 --> 00:00:47,160 PROGRAM. 11 00:00:47,160 --> 00:00:48,600 WE WANTED TO CENTER AROUND 12 00:00:48,600 --> 00:00:50,440 PATIENTS AND FAMILIES WE'VE BEEN 13 00:00:50,440 --> 00:00:52,240 PRIVILEGED TO CARE FOR AND BRING 14 00:00:52,240 --> 00:00:55,880 TOGETHER CLINICIANS, SCIENTISTS, 15 00:00:55,880 --> 00:00:59,080 GENETIC TESTING COMPANIES AND 16 00:00:59,080 --> 00:01:01,480 ADVOCACY GROUPS TO DISCUSS WHAT 17 00:01:01,480 --> 00:01:03,160 IS KNOWN ABOUT THIS DISEASE AND 18 00:01:03,160 --> 00:01:07,360 WHAT WE CURRENTLY UNDERSTAND IS 19 00:01:07,360 --> 00:01:08,680 MUTATIONS WHEN THEY OCCUR DE 20 00:01:08,680 --> 00:01:11,320 NOVO SEEM TO OCCUR TO A KNEW 21 00:01:11,320 --> 00:01:13,920 PHENOTYPE OF CHILDHOOD ONSET 22 00:01:13,920 --> 00:01:16,320 CEREBRAL PALSY DIFFERENT FROM 23 00:01:16,320 --> 00:01:18,960 THE ADULT PHENOTYPE OF THE 24 00:01:18,960 --> 00:01:19,760 CLASSIC SPG4 DISEASE. 25 00:01:19,760 --> 00:01:24,760 THE GOALS ARE TO REVIEW WHAT IS 26 00:01:24,760 --> 00:01:26,480 KNOWN ABOUT DE NOVO SPG4 AND 27 00:01:26,480 --> 00:01:28,080 INFORM TRANSLATIONAL RESEARCH 28 00:01:28,080 --> 00:01:31,920 WITH THE GOAL OF THERAPEUTICS 29 00:01:31,920 --> 00:01:32,840 DEVELOPMENT AND ESTABLISH A 30 00:01:32,840 --> 00:01:34,160 RESEARCH NETWORK. 31 00:01:34,160 --> 00:01:36,040 WE HOPE TO HAVE FUTURE IN PERSON 32 00:01:36,040 --> 00:01:36,960 MEETINGS AND IF YOU WORK IN THE 33 00:01:36,960 --> 00:01:38,320 FIELD AND WOULD LIKE TO PRESENT 34 00:01:38,320 --> 00:01:40,400 IN FUTURE MEETINGS WE WELCOME 35 00:01:40,400 --> 00:02:01,360 YOUR PARTICIPATION. 36 00:02:01,360 --> 00:02:05,080 AND WE HAVE THE ACTING DIRECTOR. 37 00:02:05,080 --> 00:02:07,800 BEFORE COMING TO NIH SHE WAS AT 38 00:02:07,800 --> 00:02:11,240 THE UNIVERSITY OF PITTSBURGH 39 00:02:11,240 --> 00:02:11,760 BECOMING THE PROFESSOR OF 40 00:02:11,760 --> 00:02:15,080 PEDIATRIC RESEARCH IN THE 41 00:02:15,080 --> 00:02:17,360 DEPARTMENT OF PEDIATRICS AND 42 00:02:17,360 --> 00:02:19,040 ASSOCIATE DEAN FOR AT THE 43 00:02:19,040 --> 00:02:21,040 MEDICAL SCHOOL. 44 00:02:21,040 --> 00:02:22,880 IN 2006 SHE BECAME THE CHAIR OF 45 00:02:22,880 --> 00:02:25,480 THE DEPARTMENT OF PEDIATRICS AND 46 00:02:25,480 --> 00:02:27,600 PEDIATRICIAN OF CHIEF AT THE 47 00:02:27,600 --> 00:02:29,320 UNIVERSITY OF RODCHESTER. 48 00:02:29,320 --> 00:02:31,320 AND THAT POST SHE HELD UNTIL 49 00:02:31,320 --> 00:02:33,120 JANUARY 2018 WHEN WE WERE LUCKY 50 00:02:33,120 --> 00:02:35,800 ENOUGH FOR HER TO COME AS DEPUTY 51 00:02:35,800 --> 00:02:37,120 DIRECTOR OF NINDS. 52 00:02:37,120 --> 00:02:39,800 FOR 27 YEARS HER RESEARCH HAS 53 00:02:39,800 --> 00:02:41,440 CENTERED ON NEURAL DEVELOPMENT 54 00:02:41,440 --> 00:02:43,760 AND HAS BEEN FUNDED BY THE NIH. 55 00:02:43,760 --> 00:02:45,840 SHE CURRENTLY LEADS THE DIVISION 56 00:02:45,840 --> 00:02:50,160 OF INTRAMURAL RESEARCH AND THE 57 00:02:50,160 --> 00:02:52,960 ULTRA RARE GENE THERAPIES AND 58 00:02:52,960 --> 00:02:53,640 CAREER DEVELOPMENT PROGRAMS AT 59 00:02:53,640 --> 00:02:56,520 NINDS AND SERVED AS THE 60 00:02:56,520 --> 00:02:57,720 NEUROLOGY DIRECTOR FOR THE 61 00:02:57,720 --> 00:02:59,840 AMERICAN BOARD OF PSYCHIATRY AND 62 00:02:59,840 --> 00:03:00,120 NEUROLOGY. 63 00:03:00,120 --> 00:03:03,840 THE SECOND WELCOMING SPEAKER 64 00:03:03,840 --> 00:03:07,840 WILL BE CYNTHIA TIFFT AND SPEAK 65 00:03:07,840 --> 00:03:13,480 ON BEHALF OF NHGRI AND WILL TALK 66 00:03:13,480 --> 00:03:16,280 ABOUT THE UNDIAGNOSED DISEASES 67 00:03:16,280 --> 00:03:20,320 NETWORK AND ABOUT HER 68 00:03:20,320 --> 00:03:21,760 GROUNDBREAKING TRIAL ON GM1 69 00:03:21,760 --> 00:03:23,120 THERAPY AND IT'S A UNIQUE 70 00:03:23,120 --> 00:03:24,920 RESOURCE FOR RARE DISEASES AND 71 00:03:24,920 --> 00:03:26,040 TREATMENT TRIALS. 72 00:03:26,040 --> 00:03:27,800 SHE RECEIVED HER Ph.D. IN 73 00:03:27,800 --> 00:03:30,800 GENETICS FROM THE UNIVERSITY OF 74 00:03:30,800 --> 00:03:33,920 TEXAS AT MD ANDERSON CANCER 75 00:03:33,920 --> 00:03:37,600 CENTER AND HER MD FROM THE 76 00:03:37,600 --> 00:03:39,280 CANCER CENTER IN HOUSTON AND 77 00:03:39,280 --> 00:03:42,480 COMPLETED HER RESIDENCY AT JOHNS 78 00:03:42,480 --> 00:03:44,480 HOPKINS AND JOINED THE FACULTY 79 00:03:44,480 --> 00:03:45,320 OF THE GEORGE WASHINGTON SCHOOL 80 00:03:45,320 --> 00:03:47,880 OF MEDICINE AT NATIONAL MEDICAL 81 00:03:47,880 --> 00:03:51,840 CENTER IN 1991 AND BECAME CHAIR 82 00:03:51,840 --> 00:03:54,200 OF GENETICS IN 2006. 83 00:03:54,200 --> 00:03:56,720 SHE WAS RECRUITED TO THE 84 00:03:56,720 --> 00:03:58,920 NATIONAL GENOME INSTITUTE AS THE 85 00:03:58,920 --> 00:04:01,320 DEPUTY CLINICAL DIRECTOR WHERE 86 00:04:01,320 --> 00:04:03,600 SHE DIRECTS THE UNDIAGNOSED 87 00:04:03,600 --> 00:04:05,200 DISEASES PROGRAM. 88 00:04:05,200 --> 00:04:07,840 HER RESEARCH HAS BEEN AROUND 89 00:04:07,840 --> 00:04:09,920 DISEASES AFFECTING THE CENTRAL 90 00:04:09,920 --> 00:04:14,640 NERVOUS SYSTEM AND THE PRINCIPLE 91 00:04:14,640 --> 00:04:18,440 INVESTIGATOR OF CHILDREN WITH 92 00:04:18,440 --> 00:04:19,800 CYTOSIS. 93 00:04:19,800 --> 00:04:23,560 THANK YOU AND WE'LL START WITH 94 00:04:23,560 --> 00:04:47,480 DR. SCHOR. 95 00:04:47,480 --> 00:04:50,120 >> I WANT TO TELL YOU ABOUT AN 96 00:04:50,120 --> 00:04:51,520 INITIATIVE INTERESTED TO ALL OF 97 00:04:51,520 --> 00:04:53,400 YOU IN RESEARCH AND DEVELOPMENT 98 00:04:53,400 --> 00:04:58,680 OF THERAPIES FOR ULTRA RARE 99 00:04:58,680 --> 00:04:59,400 GENE-BASED DISORDERS. 100 00:04:59,400 --> 00:05:03,720 THAT'S THE NINDS URGENT NETWORK. 101 00:05:03,720 --> 00:05:05,880 SO THIS AUDIENCE IS NO STRANGER 102 00:05:05,880 --> 00:05:09,560 TO ALL THE CHALLENGES THAT ARE 103 00:05:09,560 --> 00:05:15,680 PRESENTED BY DEVELOPING 104 00:05:15,680 --> 00:05:19,440 THERAPEUTICS FOR INDIVIDUALS FOR 105 00:05:19,440 --> 00:05:20,320 RARE DISORDER. 106 00:05:20,320 --> 00:05:24,480 THERE'S A COMPLEX REGULATORY 107 00:05:24,480 --> 00:05:27,800 PATH YOU HAVE TO RAISE FUNDS TO 108 00:05:27,800 --> 00:05:30,840 TWO NF IS TRIALS AND GETTING 109 00:05:30,840 --> 00:05:33,080 INTEREST FROM ACADEMIC 110 00:05:33,080 --> 00:05:34,480 RESEARCHERS FOR DISORDERS FOR 111 00:05:34,480 --> 00:05:39,800 BASIC DISEASE MECHANISMS MAY NOT 112 00:05:39,800 --> 00:05:43,520 BE KNOWN OR WHERE THIS THE TRIAL 113 00:05:43,520 --> 00:05:47,880 DESIGN IS CHALLENGING AND ACCESS 114 00:05:47,880 --> 00:05:50,040 TO THERAPY DEVELOPMENT 115 00:05:50,040 --> 00:05:52,160 EXPERIENCE OR TO TOXICOLOGY AND 116 00:05:52,160 --> 00:05:57,840 MANUFACTURING AND SCALE-UP KIND 117 00:05:57,840 --> 00:05:59,400 OF RESOURCES. 118 00:05:59,400 --> 00:06:01,120 THERE'S LITTLE IN THE WAY OF 119 00:06:01,120 --> 00:06:03,280 MARKET FOR MANY THERAPIES FOR 120 00:06:03,280 --> 00:06:08,680 THESE DISORDER SO IT'S DIFFICULT 121 00:06:08,680 --> 00:06:14,200 TO ENGAGE INDUSTRY AND THERE'S 122 00:06:14,200 --> 00:06:15,720 UNIQUE CONCERNS WHEN YOU'RE 123 00:06:15,720 --> 00:06:17,160 DOING THIS WITH SMALL ENDS AND 124 00:06:17,160 --> 00:06:18,360 THERE'S MANY CHALLENGES. 125 00:06:18,360 --> 00:06:20,200 FOR MANY OF THESE DISORDERS WE 126 00:06:20,200 --> 00:06:21,920 DON'T KNOW YET WHAT THE NATURAL 127 00:06:21,920 --> 00:06:24,920 HISTORY IS AND RECRUITING 128 00:06:24,920 --> 00:06:26,440 PATIENTS FROM A VERY VERY 129 00:06:26,440 --> 00:06:33,760 DIVERSE ARRAY OF VENUES BECOMES 130 00:06:33,760 --> 00:06:35,360 CHALLENGING AS WELL. 131 00:06:35,360 --> 00:06:38,760 SMALL NUMBERS OF PATIENTS IN 132 00:06:38,760 --> 00:06:40,520 PERHAPS HUNDREDS OF VENUES EACH 133 00:06:40,520 --> 00:06:42,240 OF WHICH PRESENT DIFFERENT 134 00:06:42,240 --> 00:06:42,520 CHALLENGES. 135 00:06:42,520 --> 00:06:47,800 THE OLE OF THE URGENT NETWORK 136 00:06:47,800 --> 00:06:50,280 THAT NINDS HAS CREATED IS TO 137 00:06:50,280 --> 00:06:51,800 FACILITATE RESEARCH ON THERAPIES 138 00:06:51,800 --> 00:06:53,320 FOR THESE DISORDERS. 139 00:06:53,320 --> 00:06:57,320 TO ACCELERATE ADVANCEMENT OF THE 140 00:06:57,320 --> 00:07:00,560 THERAPIES INTO THE CLINIC, TO 141 00:07:00,560 --> 00:07:02,320 DEMOCRATIZE THE AVAILABILITY OF 142 00:07:02,320 --> 00:07:03,240 GENE THERAPY TO PEOPLE WHO WANT 143 00:07:03,240 --> 00:07:08,480 TO DO THIS RESEARCH AND TO 144 00:07:08,480 --> 00:07:10,920 PATIENTS AND FAMILIES SUFFERING 145 00:07:10,920 --> 00:07:12,720 FROM THESE DISORDER TO DEVELOP 146 00:07:12,720 --> 00:07:18,720 THERAPEUTICS TO PATIENTS WITH 147 00:07:18,720 --> 00:07:20,520 ULTRA RARE NEUROLOGIC DISEASE 148 00:07:20,520 --> 00:07:22,280 REGARDLESS OF WHERE THEY LIVE 149 00:07:22,280 --> 00:07:24,440 AND WHAT RESOURCES ARE AROUND 150 00:07:24,440 --> 00:07:26,000 THEM AND STANDARDIZE BEST 151 00:07:26,000 --> 00:07:27,800 PRACTICES AND PROTOCOLS AN DATA 152 00:07:27,800 --> 00:07:28,840 COLLECTION TO MAKE DATA 153 00:07:28,840 --> 00:07:32,000 AVAILABLE TO PEOPLE ALL OVER THE 154 00:07:32,000 --> 00:07:36,920 GLOBE. 155 00:07:36,920 --> 00:07:39,560 AND THE RESEARCH THE NETWORK 156 00:07:39,560 --> 00:07:44,440 PROVIDES RUNS THE GAMUT FROM GMP 157 00:07:44,440 --> 00:07:49,560 MANUFACTURING OF CLINICAL LOTS 158 00:07:49,560 --> 00:07:53,800 OF VIRUS AND THERAPEUTICS AND TO 159 00:07:53,800 --> 00:07:57,720 THE NOTION OF PERFORMING FOR THE 160 00:07:57,720 --> 00:08:04,720 SCIENTIFIC AND THE PHARMACO 161 00:08:04,720 --> 00:08:07,080 KINETICS THAT MAKE OBTAINING AN 162 00:08:07,080 --> 00:08:08,720 IND AND HAVE AVAILABLE SUBJECT 163 00:08:08,720 --> 00:08:11,320 MATTER EXPERTS AS CONSULTANTS ON 164 00:08:11,320 --> 00:08:14,680 SUCH THINGS AS MANUFACTURING PK 165 00:08:14,680 --> 00:08:20,800 TOXICOLOGY AND TO REALLY DO THE 166 00:08:20,800 --> 00:08:23,320 DISCUSSION WITH THE FDA AND 167 00:08:23,320 --> 00:08:27,760 OTHER REGULATORY AGENCIES TO 168 00:08:27,760 --> 00:08:31,760 OBTAINING AN IND AND CLINICAL 169 00:08:31,760 --> 00:08:34,600 TRIAL DESIGN AND AT THE CLINICAL 170 00:08:34,600 --> 00:08:39,720 CENTER AT NIH CONDUCT OF THE 171 00:08:39,720 --> 00:08:43,760 CLINICAL TRIAL AND TO REALLY 172 00:08:43,760 --> 00:08:44,400 CENTRALIZE DATA COLLECTION AND 173 00:08:44,400 --> 00:08:47,360 COORDINATION. 174 00:08:47,360 --> 00:08:48,200 THERE'S CURRENTLY FUNDING 175 00:08:48,200 --> 00:08:48,480 AVAILABLE. 176 00:08:48,480 --> 00:08:50,600 WE'RE AT THE BEGINNING OF WHAT I 177 00:08:50,600 --> 00:08:53,360 HOPE WILL BE A LONG STORY FOR 178 00:08:53,360 --> 00:08:56,640 URGENT NETWORK. 179 00:08:56,640 --> 00:09:03,520 BUT THERE ARE TWO RFA'S OUT FOR 180 00:09:03,520 --> 00:09:14,560 FUNDING OF THE INITIAL ONE OF 181 00:09:14,560 --> 00:09:17,080 PAR22030 IS AIMED AT THE AIMED 182 00:09:17,080 --> 00:09:21,320 AT THE TRIAL READINESS 183 00:09:21,320 --> 00:09:21,560 RESOURCES. 184 00:09:21,560 --> 00:09:24,520 THE KINDS OF THINGS YOU WOULD DO 185 00:09:24,520 --> 00:09:27,760 TO GET AN IND OR TO DECIDE IF 186 00:09:27,760 --> 00:09:29,920 IT'S REASONABLE BASED ON THE YOU 187 00:09:29,920 --> 00:09:32,760 CURRENTLY HAVE. 188 00:09:32,760 --> 00:09:47,800 AND THE SECOND IS PAR22028 AND 189 00:09:47,800 --> 00:09:50,880 THAT'S BEFORE YOU DO THE STUDIES 190 00:09:50,880 --> 00:09:51,800 TO DO THE BASIC SCIENCE 191 00:09:51,800 --> 00:09:55,800 MECHANISTIC DATA TO DESIGN WHAT 192 00:09:55,800 --> 00:09:59,360 YOU USE IN THE CLINICAL TRIAL 193 00:09:59,360 --> 00:10:03,160 A 194 00:10:03,160 --> 00:10:05,360 AND TALKING ABOUT URGENT NETWORK 195 00:10:05,360 --> 00:10:10,520 AND OUTABILITY FOR WHAT IT IS 196 00:10:10,520 --> 00:10:16,840 THEY ACCOMPLISH. 197 00:10:16,840 --> 00:10:21,000 CHRIS BOSHOFF IS THE LEAD AND 198 00:10:21,000 --> 00:10:25,880 HIS COLLEAGUES YOU CAN SEND 199 00:10:25,880 --> 00:10:26,920 INQUIRIES TO. 200 00:10:26,920 --> 00:10:28,560 IF YOU HAVE INQUIRIES OR JUST 201 00:10:28,560 --> 00:10:32,320 WANT TO SET UP A TIME TO TALK 202 00:10:32,320 --> 00:10:33,800 WITH THE PRINCIPLE PROGRAM 203 00:10:33,800 --> 00:10:39,760 DIRECTORS INVOLVED IN URGENT 204 00:10:39,760 --> 00:10:46,000 NETWORK I HOPE YOU GET A ROBUST 205 00:10:46,000 --> 00:10:48,280 RESPONSE TO THE RFAs BECAUSE 206 00:10:48,280 --> 00:10:50,720 LIKE YOU I'M HOPING WE DEVELOP 207 00:10:50,720 --> 00:10:51,920 KNOWLEDGE AND CLINICAL TRIALS 208 00:10:51,920 --> 00:10:59,360 FOR RARE DISORDER INVOLVING THE 209 00:10:59,360 --> 00:11:24,560 NERVOUS SYSTEM. 210 00:11:24,560 --> 00:11:26,240 AND WE HAVE A GROUP OF SUBJECT 211 00:11:26,240 --> 00:11:30,360 MATTER EXPERTS WE ASSEMBLED AND 212 00:11:30,360 --> 00:11:31,600 ENGAGED IN ORDER TO GET YOU THE 213 00:11:31,600 --> 00:11:33,600 INFORMATION YOU NEED TO GET NOT 214 00:11:33,600 --> 00:11:38,640 WHOLE THERAPIES OUT THERE AND 215 00:11:38,640 --> 00:11:43,320 AVAILABLE TO PATIENTS AND MAKING 216 00:11:43,320 --> 00:11:44,120 IT AVAILABLE TO EVERYONE IN THE 217 00:11:44,120 --> 00:11:45,720 SCIENTIFIC COMMUNITY. 218 00:11:45,720 --> 00:11:47,840 SO I'LL CLOSE BY THANKING ALL OF 219 00:11:47,840 --> 00:11:50,600 YOU FOR BEING OUR PARTNERS IN 220 00:11:50,600 --> 00:11:50,880 THIS. 221 00:11:50,880 --> 00:11:53,360 THANKS TO OUR FUNDERS FOR THIS 222 00:11:53,360 --> 00:11:54,760 WONDERFUL CONFERENCE AND THANKS 223 00:11:54,760 --> 00:11:56,240 TO ALL OF YOU FOR BEING WITH US 224 00:11:56,240 --> 00:12:07,800 TODAY. 225 00:12:07,800 --> 00:12:10,560 >> THANK YOU SO MUCH FOR THOSE 226 00:12:10,560 --> 00:12:11,840 WONDERFUL COMMENTS AND THOSE 227 00:12:11,840 --> 00:12:12,720 WONDERFUL INITIATIVES. 228 00:12:12,720 --> 00:12:18,520 NOW I'LL PASS IT OVER TO 229 00:12:18,520 --> 00:12:21,320 DR. TIFFT. 230 00:12:21,320 --> 00:12:26,680 >> THANK YOU FOR THE KIND 231 00:12:26,680 --> 00:12:31,240 INTRODUCTION ARRINE. 232 00:12:31,240 --> 00:12:31,840 ARE YOU SEEING THIS IN THE 233 00:12:31,840 --> 00:12:33,200 APPROPRIATE WAY? 234 00:12:33,200 --> 00:12:35,400 >> YES. 235 00:12:35,400 --> 00:12:38,720 >> OKAY, PERFECT. 236 00:12:38,720 --> 00:12:40,440 SO MY ROLE AS I UNDERSTAND IT IS 237 00:12:40,440 --> 00:12:41,920 TO TALK ABOUT THE UNDIAGNOSED 238 00:12:41,920 --> 00:12:43,920 DISEASE PROGRAM AND A PATHWAY OR 239 00:12:43,920 --> 00:12:47,760 AS A PATHWAY MAYBE EVEN TO RARE 240 00:12:47,760 --> 00:12:53,400 DISEASE RESEARCH AND SHARE MY 241 00:12:53,400 --> 00:13:07,320 EXPERIENCE IN THAT VENUE THE NIN 242 00:13:07,320 --> 00:13:10,520 CLINICAL CENTER IS A 200 BED 243 00:13:10,520 --> 00:13:11,800 HOSPITAL DEDICATED SOLELY TO 244 00:13:11,800 --> 00:13:15,840 CLINICAL RESEARCH AND IMPROVING 245 00:13:15,840 --> 00:13:17,400 THE NATION'S HEALTH. 246 00:13:17,400 --> 00:13:20,800 AND PATIENTS WHO COME TO THE NIH 247 00:13:20,800 --> 00:13:22,800 INCUR NO COST TO BEING INVOLVED 248 00:13:22,800 --> 00:13:26,120 AND THERE'S ROUGHLY 1600 ACTIVE 249 00:13:26,120 --> 00:13:27,800 RESEARCH PROTOCOLS AND HALF OF 250 00:13:27,800 --> 00:13:28,760 THESE STUDIES ARE NATURAL 251 00:13:28,760 --> 00:13:30,640 HISTORY STUDIES ESPECIALLY FOR 252 00:13:30,640 --> 00:13:32,760 RARE AND ULTRA RARE DISEASES AND 253 00:13:32,760 --> 00:13:34,480 THE OTHER HALF WILL CLINICAL 254 00:13:34,480 --> 00:13:35,800 TRIALS AND OFTEN THEY'RE FIRST 255 00:13:35,800 --> 00:13:39,800 IN HUMAN STUDIES TO TEST SAFETY 256 00:13:39,800 --> 00:13:42,600 AND EFFICACY OF NEW 257 00:13:42,600 --> 00:13:42,920 THERAPEUTICS. 258 00:13:42,920 --> 00:13:46,360 THE VAST MAJORITY OF THE 259 00:13:46,360 --> 00:13:47,840 PROTOCOLS ARE DISEASE BASED. 260 00:13:47,840 --> 00:13:50,120 AS A RESULT OF THAT IN 2008, THE 261 00:13:50,120 --> 00:13:55,720 NIH UNDIAGNOSED DISEASES PROGRAM 262 00:13:55,720 --> 00:13:59,840 WAS LAUNCHED TO BASICALLY ALLOW 263 00:13:59,840 --> 00:14:01,640 ACCESS TO THE NIH CLINICAL 264 00:14:01,640 --> 00:14:03,080 CENTER FOR FOLKS WHO DIDN'T HAVE 265 00:14:03,080 --> 00:14:05,400 A DIAGNOSIS AND WERE NOT 266 00:14:05,400 --> 00:14:08,400 ELIGIBLE FOR THE PROTOCOLS OR 267 00:14:08,400 --> 00:14:09,880 RESOURCES OF THE NIH. 268 00:14:09,880 --> 00:14:11,400 THERE'S TWO OBJECTIVES TO 269 00:14:11,400 --> 00:14:13,560 REFLECT THE MISSION OF THE NIH 270 00:14:13,560 --> 00:14:17,480 BOTH FOR PUBLIC SERVICE AND FOR 271 00:14:17,480 --> 00:14:21,520 ADVANCING BIOMEDICAL RESEARCH. 272 00:14:21,520 --> 00:14:25,240 SO THE NIH UNDIAGNOSED DISEASE 273 00:14:25,240 --> 00:14:27,320 PROGRAM OVER THE LAST 12 YEARS 274 00:14:27,320 --> 00:14:29,240 WE ESSENTIALLY LOOKED AT ABOUT 275 00:14:29,240 --> 00:14:31,720 4,000 MEDICAL RECORDS AND WE DID 276 00:14:31,720 --> 00:14:34,320 THIS ON PAPER IN VAST STACKS AND 277 00:14:34,320 --> 00:14:35,600 NOW DOING MOST ELECTRONICALLY. 278 00:14:35,600 --> 00:14:38,520 WE HAVE ACCEPTED ROUGHLY 1200 279 00:14:38,520 --> 00:14:43,800 PATIENTS OF WHICH 40% ARE KIDS. 280 00:14:43,800 --> 00:14:47,160 CONSIDERABLY MORE THAN 50% OF 281 00:14:47,160 --> 00:14:48,520 PARTICIPANTS HAVE NEUROLOGIC 282 00:14:48,520 --> 00:14:49,400 CONDITIONS RELEVANT TO THE 283 00:14:49,400 --> 00:14:51,200 CONFERENCE TODAY. 284 00:14:51,200 --> 00:14:55,840 THERE'S BEEN AT LEAST TWO SPG4 285 00:14:55,840 --> 00:14:59,120 DIAGNOSES THUS FAR AND WE FOUND 286 00:14:59,120 --> 00:15:00,600 THE DIAGNOSIS IN A THIRD OF THE 287 00:15:00,600 --> 00:15:03,840 PATIENTS THAT APPLY AND 288 00:15:03,840 --> 00:15:05,320 GENERATED PUBLICATIONS MANY ON 289 00:15:05,320 --> 00:15:10,680 ULTRA RARE OR UNIQUE DISEASES. 290 00:15:10,680 --> 00:15:18,360 AND IN 2013 WE BECAME PART OF 291 00:15:18,360 --> 00:15:21,520 THE NIH UNDIAGNOSED DISEASES 292 00:15:21,520 --> 00:15:26,400 NETWORK WHICH EVENTUALLY MORPHED 293 00:15:26,400 --> 00:15:27,360 TO 12 CLINICAL SITES THROUGHOUT 294 00:15:27,360 --> 00:15:29,360 THE COUNTRY AND A COORDINATING 295 00:15:29,360 --> 00:15:33,160 CENTER AT HARVARD, A DNA 296 00:15:33,160 --> 00:15:35,400 COORDINATING CENTER AT THE 297 00:15:35,400 --> 00:15:39,800 BAYLOR COLLEGE OF MEDICINE AND A 298 00:15:39,800 --> 00:15:41,400 LOCATION AT VANDERBILT 299 00:15:41,400 --> 00:15:43,120 UNIVERSITY AND A MODEL SCREENING 300 00:15:43,120 --> 00:15:49,680 UNIVERSITY AND A METABOLOMICS 301 00:15:49,680 --> 00:15:52,760 WARD AT MAYO CLINICAL WORKING 302 00:15:52,760 --> 00:15:54,880 TOGETHER TRYING TO SOLVE THESE 303 00:15:54,880 --> 00:15:56,920 WHILE LINKED THROUGH A COMMON 304 00:15:56,920 --> 00:15:57,200 DATABASE. 305 00:15:57,200 --> 00:16:00,800 SO FAR THE UDN EXPERIENCE AS OF 306 00:16:00,800 --> 00:16:03,840 THIS MORNING HAD RECEIVED 5700 307 00:16:03,840 --> 00:16:04,160 APPLICATIONS. 308 00:16:04,160 --> 00:16:07,800 PATIENTS APPLY ONLINE AND IT IS 309 00:16:07,800 --> 00:16:10,880 A PATIENT-INITIATED AN 310 00:16:10,880 --> 00:16:12,640 EXPERIENCE AND THEY UPLOAD A 311 00:16:12,640 --> 00:16:14,960 LETTER FROM A PRACTITIONER THAT 312 00:16:14,960 --> 00:16:19,840 SUMMARIZES THE WORK THEY'VE 313 00:16:19,840 --> 00:16:21,560 ALREADY HAD AND ASKING TO BE 314 00:16:21,560 --> 00:16:25,120 CONSIDERED FOR ADMISSION TO THE 315 00:16:25,120 --> 00:16:25,320 UDN. 316 00:16:25,320 --> 00:16:27,600 WE HAVE APPLICATIONS UNDER 317 00:16:27,600 --> 00:16:31,080 REVIEW OF ABOUT 2200 HAVE BEEN 318 00:16:31,080 --> 00:16:33,120 ACCEPTED ACROSS THE NETWORK AND 319 00:16:33,120 --> 00:16:38,120 WE EVALUATED A LITTLE OVER 1300 320 00:16:38,120 --> 00:16:42,040 PATIENTS AND SEQUENCED 1700 BY 321 00:16:42,040 --> 00:16:43,800 GENOME SEQUENCING AND MADE MODEL 322 00:16:43,800 --> 00:16:45,680 ORGANISMS AND HAVE CELL LINES IN 323 00:16:45,680 --> 00:16:49,680 THE REPOSITORY AND HAVE DONE 324 00:16:49,680 --> 00:16:52,520 METABOLOMICS AND TOGETHER SINCE 325 00:16:52,520 --> 00:16:54,600 2013, NOT COUNTING THE DIAGNOSES 326 00:16:54,600 --> 00:16:56,320 BETWEEN 2008 AND 2013 BUT 327 00:16:56,320 --> 00:16:59,800 WORKING TOGETHER AS PART OF THE 328 00:16:59,800 --> 00:17:09,600 UDN MADE ROUGHLY 550 DIAGNOSES. 329 00:17:09,600 --> 00:17:11,800 ONE OF THE FIRST WE EVER SOLVED 330 00:17:11,800 --> 00:17:15,720 AND LINKED TO MY SECOND INTEREST 331 00:17:15,720 --> 00:17:18,840 IS A PATIENT NAMED JESSIE AND 332 00:17:18,840 --> 00:17:20,520 SHE WAS 17 YEARS OLD AND HAD 333 00:17:20,520 --> 00:17:25,160 BEEN SEARCHING FOR A DIAGNOSIS 334 00:17:25,160 --> 00:17:26,080 ALMOST 12 YEARS. 335 00:17:26,080 --> 00:17:29,320 HER PARENTS HAD BEEN TO MULTIPLE 336 00:17:29,320 --> 00:17:30,760 ACADEMIC INSTITUTIONS AND ON 337 00:17:30,760 --> 00:17:34,680 EXOME SEQUENCE WE FOUND SHE HAD 338 00:17:34,680 --> 00:17:38,600 MUTATIONS IN GLB1. 339 00:17:38,600 --> 00:17:40,640 AND HAD THE TYPE 2 JUVENILE 340 00:17:40,640 --> 00:17:43,200 ONSET FORM BEGINNING AT ABOUT 341 00:17:43,200 --> 00:17:45,600 AGE 4 OR 5. 342 00:17:45,600 --> 00:17:56,520 SHE ACTUALLY HAD HAD A LYSOMAL 343 00:17:56,520 --> 00:18:05,160 SCREEN AND WAS A JUVENILE ONSET 344 00:18:05,160 --> 00:18:07,120 CASE AND HER CONDITION WAS RARE 345 00:18:07,120 --> 00:18:09,120 AND THERE WAS NO APPROVED 346 00:18:09,120 --> 00:18:10,680 THERAPY. 347 00:18:10,680 --> 00:18:12,480 JESSIE WAS ONE OF THE FIRST 348 00:18:12,480 --> 00:18:15,720 PATIENTS WE ENROLLED FOR GM1 AND 349 00:18:15,720 --> 00:18:18,720 GM2 AND 12 YEARS LATER WE'VE 350 00:18:18,720 --> 00:18:21,720 SEEN ROUGHLY 50 PATIENTS TO 351 00:18:21,720 --> 00:18:22,800 CHARACTERIZE THE DISEASE 352 00:18:22,800 --> 00:18:24,440 PROGRESSION IN THAT DISEASE. 353 00:18:24,440 --> 00:18:25,760 AFTER 12 YEARS OF CHARACTERIZING 354 00:18:25,760 --> 00:18:27,640 THE DISEASE PROGRESSION, WORKING 355 00:18:27,640 --> 00:18:29,360 WITH OUR COLLEAGUES AT THE 356 00:18:29,360 --> 00:18:31,760 UNIVERSITY OF MASSACHUSETTS AT 357 00:18:31,760 --> 00:18:35,000 AUBURN UNIVERSITY WHO DEVELOPED 358 00:18:35,000 --> 00:18:40,280 THE VIRAL AAV9 VECTOR AND TESTED 359 00:18:40,280 --> 00:18:42,760 IT IN AN ANIMAL MODEL WE 360 00:18:42,760 --> 00:18:44,000 LAUNCHED OUR THERAPY TRIAL IN 361 00:18:44,000 --> 00:18:44,920 MAY OF 2019. 362 00:18:44,920 --> 00:18:49,240 YOU CAN SEE HERE OUR FIRST 363 00:18:49,240 --> 00:18:52,920 PARTICIPANTS AND A WHOLE GROUP 364 00:18:52,920 --> 00:18:58,720 OF FOLKS AND U-MASS AND BECAME 365 00:18:58,720 --> 00:18:59,360 CYTOGENE THERAPIES HELPING 366 00:18:59,360 --> 00:19:00,920 SUPPORT US IN THE TRIAL AND IF 367 00:19:00,920 --> 00:19:03,800 YOU WANT THE FULL GOOD STORY, 368 00:19:03,800 --> 00:19:05,120 THAT'S THE LINK. 369 00:19:05,120 --> 00:19:07,320 BUT OVER THE NEXT TWO AND A HALF 370 00:19:07,320 --> 00:19:11,280 YEARS AND ONE PANDEMIC, WE HAVE 371 00:19:11,280 --> 00:19:13,360 ENROLLED AN ADDITIONAL 10 372 00:19:13,360 --> 00:19:15,200 PATIENTS INTO OUR CLINICAL TRIAL 373 00:19:15,200 --> 00:19:17,360 AND TREATED THEM WITH GENE 374 00:19:17,360 --> 00:19:20,640 THERAPY INCLUDING TWO INFANTS 375 00:19:20,640 --> 00:19:22,880 THAT DR. SCHOR IS WELL AWARE OF 376 00:19:22,880 --> 00:19:24,280 BECAUSE SHE WAS INSTRUMENTAL IN 377 00:19:24,280 --> 00:19:27,040 HELPING US WORK THROUGH THE 378 00:19:27,040 --> 00:19:28,400 ISSUES WITH THE CLINICAL CENTER. 379 00:19:28,400 --> 00:19:31,480 THESE WERE THE FIRST TWO INFANTS 380 00:19:31,480 --> 00:19:33,560 TO BE TREATED AT THE CENTER IN 381 00:19:33,560 --> 00:19:33,800 DECADES. 382 00:19:33,800 --> 00:19:36,240 IT WAS GRATIFYING TO BE ABLE TO 383 00:19:36,240 --> 00:19:37,520 DO THAT. 384 00:19:37,520 --> 00:19:41,840 AND WE'VE HAD NO SERIOUS 385 00:19:41,840 --> 00:19:43,200 DRUG-RELATED ADVERSE EVENTS AS A 386 00:19:43,200 --> 00:19:44,480 RESULT OF THE TRIAL THAT IS 387 00:19:44,480 --> 00:19:46,920 ONGOING AND WE NEED THE 388 00:19:46,920 --> 00:19:48,200 RESOURCES OF THE NIH CLINICAL 389 00:19:48,200 --> 00:19:50,520 CENTER NOW MORE THAN EVER 390 00:19:50,520 --> 00:19:51,840 BECAUSE LESS THAN 48 HOURS AGO 391 00:19:51,840 --> 00:19:54,440 OUR PARTNER IN THIS WHO WAS 392 00:19:54,440 --> 00:19:55,800 FUNDING THE TRIAL ANNOUNCED IT 393 00:19:55,800 --> 00:19:58,480 WAS TERMINATING BOTH OUR TRIAL, 394 00:19:58,480 --> 00:20:01,640 THE GM1 TRIAL AT THE NIH AND A 395 00:20:01,640 --> 00:20:03,880 COMPANION GM2 TRIAL AT THE 396 00:20:03,880 --> 00:20:05,000 UNIVERSITY OF MASSACHUSETTS. 397 00:20:05,000 --> 00:20:07,800 SO FOR THE LAST 36, 48 HOURS 398 00:20:07,800 --> 00:20:11,200 WE'VE BEEN SCRAMBLING. 399 00:20:11,200 --> 00:20:16,200 FORTUNATELY, CARE AT THE NIH IS 400 00:20:16,200 --> 00:20:17,720 PROVIDED TO NO COST TO PATIENTS 401 00:20:17,720 --> 00:20:19,720 AND BASED ON THAT WE'RE IN HOPES 402 00:20:19,720 --> 00:20:23,720 OF BEING ABLE TO CONTINUE TO 403 00:20:23,720 --> 00:20:25,560 TREAT OUR PATIENTS BOTH FOR THE 404 00:20:25,560 --> 00:20:26,680 PATIENTS WE CURRENTLY ENROLLED 405 00:20:26,680 --> 00:20:29,320 AND FOR THE ENTIRE GM1 COMMUNITY 406 00:20:29,320 --> 00:20:31,760 WHO WORKED SO HARD TO BRING THIS 407 00:20:31,760 --> 00:20:32,760 STUDY TO FRUITION. 408 00:20:32,760 --> 00:20:34,760 SO WITH THAT, I WON'T TAKE 409 00:20:34,760 --> 00:20:35,760 QUESTIONS BECAUSE WE'LL SAVE 410 00:20:35,760 --> 00:20:36,160 THEM FOR THE END. 411 00:20:36,160 --> 00:20:46,000 THANK YOU. 412 00:20:46,000 --> 00:20:47,120 >> THANK YOU VERY MUCH FOR THOSE 413 00:20:47,120 --> 00:20:50,280 IMPORTANT REMARKS AND HOPE 414 00:20:50,280 --> 00:20:53,400 YOU'RE TRIAL WILL BE ABLE TO 415 00:20:53,400 --> 00:20:55,520 CONTINUE AS IT'S SO IMPORTANT. 416 00:20:55,520 --> 00:20:59,400 I'LL INTRODUCE THE MODERATOR OF 417 00:20:59,400 --> 00:21:04,520 OUR FIRST SYMPOSIUM. 418 00:21:04,520 --> 00:21:06,520 DO PEOPLE SEE MY SLIDES? 419 00:21:06,520 --> 00:21:06,720 GREAT. 420 00:21:06,720 --> 00:21:10,320 THE FIRST SYMPOSIUM IS GOING TO 421 00:21:10,320 --> 00:21:11,360 REVIEW THE CLINIC PHENOTYPE OF 422 00:21:11,360 --> 00:21:14,920 DE NOVO SPG4 MODERATED BY 423 00:21:14,920 --> 00:21:16,480 DR. KATHARINE ALTER. 424 00:21:16,480 --> 00:21:18,760 SHE IS BOARD-CERTIFIED IN 425 00:21:18,760 --> 00:21:21,840 PEDIATRICS, PHYSICAL MEDICINE 426 00:21:21,840 --> 00:21:23,360 AND ELECTRODIAGNOSTIC MEDICINE 427 00:21:23,360 --> 00:21:27,760 AND MEDICAL DIRECTOR OF THE NIH 428 00:21:27,760 --> 00:21:29,360 REHABILITATION FUNCTIONAL AND 429 00:21:29,360 --> 00:21:31,800 APPLIED BIOMECHANICS SECTION 430 00:21:31,800 --> 00:21:33,840 WITH MEASUREMENTS AND 431 00:21:33,840 --> 00:21:35,120 QUANTIFICATION OF GAIT IN MANY 432 00:21:35,120 --> 00:21:36,120 CLINICAL TRIALS AT THE NIH AND 433 00:21:36,120 --> 00:21:39,800 HAS EXPERTISE IN CEREBRAL PALSY 434 00:21:39,800 --> 00:21:42,720 AND GAIT ANALYSIS IN RARE 435 00:21:42,720 --> 00:21:43,760 NEUROLOGICAL DISEASES AND HAS 436 00:21:43,760 --> 00:21:47,400 SEEN MANY OF THE NIH PATIENTS 437 00:21:47,400 --> 00:21:48,520 WITH DE NOVO SPG4. 438 00:21:48,520 --> 00:21:50,480 TO BRIEFLY GO OVER OUR SCHEDULE 439 00:21:50,480 --> 00:21:53,400 FOR THE FIRST SYMPOSIUM. 440 00:21:53,400 --> 00:21:55,840 WE'LL HAVE SPEAKERS TO 11:05 AND 441 00:21:55,840 --> 00:21:58,320 THEN A TEN MINUTE BREAK AND 442 00:21:58,320 --> 00:22:02,640 SPEAKERS TO 12:05 AND THEN A 443 00:22:02,640 --> 00:22:03,800 30-MINUTE LUNCH BREAK. 444 00:22:03,800 --> 00:22:06,840 I'LL PASS IT OVER TO DR. ALTER. 445 00:22:06,840 --> 00:22:07,520 >> THANK YOU. 446 00:22:07,520 --> 00:22:11,800 THE FIRST PORTION OF OUR PROGRAM 447 00:22:11,800 --> 00:22:14,640 THIS MORNING WILL BE TWO SETS 448 00:22:14,640 --> 00:22:17,760 OF, WELL, FOUR PARENTS OF FOUR 449 00:22:17,760 --> 00:22:22,960 CHILDREN WHO ARE AFFECTED BY 450 00:22:22,960 --> 00:22:24,560 SPG4 DE NOVO VARIANTS AND 451 00:22:24,560 --> 00:22:26,920 THEY'LL BRING THEIR EXPERTISE TO 452 00:22:26,920 --> 00:22:29,680 THE CHALLENGES OF NAVIGATING THE 453 00:22:29,680 --> 00:22:31,520 MEDICAL AND REHABILITATION 454 00:22:31,520 --> 00:22:34,240 SYSTEM AND ALL THE OTHER 455 00:22:34,240 --> 00:22:35,360 CHALLENGES THAT ARE ASSOCIATED 456 00:22:35,360 --> 00:22:37,520 WITH RAISING A CHILD WITH A 457 00:22:37,520 --> 00:22:42,920 DISABILITY ESPECIALLY A RARE 458 00:22:42,920 --> 00:22:47,400 GENETIC DISEASE. 459 00:22:47,400 --> 00:22:55,640 AND WE'LL HAVE MORE ABOUT AN 460 00:22:55,640 --> 00:22:58,600 OVERVIEW OF THE CURE SPG4 461 00:22:58,600 --> 00:23:03,680 NETWORK WHICH SOME ARE BEEN 462 00:23:03,680 --> 00:23:06,560 INSTRUMENTAL IN THE DEVELOPMENT 463 00:23:06,560 --> 00:23:11,720 AND DR. SCHULE FROM TUBINGEN, 464 00:23:11,720 --> 00:23:17,400 GERMANY WILL TALK ABOUT THE 465 00:23:17,400 --> 00:23:22,240 SPASTIC PARAPLEGIC PHENOTYPE AND 466 00:23:22,240 --> 00:23:35,000 CONDUCTS RESEARCH IN GERMANY AND 467 00:23:35,000 --> 00:23:36,720 WORKED ON THERAPY IN THE RATING 468 00:23:36,720 --> 00:23:38,400 SCALE WHICH HAS BEEN 469 00:23:38,400 --> 00:23:43,800 INSTRUMENTAL FOR US IN MEASURING 470 00:23:43,800 --> 00:23:46,000 QUANTITATIVELY ACROSS MULTIPLE 471 00:23:46,000 --> 00:23:53,400 CENTERS FORM AND FUNCTION AND 472 00:23:53,400 --> 00:23:54,160 IMPAIRMENT. 473 00:23:54,160 --> 00:23:56,520 AND IS COORDINATING THE NETWORK. 474 00:23:56,520 --> 00:24:00,080 WE WANT TO WELCOME ALL THE 475 00:24:00,080 --> 00:24:05,400 SPEAKERS AND START OFF WITH THE 476 00:24:05,400 --> 00:24:11,400 FIRST SET OF PARENTS, CHRIS AND 477 00:24:11,400 --> 00:24:15,160 KATIE GREGG. 478 00:24:15,160 --> 00:24:16,520 >> THANK YOU FOR THE 479 00:24:16,520 --> 00:24:17,400 INTRODUCTION. 480 00:24:17,400 --> 00:24:22,320 I'LL JUST SHARE MY SCREEN. 481 00:24:22,320 --> 00:24:24,360 HOPEFULLY YOU CAN ALL SEE IT? 482 00:24:24,360 --> 00:24:26,920 CAN YOU CONFIRM? 483 00:24:26,920 --> 00:24:27,320 >> YES. 484 00:24:27,320 --> 00:24:29,320 >> GREAT. 485 00:24:29,320 --> 00:24:30,800 AGAIN, THANK YOU DR. ALTER AND 486 00:24:30,800 --> 00:24:31,960 NIH FOR ARRANGING THIS MEETING 487 00:24:31,960 --> 00:24:35,120 AND FOR THE INVITATION TO SPEAK. 488 00:24:35,120 --> 00:24:39,800 I COULD NEVER HAVE IMAGINED I 489 00:24:39,800 --> 00:24:42,120 WOULD HELP OPEN A MEDICAL 490 00:24:42,120 --> 00:24:43,800 SYMPOSIUM WITH DOCTORS ALL OVER 491 00:24:43,800 --> 00:24:45,920 THE WORLD AND HAVING A CHILD 492 00:24:45,920 --> 00:24:49,080 DIAGNOSED WITH AN INCURRABLE 493 00:24:49,080 --> 00:24:49,960 DEBILITATING DISEASE FINDS YOU 494 00:24:49,960 --> 00:24:51,840 IN PLACES YOU WOULD NEVER 495 00:24:51,840 --> 00:24:52,760 IMAGINE. 496 00:24:52,760 --> 00:24:53,440 SCIENTIFICALLY SPEAKING WE ALL 497 00:24:53,440 --> 00:24:54,840 KNOW WHY WE'RE HERE. 498 00:24:54,840 --> 00:24:57,520 AS THE PROGRAM STATES WE'RE HERE 499 00:24:57,520 --> 00:25:01,000 TO SHARE INFORMATION ABOUT DE 500 00:25:01,000 --> 00:25:02,880 NOVO SPG4 TO INFORM FUTURE 501 00:25:02,880 --> 00:25:03,800 RESEARCH AND THE REASON I'M HERE 502 00:25:03,800 --> 00:25:05,360 TODAY IS TO SEE IF I HAVE HOPE 503 00:25:05,360 --> 00:25:06,240 FOR MY DAUGHTER. 504 00:25:06,240 --> 00:25:10,320 DEVELOPING A TREATMENT FOR CURE 505 00:25:10,320 --> 00:25:16,360 OR DE NOVO CASES OF SPG WOULD 506 00:25:16,360 --> 00:25:17,080 HAVE RECOGNITION ON THE 507 00:25:17,080 --> 00:25:18,200 CONTRIBUTORS IT'S MORE THAN 508 00:25:18,200 --> 00:25:18,880 THAT. 509 00:25:18,880 --> 00:25:19,880 IT WILL FUNDAMENTALLY ALTER THE 510 00:25:19,880 --> 00:25:21,920 COURSE OF THE LIVES OF PEOPLE 511 00:25:21,920 --> 00:25:24,480 THAT LIVE WITH THIS DISEASE AND 512 00:25:24,480 --> 00:25:25,800 EVERYONE WHO CARES DEEPLY ABOUT 513 00:25:25,800 --> 00:25:26,520 THEM. 514 00:25:26,520 --> 00:25:29,480 THE IMPACTS OF THE DISEASE MAY 515 00:25:29,480 --> 00:25:31,040 BE UNDERSTAND BUT FELT BY THE 516 00:25:31,040 --> 00:25:33,320 PATIENTS AND EVERYONE WHO HELPS 517 00:25:33,320 --> 00:25:33,880 CARE FOR THEM. 518 00:25:33,880 --> 00:25:36,040 I WILL NEVER BE ABLE TO FULLY 519 00:25:36,040 --> 00:25:38,320 UNDERSTAND OR APPRECIATE ALL THE 520 00:25:38,320 --> 00:25:41,080 CHALLENGES THAT MY 4-YEAR-OLD 521 00:25:41,080 --> 00:25:43,720 DAUGHTER BLAIR DIAGNOSED WITH 522 00:25:43,720 --> 00:25:46,120 THE DE NOVO SPG4 WILL FACE. 523 00:25:46,120 --> 00:25:48,400 I CAN OBSERVE SOME CHALLENGES 524 00:25:48,400 --> 00:25:51,120 INCLUDING THE FACT SHE'S MISSED 525 00:25:51,120 --> 00:25:52,440 NUMEROUS DEVELOPMENTAL 526 00:25:52,440 --> 00:25:53,040 MILESTONES. 527 00:25:53,040 --> 00:25:54,240 EVEN AT 4 YEARS OF AGE SHE'S NOT 528 00:25:54,240 --> 00:25:57,680 ABLE TO STAND OR WALK. 529 00:25:57,680 --> 00:26:00,160 I CAN WATCH HER AT THE 530 00:26:00,160 --> 00:26:02,720 PLAYGROUND WITH A LONGING LOOK 531 00:26:02,720 --> 00:26:05,000 ON HER FACE WHILE OTHERS RUN 532 00:26:05,000 --> 00:26:06,640 AROUND AND SEE FRUSTRATION IN 533 00:26:06,640 --> 00:26:08,920 HER EYES WHEN SHE WANTS A TOY ON 534 00:26:08,920 --> 00:26:11,400 THE OTHER SIDE OF THE ROOM BUT 535 00:26:11,400 --> 00:26:14,440 WAITING FOR US TO GET IT FOR HER 536 00:26:14,440 --> 00:26:19,840 AND SEE THE FEAR ON HER FACE TO 537 00:26:19,840 --> 00:26:22,040 SIT IN A RESTAURANT AND NEEDS TO 538 00:26:22,040 --> 00:26:25,160 CLUTCH ON US TO MY WIFE AND I 539 00:26:25,160 --> 00:26:26,720 FOR THE ENTIRE MEAL TO HAVE A 540 00:26:26,720 --> 00:26:28,920 SENSE OF STABILITY. 541 00:26:28,920 --> 00:26:32,360 I CANNOT UNDERSTAND WHAT SHE 542 00:26:32,360 --> 00:26:34,080 THINKS OR FEELS INSIDE 543 00:26:34,080 --> 00:26:35,640 ESPECIALLY WHEN OTHER CHILDREN 544 00:26:35,640 --> 00:26:38,440 ASK WHY CAN'T YOU WALK OR DROOL 545 00:26:38,440 --> 00:26:39,800 SO MUCH OR WHAT'S WRONG WITH 546 00:26:39,800 --> 00:26:40,800 YOU? 547 00:26:40,800 --> 00:26:43,920 ALL I CAN COMMENT ON IS HER LIFE 548 00:26:43,920 --> 00:26:45,000 THROUGH THE PERSPECTIVE AND 549 00:26:45,000 --> 00:26:47,360 THROUGH MY PERSPECTIVE IT'S A 550 00:26:47,360 --> 00:26:49,040 CHALLENGING LIFE SHE DOESN'T 551 00:26:49,040 --> 00:26:50,520 DESERVE. 552 00:26:50,520 --> 00:26:52,240 LIKE WE CAN'T UNDERSTAND WHAT IT 553 00:26:52,240 --> 00:26:54,720 FEELS LIKE WITHOUT BEING IN THAT 554 00:26:54,720 --> 00:26:55,800 POSITION IT'S HARD TO UNDERSTAND 555 00:26:55,800 --> 00:26:59,640 WHAT IT'S LIKE TO BE PARENTS. 556 00:26:59,640 --> 00:27:06,800 IT'S NOT UNCKOCON COMMON TO HAVE 557 00:27:06,800 --> 00:27:11,360 THE UNEASE OF KNOWING OUR CHILD 558 00:27:11,360 --> 00:27:12,800 HAS A PROGRESS DISEASE AND WE 559 00:27:12,800 --> 00:27:15,520 HAVE GUILT WE DON'T DO ENOUGH 560 00:27:15,520 --> 00:27:16,080 FOR BLAIR. 561 00:27:16,080 --> 00:27:19,120 THE VAST MAJORITY OF OUR TIME 562 00:27:19,120 --> 00:27:21,960 GOES TO HER INCLUDING PHYSICALLY 563 00:27:21,960 --> 00:27:25,200 MOVING HER AROUND THE HOUSE AND 564 00:27:25,200 --> 00:27:28,640 HELPING WITH HER STRETCHING 565 00:27:28,640 --> 00:27:33,360 ROUTINE OR JUST HELPING HER EAT 566 00:27:33,360 --> 00:27:35,320 THOUGH WE DON'T HAVE TIME FOR 567 00:27:35,320 --> 00:27:42,920 ALL THE ASSIGNMENTS FROM OTHER 568 00:27:42,920 --> 00:27:43,720 THERAPISTS. 569 00:27:43,720 --> 00:27:45,760 THERE'S EMOTIONAL AND PHYSICAL 570 00:27:45,760 --> 00:27:46,320 DEMANDS. 571 00:27:46,320 --> 00:27:47,400 AN OFTEN OVERLOOKED CHALLENGE IS 572 00:27:47,400 --> 00:27:50,640 THE ADMINISTRATIVE BURDEN. 573 00:27:50,640 --> 00:27:52,760 CONSTANTLY SCHEDULING AND 574 00:27:52,760 --> 00:27:54,520 RESCHEDULING DOCTOR AND 575 00:27:54,520 --> 00:27:55,800 THERAPIST APPOINTMENTS AND 576 00:27:55,800 --> 00:27:58,000 COMPLETING MEDICAID APPLICATIONS 577 00:27:58,000 --> 00:27:58,760 OR DEALING WITH INSURANCE 578 00:27:58,760 --> 00:28:00,120 COMPANIES TO NAME A FEW. 579 00:28:00,120 --> 00:28:01,520 IT'S HARD TO DESCRIBE THE 580 00:28:01,520 --> 00:28:03,800 EMOTION I FELT WHEN MY WIFE CAME 581 00:28:03,800 --> 00:28:06,280 UP TO ME WITH TEARS BECAUSE 582 00:28:06,280 --> 00:28:08,600 ASSIST AFTER HAVING BEEN ON THE 583 00:28:08,600 --> 00:28:11,360 PHONE TWO HOURS ARGUING WITH THE 584 00:28:11,360 --> 00:28:14,960 INSURANCE COMPANY WE WERE DENIED 585 00:28:14,960 --> 00:28:17,000 A MEDICAL DEVICE PRESCRIBED. 586 00:28:17,000 --> 00:28:20,440 IT WAS A CULMINATION OF 587 00:28:20,440 --> 00:28:21,800 THOUSANDS OF HOURS BATTLING 588 00:28:21,800 --> 00:28:23,800 INSURANCE COMPANIES TO GET WHAT 589 00:28:23,800 --> 00:28:27,360 WAS PRESCRIBED AND OWED. 590 00:28:27,360 --> 00:28:29,320 IT'S NORMAL TO WOND HER WHAT 591 00:28:29,320 --> 00:28:32,280 KIND OF LIFE YOU'RE CHILD WILL 592 00:28:32,280 --> 00:28:34,440 HAVE AND WILL THEY ARE BE 593 00:28:34,440 --> 00:28:36,840 SUCCESSFUL OR FIND A LOVING 594 00:28:36,840 --> 00:28:37,120 PARTNERS. 595 00:28:37,120 --> 00:28:42,520 WE FIND OURSELVES FOCUSSED ON 596 00:28:42,520 --> 00:28:43,760 OTHER QUESTIONS, WILL OUR 597 00:28:43,760 --> 00:28:47,520 DAUGHTER BE ABLE TO WALK OR BE 598 00:28:47,520 --> 00:28:49,720 SPEAK OR RELYING ON US THE REST 599 00:28:49,720 --> 00:28:51,320 OF HER LIFE AND WHO WILL TAKE 600 00:28:51,320 --> 00:28:54,880 CARE OF HER IF WE CANNOT? 601 00:28:54,880 --> 00:28:56,720 DESPITE HER CHALLENGES, BLAIR IS 602 00:28:56,720 --> 00:28:58,160 ONE OF THE HAPPIEST CHALLENGES 603 00:28:58,160 --> 00:29:00,520 YOU'LL EVER MEET AND HAS A SMILE 604 00:29:00,520 --> 00:29:03,480 THAT LIGHTS UP EVERY ROOM SHE 605 00:29:03,480 --> 00:29:05,440 ENTERS AND SOMEHOW CONTINUES TO 606 00:29:05,440 --> 00:29:06,760 BE PATIENT THROUGH HER SESSIONS 607 00:29:06,760 --> 00:29:07,680 AND PROCEDURES. 608 00:29:07,680 --> 00:29:11,360 WE CONTINUE WITH HER REGIMENT IN 609 00:29:11,360 --> 00:29:17,840 HOPE WE CAN HER HER MEET HER 610 00:29:17,840 --> 00:29:20,640 POTENTIAL AND IN HER YEARS SHE 611 00:29:20,640 --> 00:29:23,320 TAUGHT EVERYONE A VALUABLE 612 00:29:23,320 --> 00:29:24,720 LESSON ON PERSEVERANCE. 613 00:29:24,720 --> 00:29:26,320 I'M PROVIDING INSIGHT TO OUR 614 00:29:26,320 --> 00:29:27,760 LIVES NOT BECAUSE I WANT YOU TO 615 00:29:27,760 --> 00:29:30,000 FEEL BAD OR HAVE SYMPATHY FOR US 616 00:29:30,000 --> 00:29:32,320 BUT TO PROVIDE INSIGHT TO THE 617 00:29:32,320 --> 00:29:33,720 UNSEEN IMPACT OF THE DISEASE AND 618 00:29:33,720 --> 00:29:36,120 STRESS THE IMPORTANCE OF WHAT 619 00:29:36,120 --> 00:29:37,520 WE'RE HERE TO DO TODAY AND 620 00:29:37,520 --> 00:29:39,760 TOMORROW. 621 00:29:39,760 --> 00:29:42,320 I BELIEVE HNIH HAS BEEN ABLE TO 622 00:29:42,320 --> 00:29:44,720 COLLECT THE BEST MINDS TO SOLVE 623 00:29:44,720 --> 00:29:45,360 THE PROBLEM. 624 00:29:45,360 --> 00:29:49,840 I HAVE SPOKEN WITH A NUMBER OF 625 00:29:49,840 --> 00:29:52,520 YOU AND KNOW YOUR TALENTED 626 00:29:52,520 --> 00:29:53,920 PROFESSIONALS AND SUPPORTIVE OF 627 00:29:53,920 --> 00:29:55,320 THE PATIENTS. 628 00:29:55,320 --> 00:29:58,720 THIS SYMPOSIUM IS AN IMPORTANT 629 00:29:58,720 --> 00:30:00,520 STEP TO BRING FOCUS TO DE NOVO 630 00:30:00,520 --> 00:30:03,280 SPG4 BECAUSE I FEEL FINDING A 631 00:30:03,280 --> 00:30:06,120 CURE TO STOP THIS DISEASE IS NOT 632 00:30:06,120 --> 00:30:09,560 IF BUT WHEN BUT TIME THE 633 00:30:09,560 --> 00:30:09,800 ESSENCE. 634 00:30:09,800 --> 00:30:11,720 EACH DAY THAT PASSES RESULTS IN 635 00:30:11,720 --> 00:30:15,800 A WORSENING STATE FOR BLAIR AND 636 00:30:15,800 --> 00:30:19,800 ALL OTHER IMPACTED PATIENTS. 637 00:30:19,800 --> 00:30:25,280 IT'S THE ONLY GROUP THAT CAN 638 00:30:25,280 --> 00:30:26,280 HELP LEAD PROGRESS AND CURRENTLY 639 00:30:26,280 --> 00:30:28,920 THERE ARE NO OTHER OPTIONS. 640 00:30:28,920 --> 00:30:31,680 PLEASE, HELP ME TO HAVE HOPE. 641 00:30:31,680 --> 00:30:33,440 HAVE BLAIR TO HAVE HOPE. 642 00:30:33,440 --> 00:30:36,360 HELP ALL FAMILIES IMPACTED BY 643 00:30:36,360 --> 00:30:38,880 THE DISEASE TO HAVE HOPE. 644 00:30:38,880 --> 00:30:40,920 LET'S STOP THE DISEASE AND 645 00:30:40,920 --> 00:30:43,080 RELIEVE ALL FUTURE GENERATIONS 646 00:30:43,080 --> 00:30:44,760 FROM AN UNJUST LIFE. 647 00:30:44,760 --> 00:30:46,440 I SINCERELY THANK YOU FOR ALL 648 00:30:46,440 --> 00:30:47,800 THE CONTRIBUTIONS YOU'VE MADE AS 649 00:30:47,800 --> 00:30:50,080 DOCTORS, CLINICIANS, 650 00:30:50,080 --> 00:30:53,280 RESEARCHERS, THERAPISTS, 651 00:30:53,280 --> 00:30:54,920 GENETICISTS AND SUPPORTERS AND 652 00:30:54,920 --> 00:30:56,680 THANK YOU FOR JOINING US TODAY. 653 00:30:56,680 --> 00:30:58,840 I'LL DO ANYTHING NECESSARY AS A 654 00:30:58,840 --> 00:31:00,320 PATIENT ADVOCATE TO PARTNER WITH 655 00:31:00,320 --> 00:31:02,400 YOU TO SOLVE THE CHALLENGE AND 656 00:31:02,400 --> 00:31:03,800 LOOK FORWARD TO THE PROGRESS 657 00:31:03,800 --> 00:31:04,240 WE'LL MAKE TOGETHER. 658 00:31:04,240 --> 00:31:11,360 THANK YOU. 659 00:31:11,360 --> 00:31:14,360 >> THANK YOU SO MUCH FOR THE 660 00:31:14,360 --> 00:31:16,320 BEAUTIFUL WORDS AND THANKS FOR 661 00:31:16,320 --> 00:31:17,080 SHARING YOUR EXPERIENCE AND 662 00:31:17,080 --> 00:31:19,800 WE'LL PASS IT ON TO KATIE. 663 00:31:19,800 --> 00:31:28,920 >> GOOD MORNING. 664 00:31:28,920 --> 00:31:31,040 LET ME GO TO MY SCREEN SHARE AND 665 00:31:31,040 --> 00:31:32,960 LET ME NO IF THERE'S ANY ISSUES 666 00:31:32,960 --> 00:31:33,720 WITH SEEING IT. 667 00:31:33,720 --> 00:31:35,320 >> ARE WE GOOD? 668 00:31:35,320 --> 00:31:39,800 >> JUST MAKE IT PRESENTER MODE, 669 00:31:39,800 --> 00:31:41,320 IF YOU DON'T MIND. 670 00:31:41,320 --> 00:31:48,400 >> IT SAYS IT IS. 671 00:31:48,400 --> 00:31:49,080 >> THAT'S GREAT. 672 00:31:49,080 --> 00:31:49,880 >> PERFECT. 673 00:31:49,880 --> 00:31:51,400 GOOD MORNING, EVERYONE. 674 00:31:51,400 --> 00:31:54,560 DOWNTOWN, I'M KATIE GREG. 675 00:31:54,560 --> 00:31:56,920 I'M SO GLAD WE'RE ALL HERE 676 00:31:56,920 --> 00:31:59,840 TOGETHER AND SOMEHOW ALMOST MAY. 677 00:31:59,840 --> 00:32:01,600 TIME FLIES AND I BELIEVE NO MORE 678 00:32:01,600 --> 00:32:03,840 SO THAN FOR A LOT OF HERE TODAY. 679 00:32:03,840 --> 00:32:09,360 MY DAUGHTER LILY HAS EARLY ONSET 680 00:32:09,360 --> 00:32:09,640 SPG4. 681 00:32:09,640 --> 00:32:12,600 A LITTLE BACKGROUND SHE MISSED 682 00:32:12,600 --> 00:32:13,960 MILESTONES EARLY IN LIFE. 683 00:32:13,960 --> 00:32:16,360 AT 15 AND 18 MONTHS THE 684 00:32:16,360 --> 00:32:18,320 PEDIATRICIAN ADVISED US TO WAIT 685 00:32:18,320 --> 00:32:19,000 ON INTERVENTION. 686 00:32:19,000 --> 00:32:20,920 AT 20 MONTHS WE CHOSE TO MOVE 687 00:32:20,920 --> 00:32:25,080 AHEAD ON OUR OWN AND WE RECEIVED 688 00:32:25,080 --> 00:32:28,880 A VERY CONFIDENT CP DIAGNOSIS 689 00:32:28,880 --> 00:32:30,680 EVEN IN THE ABSENCE OF MRI. 690 00:32:30,680 --> 00:32:32,560 WE PURSUED GENETIC TESTING ON 691 00:32:32,560 --> 00:32:34,120 OUR OWN AND TWO MONTHS LATER WE 692 00:32:34,120 --> 00:32:38,280 HAD RESULTS DELIVERED TO US BY A 693 00:32:38,280 --> 00:32:39,520 GENETICISTS WHO CRIED WHEN SHE 694 00:32:39,520 --> 00:32:42,800 GAVE US THE NEWS. 695 00:32:42,800 --> 00:32:45,760 SHE GAVE US HER SYMPATHIES BUT 696 00:32:45,760 --> 00:32:48,360 NO REALS TO OUR QUESTIONS AND WE 697 00:32:48,360 --> 00:32:49,720 STILL HAVE A LOT OF QUESTIONS. 698 00:32:49,720 --> 00:32:52,440 I DON'T SAY THAT FOR SYMPATHY OR 699 00:32:52,440 --> 00:32:53,280 TO DISCOUNT THE WORK THAT'S 700 00:32:53,280 --> 00:32:54,720 BEING DONE. 701 00:32:54,720 --> 00:32:57,160 I SAY THAT BECAUSE ONE DAY IT 702 00:32:57,160 --> 00:32:58,760 WON'T BE ME ASKING THE QUESTION 703 00:32:58,760 --> 00:33:00,120 IT WILL BE LILLY. 704 00:33:00,120 --> 00:33:03,400 AND MY JOB IS TO PROTECT HER. 705 00:33:03,400 --> 00:33:05,280 I DON'T WANT MY DAUGHTER GROWING 706 00:33:05,280 --> 00:33:09,280 UP IN A WORLD WHERE HER 707 00:33:09,280 --> 00:33:11,200 QUESTIONS OR CONCERNS AREN'T BE 708 00:33:11,200 --> 00:33:12,520 ADDRESSED AND HER ACCESS ARE 709 00:33:12,520 --> 00:33:15,800 WITH LIMITATIONS. 710 00:33:15,800 --> 00:33:17,600 TODAY LILLY IS 3 1/2 AND BRIGHT 711 00:33:17,600 --> 00:33:19,800 AND CURIOUS AND FUNNY AND THE 712 00:33:19,800 --> 00:33:21,720 MOST MOTIVATED AND DETERMINED 713 00:33:21,720 --> 00:33:23,560 LITTLE GIRL I KNOW. 714 00:33:23,560 --> 00:33:25,400 SHE CAN'T STAND OR WALK 715 00:33:25,400 --> 00:33:26,440 INDEPENDENTLY AND USE AS A 716 00:33:26,440 --> 00:33:28,480 WALKER TO NAVIGATE AT SCHOOL AND 717 00:33:28,480 --> 00:33:32,840 WHEEL CLAIR FOR LONGER 718 00:33:32,840 --> 00:33:33,120 DISTANCES. 719 00:33:33,120 --> 00:33:37,800 SHE DOES AQUATIC THERAPIES, GOES 720 00:33:37,800 --> 00:33:41,360 TO PRESCHOOL AND INTENSIVES THAT 721 00:33:41,360 --> 00:33:43,000 REQUIRED US MOVING TO VIRGINIA 722 00:33:43,000 --> 00:33:44,640 THREE TO FOUR WEEKS AT A TIME 723 00:33:44,640 --> 00:33:46,040 THREE OR FOUR TIMES A YEAR. 724 00:33:46,040 --> 00:33:48,520 MEANWHILE THE OBLIGATIONS OF MY 725 00:33:48,520 --> 00:33:51,200 HUSBAND AND I GO BEYOND THERAPY, 726 00:33:51,200 --> 00:33:52,760 SCHOOL AND SOCIAL SCHEDULE, WE 727 00:33:52,760 --> 00:33:54,440 STRETCH HER MULTIPLE TIMES A DAY 728 00:33:54,440 --> 00:33:55,840 FOR 20 MINUTES AT A TIME AND 729 00:33:55,840 --> 00:33:59,400 WORK ON HER ADLs SHE CAN'T DO 730 00:33:59,400 --> 00:34:01,760 WITHOUT ASSISTANCE AND PUT HER 731 00:34:01,760 --> 00:34:04,920 ON HER STANDER AND SHE USES 732 00:34:04,920 --> 00:34:10,120 CRUSHES AND ROLLING WALKER THAT 733 00:34:10,120 --> 00:34:13,520 OFFER HER OPTIONS BUT TAKE TIME 734 00:34:13,520 --> 00:34:15,880 TO SET HER UP IN AND SHE HAS 735 00:34:15,880 --> 00:34:17,960 ROTATION STRAPS THAT HAVE TO BE 736 00:34:17,960 --> 00:34:19,800 UNDONE EVERY TIME HER PANTS NEED 737 00:34:19,800 --> 00:34:20,760 TO BE REMOVED. 738 00:34:20,760 --> 00:34:25,760 WE ALSO CARRY AND LIFT HER INTO 739 00:34:25,760 --> 00:34:29,160 CHAIRS, BEDS, CARS AND IN THE 740 00:34:29,160 --> 00:34:30,360 BACK YARD. 741 00:34:30,360 --> 00:34:32,920 OUTSIDE THE EQUIPMENT, RESEARCH, 742 00:34:32,920 --> 00:34:35,600 READING, CALLS TO DOCTOR'S 743 00:34:35,600 --> 00:34:40,320 OFFICES, INSURANCE PROVIDERS AND 744 00:34:40,320 --> 00:34:41,400 HOME MODIFICATION PROVIDERS ARE 745 00:34:41,400 --> 00:34:42,520 ENDLESS AND THERE'S NOT ENOUGH 746 00:34:42,520 --> 00:34:43,720 HOURS IN THE DAY AND THERE'S NO 747 00:34:43,720 --> 00:34:45,760 CLEAR DIRECTION FOR A PATH 748 00:34:45,760 --> 00:34:46,040 FORWARD. 749 00:34:46,040 --> 00:34:47,040 WE FIND OURSELVES DOING 750 00:34:47,040 --> 00:34:49,200 EVERYTHING AND YET AT THE END OF 751 00:34:49,200 --> 00:34:51,800 THE DAY FEELING LIKE IT'S NEVER 752 00:34:51,800 --> 00:34:52,120 ENOUGH. 753 00:34:52,120 --> 00:34:54,720 BUT IT'S NOT MY TIME I'M WORRIED 754 00:34:54,720 --> 00:34:56,120 ABOUT IT'S HERS. 755 00:34:56,120 --> 00:34:57,560 SHE SPENDS HER HOURS IN THE 756 00:34:57,560 --> 00:34:59,640 TRAPPINGS OF ROUTINE AND 757 00:34:59,640 --> 00:35:05,400 EQUIPMENT AND WE'RE HARD PRESSED 758 00:35:05,400 --> 00:35:08,400 ALBEIT DETERMINED TO HAVE HER 759 00:35:08,400 --> 00:35:09,560 EXPLORE HER ENVIRONMENT AND MEET 760 00:35:09,560 --> 00:35:11,680 NEW PEOPLE ALL HINDERED IF WE 761 00:35:11,680 --> 00:35:14,080 CAN'T FIGURE OUT THE BEST WAY TO 762 00:35:14,080 --> 00:35:15,240 MANAGE HER CONDITION AND EQUIP 763 00:35:15,240 --> 00:35:17,400 HER FOR THE DAY AND FRANKLY HER 764 00:35:17,400 --> 00:35:19,320 LIFE AND WE DON'T KNOW HOW MUCH 765 00:35:19,320 --> 00:35:20,680 TIME SHE HAS TO DO THIS OR WHAT 766 00:35:20,680 --> 00:35:21,920 WILL GIVE THE BEST OUTCOME AND 767 00:35:21,920 --> 00:35:24,440 I'M NOT FAULTING HER CARE TEAM. 768 00:35:24,440 --> 00:35:26,600 THERE'S A LACK OF INFORMATION, 769 00:35:26,600 --> 00:35:29,400 INFORMATION, OPTIONS, 770 00:35:29,400 --> 00:35:31,120 FAMILIARITY AND PRESENTATION. 771 00:35:31,120 --> 00:35:32,480 I CHALLENGE US TODAY TO CONSIDER 772 00:35:32,480 --> 00:35:34,920 HOW WE GET A COMMON 773 00:35:34,920 --> 00:35:35,360 UNDERSTANDING. 774 00:35:35,360 --> 00:35:38,600 A COMMON CONSENSUS AND GET HOPE. 775 00:35:38,600 --> 00:35:40,720 I WOULD ARGUE THAT LILLY HAS 776 00:35:40,720 --> 00:35:42,360 MORE HOPE IN HER LITTLE HEART 777 00:35:42,360 --> 00:35:43,800 THAN ANYONE I KNOW BUT I ALSO 778 00:35:43,800 --> 00:35:46,040 KNOW IT WILL START TO CHANGE. 779 00:35:46,040 --> 00:35:47,720 SHE'LL GET OLDER AND ASK 780 00:35:47,720 --> 00:35:48,480 QUESTIONS ABOUT HER CONDITIONS 781 00:35:48,480 --> 00:35:50,560 AS SHE'S STARTED TO. 782 00:35:50,560 --> 00:35:51,640 GOING FROM YESTERDAY'S QUESTION 783 00:35:51,640 --> 00:35:53,840 OF HEY, MOMMY, THAT PERSON IS 784 00:35:53,840 --> 00:35:55,480 STANDING ON THEIR OWN, CAN I DO 785 00:35:55,480 --> 00:35:58,760 THAT WHEN I'M A GROWN UP TO THE 786 00:35:58,760 --> 00:35:59,880 MORE LIKELY REALITY OF WHAT'S 787 00:35:59,880 --> 00:36:01,520 BEING DONE? 788 00:36:01,520 --> 00:36:02,920 HOW CAN I MANAGE THIS? 789 00:36:02,920 --> 00:36:04,920 HOW CAN I HAVE HOPE? 790 00:36:04,920 --> 00:36:06,840 IT'S MY HOPE WHEN SHE'S OLDER 791 00:36:06,840 --> 00:36:08,280 AND STARTS TO ASK THOSE 792 00:36:08,280 --> 00:36:10,240 QUESTIONS THERE ARE SOME 793 00:36:10,240 --> 00:36:10,640 ANSWERS. 794 00:36:10,640 --> 00:36:11,720 SHE'S WORTHY OF THE 795 00:36:11,720 --> 00:36:13,240 ACCOMMODATION AND ACCESS AND 796 00:36:13,240 --> 00:36:15,520 FRANKLY THE CONSIDERATION THAT 797 00:36:15,520 --> 00:36:17,240 WE ARE ALL AFFORDED EACH AND 798 00:36:17,240 --> 00:36:18,240 EVERY DAY. 799 00:36:18,240 --> 00:36:19,960 AND THAT ALL STARTS HERE AND HAS 800 00:36:19,960 --> 00:36:22,320 TO START NOW. 801 00:36:22,320 --> 00:36:23,880 THE VERY PEOPLE AT THIS 802 00:36:23,880 --> 00:36:27,120 SYMPOSIUM ARE THE PEOPLE I KNOW 803 00:36:27,120 --> 00:36:28,520 CAPABLE OF MAKING AN 804 00:36:28,520 --> 00:36:30,320 IMMEASURABLE IMPACT OF THE LIVES 805 00:36:30,320 --> 00:36:31,800 OF THOSE AFFLICTED WITH THIS 806 00:36:31,800 --> 00:36:32,040 DISEASE. 807 00:36:32,040 --> 00:36:34,040 I'M NOT A SCIENTIST, RESEARCHER 808 00:36:34,040 --> 00:36:36,800 OR DOCTOR BUT I AM A FORMER 809 00:36:36,800 --> 00:36:39,160 NON-PROFIT EXECUTIVE, A MOM, A 810 00:36:39,160 --> 00:36:40,320 CARETAKER AND ADVOCATE. 811 00:36:40,320 --> 00:36:42,120 AND I'M HONORED TO BE HERE WITH 812 00:36:42,120 --> 00:36:44,320 SUCH BRIGHT AND DEDICATED 813 00:36:44,320 --> 00:36:46,200 PROFESSIONALS AND SUCH DEVOTED 814 00:36:46,200 --> 00:36:47,360 AND PASSIONATE FAMILIES. 815 00:36:47,360 --> 00:36:49,960 LIKE I SAID, THOSE OF US 816 00:36:49,960 --> 00:36:51,480 NAVIGATING THIS EXPERIENCE KNOW 817 00:36:51,480 --> 00:36:54,000 ALL TOO WELL TIME FLIES. 818 00:36:54,000 --> 00:36:55,480 BUT THIS SYMPOSIUM IS GIVING US 819 00:36:55,480 --> 00:36:58,520 A CHANCE TO BE THE PILOT AND TO 820 00:36:58,520 --> 00:36:59,800 STEER US TOWARDS SOME 821 00:36:59,800 --> 00:37:01,480 INFORMATION, SOME ANSWERS AND 822 00:37:01,480 --> 00:37:02,040 SOME HOPE. 823 00:37:02,040 --> 00:37:03,600 THANK YOU ALL SO SO FOR YOUR 824 00:37:03,600 --> 00:37:04,600 TIME AND FOR YOUR DEDICATION AND 825 00:37:04,600 --> 00:37:07,720 A LOOK FORWARD TO WORKING WITH 826 00:37:07,720 --> 00:37:12,200 YOU. 827 00:37:12,200 --> 00:37:17,320 >> THANKS SO MUCH, KATIE. 828 00:37:17,320 --> 00:37:29,320 NEXT WE'LL WELCOME REBECCA 829 00:37:29,320 --> 00:37:30,680 SCHULE. 830 00:37:33,240 --> 00:37:35,720 >> CAN YOU HEAR ME? 831 00:37:35,720 --> 00:37:36,720 >> YES. 832 00:37:36,720 --> 00:37:39,720 >> WONDERFUL. 833 00:37:39,720 --> 00:37:48,720 I'LL SHARE MY SCREEN. 834 00:37:48,720 --> 00:37:49,520 >> GREAT. 835 00:37:49,520 --> 00:37:51,800 SO HI, THANK YOU SO MUCH FOR 836 00:37:51,800 --> 00:37:53,360 HAVING US HERE. 837 00:37:53,360 --> 00:37:59,360 I'M ANDREA McCONNELL AND ERIN 838 00:37:59,360 --> 00:38:01,400 DEAR AND I WILL TAKE TIME TO 839 00:38:01,400 --> 00:38:03,600 TALK ABOUT OUR FAMILIES AND 840 00:38:03,600 --> 00:38:06,240 CHILDREN AND MOVE ON TO TALK 841 00:38:06,240 --> 00:38:07,800 ABOUT OUR CURE SPG4 FOUNDATION 842 00:38:07,800 --> 00:38:11,360 YOU CAN SEE HERE. 843 00:38:11,360 --> 00:38:13,520 SO HOUR NOW 6-YEAR-OLD SON 844 00:38:13,520 --> 00:38:15,680 CONNOR WAS DIAGNOSED WITH SPG4 845 00:38:15,680 --> 00:38:18,280 WHEN HE WAS ABOUT 3 YEARS OLD. 846 00:38:18,280 --> 00:38:20,080 FOR THE FIRST YEAR OF CONNOR'S 847 00:38:20,080 --> 00:38:22,520 LIFE HE HIT ALL MILESTONES 848 00:38:22,520 --> 00:38:23,800 HOWEVER, LOOKING BACK THERE WERE 849 00:38:23,800 --> 00:38:27,520 SOME SUBTLE NUANCES, FOR 850 00:38:27,520 --> 00:38:29,000 EXAMPLE, HE ARMY CRAWLED FOR A 851 00:38:29,000 --> 00:38:31,440 LITTLE LONGER BEFORE MOVING ON 852 00:38:31,440 --> 00:38:33,120 TO BEAR CRAWLING. 853 00:38:33,120 --> 00:38:35,360 HIS BEAR CRAWLING WASN'T MAYBE 854 00:38:35,360 --> 00:38:39,760 AS FLUID AS WE NOW SEE WITH OUR 855 00:38:39,760 --> 00:38:42,120 YOUNGER CHILDREN. 856 00:38:42,120 --> 00:38:44,360 OR HE DIDN'T SIT UP MAYBE AS 857 00:38:44,360 --> 00:38:47,080 STRAIGHT BUT VERY VERY SUBTLE 858 00:38:47,080 --> 00:38:50,320 NUANCES AND REALLY NO RED FLAGS. 859 00:38:50,320 --> 00:38:52,320 IT WASN'T UNTIL ABOUT 14 OR SO 860 00:38:52,320 --> 00:38:54,080 MONTHS AROUND THE TIME HE WAS 861 00:38:54,080 --> 00:38:57,120 SUPPOSED TO BE WALKING THAT WE 862 00:38:57,120 --> 00:38:59,160 DID START TO DO PT AND HAD 863 00:38:59,160 --> 00:39:01,000 INITIAL CONCERNS WHEN WE WENT TO 864 00:39:01,000 --> 00:39:05,160 OUR PEDIATRICIAN IT WAS KIND OF 865 00:39:05,160 --> 00:39:06,360 BRUSHED OFF AS HE'S JUST A 866 00:39:06,360 --> 00:39:07,120 DELAYED WALKER. 867 00:39:07,120 --> 00:39:08,080 HE'LL CATCH UP. 868 00:39:08,080 --> 00:39:09,440 NO BIG RED FLAGS. 869 00:39:09,440 --> 00:39:13,480 THEN WHEN CONNOR WAS ABOUT 16, 870 00:39:13,480 --> 00:39:15,440 17 MONTHS HE WAS TAKING 871 00:39:15,440 --> 00:39:17,960 INDEPENDENT STEPS BUT STILL HAD 872 00:39:17,960 --> 00:39:22,520 AN AWKWARD GAIT AND WAS GIVEN A 873 00:39:22,520 --> 00:39:28,200 DIAGNOSIS OF CP, SPASTIC 874 00:39:28,200 --> 00:39:33,360 DYSPLASIA AND A DIAGNOSIS 875 00:39:33,360 --> 00:39:36,800 SIMILAR TO WHAT I'M HEARING FROM 876 00:39:36,800 --> 00:39:37,720 KATIE'S STORY. 877 00:39:37,720 --> 00:39:40,800 THIS NEVER REALLY FELT RIGHT TO 878 00:39:40,800 --> 00:39:41,320 US. 879 00:39:41,320 --> 00:39:43,560 VERY NORMAL PREGNANCY AND LABOR. 880 00:39:43,560 --> 00:39:45,160 WE DID CONTINUE TO PUSH FOR 881 00:39:45,160 --> 00:39:50,360 ADDITIONAL TESTING AND WE DID 882 00:39:50,360 --> 00:39:54,680 GET THE RESULTS WHICH CONFIRMED 883 00:39:54,680 --> 00:39:56,560 THE SPAST MUTATION IN THE FOUND 884 00:39:56,560 --> 00:39:58,920 IN MY HUSBAND OR MYSELF. 885 00:39:58,920 --> 00:40:01,720 WE'RE NOW GRATEFUL TO HAVE THE 886 00:40:01,720 --> 00:40:04,960 DIAGNOSIS TO PUT A PLAN IN PLACE 887 00:40:04,960 --> 00:40:05,760 TODAY TO SUPPORT CORNER IN THE 888 00:40:05,760 --> 00:40:09,120 BEST WAY WE CAN AND ALSO PUSH 889 00:40:09,120 --> 00:40:10,720 FOR ADVANCEMENTS FOR HIS FUTURE 890 00:40:10,720 --> 00:40:12,680 AND FOR RESEARCH. 891 00:40:12,680 --> 00:40:15,040 SO WE DO FEEL GRATEFUL TO HAVE 892 00:40:15,040 --> 00:40:18,360 FINALLY LANDED ON THE DIAGNOSIS. 893 00:40:18,360 --> 00:40:20,400 AND JUST A LITTLE BIT ABOUT 894 00:40:20,400 --> 00:40:23,000 CONNOR TODAY, HERE'S HIS CUTE 895 00:40:23,000 --> 00:40:23,840 LITTLE SMILE. 896 00:40:23,840 --> 00:40:27,720 HE WAS TAKE INDEPENDENT STEPS 897 00:40:27,720 --> 00:40:29,400 UNTIL ABOUT 4 YEARS OLD WHEN HE 898 00:40:29,400 --> 00:40:33,160 DID START TO USE A WALKER MORE 899 00:40:33,160 --> 00:40:33,640 CONSISTENTLY. 900 00:40:33,640 --> 00:40:36,280 HE TRULY IS THE HAPPIEST MOST 901 00:40:36,280 --> 00:40:38,640 CONFIDENT LITTLE BOY WITH THE 902 00:40:38,640 --> 00:40:39,320 BRIGHTEST SMILE. 903 00:40:39,320 --> 00:40:42,920 IF HE FALLS, HE GETS RIGHT BACK 904 00:40:42,920 --> 00:40:46,160 UP AND IT DOESN'T GET HIM DOWN. 905 00:40:46,160 --> 00:40:51,120 WE'RE TRULY BLESSED WITH HIS 906 00:40:51,120 --> 00:40:54,000 POSITIVE ATTITUDE AND OUR JOB AS 907 00:40:54,000 --> 00:40:54,920 PARENTS IS TO HOPEFULLY ENSURE 908 00:40:54,920 --> 00:40:58,680 THE POSITIVE ATTITUDE CONTINUES 909 00:40:58,680 --> 00:41:03,760 BECAUSE WE DO SEE IT DOES HELP. 910 00:41:03,760 --> 00:41:08,160 I'LL PASS IT ON TO ERIN TO TALK 911 00:41:08,160 --> 00:41:16,760 A LITTLE BIT ABOUT ALICE. 912 00:41:16,760 --> 00:41:19,520 >> HI, MY NAME IS ERIN DEAR. 913 00:41:19,520 --> 00:41:20,600 CAN YOU SEE ME? 914 00:41:20,600 --> 00:41:22,920 >> YES, THANKS. 915 00:41:22,920 --> 00:41:24,640 >> GREAT. 916 00:41:24,640 --> 00:41:29,520 I HAVE A 4-YEAR-OLD DAUGHTER 917 00:41:29,520 --> 00:41:31,120 DIAGNOSED WITH DE NOVO SPG4 WHEN 918 00:41:31,120 --> 00:41:32,760 SHE WAS 4 YEARS OLD. 919 00:41:32,760 --> 00:41:35,360 SHE'S ACTUALLY A TWIN AND WE 920 00:41:35,360 --> 00:41:37,320 WERE ABLE TO SEE HER GROSS MORT 921 00:41:37,320 --> 00:41:41,120 DELAYS ALONGSIDE HER TWIN 922 00:41:41,120 --> 00:41:43,680 BROTHER AND SHE -- WE STARTED 923 00:41:43,680 --> 00:41:44,880 SEEKING ANSWERS SHORTLY AFTER 924 00:41:44,880 --> 00:41:46,720 SHE BEGAN WALKING. 925 00:41:46,720 --> 00:41:49,160 WE NOTICED SHE WAS FALLING A LOT 926 00:41:49,160 --> 00:41:52,680 AND HAD AN AWKWARD GAIT. 927 00:41:52,680 --> 00:41:55,320 WE SPENT A LITTLE OVER A YEAR 928 00:41:55,320 --> 00:41:56,920 RULING OUT CP AND THE OTHER 929 00:41:56,920 --> 00:41:58,400 POSSIBLE THINGS IT COULD BE. 930 00:41:58,400 --> 00:42:02,040 WE HAD HEARD ABOUT HSP HALFWAY 931 00:42:02,040 --> 00:42:05,400 THROUGH OUR DIAGNOSIS JOURNEY 932 00:42:05,400 --> 00:42:08,760 AND EVERYTHING WE READ INDICATED 933 00:42:08,760 --> 00:42:10,320 A HEREDITARY DISEASE AND KNEW 934 00:42:10,320 --> 00:42:12,040 OUR FAMILY TREE PRETTY WELL AND 935 00:42:12,040 --> 00:42:13,480 DIDN'T THINK THAT WAS POSSIBLE 936 00:42:13,480 --> 00:42:15,800 FOR HER TO HAVE HSP. 937 00:42:15,800 --> 00:42:19,680 SO OF COURSE IT WAS A BIG SHOCK 938 00:42:19,680 --> 00:42:22,920 FOR US WHEN WE GOT THE DIAGNOSIS 939 00:42:22,920 --> 00:42:24,360 AND LEARNED ABOUT DE NOVO SPG4. 940 00:42:24,360 --> 00:42:29,320 LIKE ANYONE ELSE WHO RECEIVES 941 00:42:29,320 --> 00:42:31,840 THIS KIND OF DIAGNOSIS AND WE 942 00:42:31,840 --> 00:42:33,720 FELT HOPELESS AND WEREN'T SURE 943 00:42:33,720 --> 00:42:36,520 WHAT TO DO NEXT BUT KNEW WE 944 00:42:36,520 --> 00:42:37,720 COULDN'T SIT AND DO NOTHING. 945 00:42:37,720 --> 00:42:40,560 WE HAD TO DO SOMETHING AND 946 00:42:40,560 --> 00:42:43,440 STARTED REACHING OUT TO DOCTORS 947 00:42:43,440 --> 00:42:44,400 AND SCIENTISTS CONNECTED WITH 948 00:42:44,400 --> 00:42:48,480 SOME AMAZING FAMILIES WHO ALSO 949 00:42:48,480 --> 00:42:49,720 HAVE CHILDREN WITH SPG4. 950 00:42:49,720 --> 00:42:51,840 WE JUST NEEDED A WAY TO FEEL 951 00:42:51,840 --> 00:42:55,840 LIKE WE CAN MAKE A DIFFERENCE 952 00:42:55,840 --> 00:42:57,480 FOR SPG4 SPECIFICALLY EVEN IF IN 953 00:42:57,480 --> 00:42:58,640 THE SMALLEST OF WAYS. 954 00:42:58,640 --> 00:43:02,840 WE ALSO WANTED A WAY TO DIRECT 955 00:43:02,840 --> 00:43:03,840 OUR FAMILY AND FRIENDS WHO 956 00:43:03,840 --> 00:43:05,920 WANTED TO KNOW ABOUT THE DISEASE 957 00:43:05,920 --> 00:43:07,840 AND WANTED TO HELP IN SOME WAY 958 00:43:07,840 --> 00:43:13,160 AND ASKED HOW CAN WE HELP. 959 00:43:13,160 --> 00:43:15,760 WE WANTED A WAY THAT'S 960 00:43:15,760 --> 00:43:17,120 MEANINGFUL FOR THEM AND WHERE 961 00:43:17,120 --> 00:43:20,800 THE SPG4 FOUNDATION COMES TO 962 00:43:20,800 --> 00:43:21,160 PLAY. 963 00:43:21,160 --> 00:43:22,240 SO JUST LIKE ALL THE OTHER 964 00:43:22,240 --> 00:43:24,520 CHILDREN WITH SPG4 I THINK IT'S 965 00:43:24,520 --> 00:43:27,400 A COMMON THEME THEY ALL HAVE 966 00:43:27,400 --> 00:43:29,400 SUCH POSITIVE ATTITUDES AND WORK 967 00:43:29,400 --> 00:43:31,840 SO HARD AND TEACH US SOMETHING 968 00:43:31,840 --> 00:43:34,400 DAILY ABOUT PERSEVERANCE. 969 00:43:34,400 --> 00:43:39,680 SO I'M GOING TO LET ANDREA TALK 970 00:43:39,680 --> 00:43:40,200 ABOUT OUR FOUNDATION AND 971 00:43:40,200 --> 00:43:40,440 MISSION. 972 00:43:40,440 --> 00:43:41,360 >> THANK YOU. 973 00:43:41,360 --> 00:43:45,720 SO OUR FOUNDATION IS CURE SPG4 974 00:43:45,720 --> 00:43:47,840 FOUNDATION AND MORE ABOUT HOW IT 975 00:43:47,840 --> 00:43:49,840 CAME ABOUT AND WHAT WE FOCUS ON. 976 00:43:49,840 --> 00:43:53,440 SO WE CONNECTED WITH THE DEAR 977 00:43:53,440 --> 00:43:58,360 FAMILY SHORTLY AFTER ALICE'S 978 00:43:58,360 --> 00:44:00,600 DIAGNOSIS AND NOT TOO LONG AFTER 979 00:44:00,600 --> 00:44:01,560 CONNOR'S DIAGNOSIS AND IT WAS 980 00:44:01,560 --> 00:44:04,400 HELPFUL TO CONNECT WITH A FAMILY 981 00:44:04,400 --> 00:44:09,120 WITH SIMILAR EXPERIENCES AND 982 00:44:09,120 --> 00:44:13,200 PARALLEL STORIES IN DIAGNOSIS 983 00:44:13,200 --> 00:44:15,280 JOURNEY AND FELT COMPELLED TO 984 00:44:15,280 --> 00:44:17,800 TAKE ACTION AND BOTH FELT 985 00:44:17,800 --> 00:44:20,120 HOPELESS AND HELPLESS LEAVING 986 00:44:20,120 --> 00:44:21,320 THE NEUROLOGIST APPOINTMENT 987 00:44:21,320 --> 00:44:23,240 WHERE ALL WE CAN DO WAS TO 988 00:44:23,240 --> 00:44:25,920 CONTINUE PT AND THAT WAS IT. 989 00:44:25,920 --> 00:44:28,920 SO WE BANDED TOGETHER AND FORMED 990 00:44:28,920 --> 00:44:30,320 THE CURE SPG4 FOUNDATION WHERE 991 00:44:30,320 --> 00:44:35,400 WE WANTED TO HAVE DIRECT IMPACT 992 00:44:35,400 --> 00:44:36,480 ON FUND RAISING AND INITIATING 993 00:44:36,480 --> 00:44:38,920 RESEARCH TO HELP FIND A CURE OR 994 00:44:38,920 --> 00:44:39,160 TREATMENT. 995 00:44:39,160 --> 00:44:47,120 AND SO WHILE WE DO FOCUS ON SPG4 996 00:44:47,120 --> 00:44:51,880 HOLISTICALLY WHETHER DE NOVO OR 997 00:44:51,880 --> 00:44:54,200 HEREDITARY WE HAVE KIDS WITH 998 00:44:54,200 --> 00:44:55,840 SPG4 AND WE DO WANT TO ENSURE 999 00:44:55,840 --> 00:44:58,600 THIS IS AN AREA THAT IS GETTING 1000 00:44:58,600 --> 00:45:01,160 ATTENTION AS WE HAVE FOUND THAT 1001 00:45:01,160 --> 00:45:03,040 DE NOVO AND INFANT ONSET CASES 1002 00:45:03,040 --> 00:45:05,400 ARE NOT AS COMMONLY TALKED ABOUT 1003 00:45:05,400 --> 00:45:06,720 OR REALLY EVEN FOCUSSED ON. 1004 00:45:06,720 --> 00:45:11,840 SO WE'RE SO GRATEFUL AND HAPPY 1005 00:45:11,840 --> 00:45:14,080 THIS SYMPOSIUM IS HAPPENING 1006 00:45:14,080 --> 00:45:15,840 TODAY. 1007 00:45:15,840 --> 00:45:24,800 SO AS A PARENT-LED ORGANIZATION, 1008 00:45:24,800 --> 00:45:29,400 100% OF OUR DONATIONS ARE 1009 00:45:29,400 --> 00:45:31,120 FOCUSSED ON RESEARCH. 1010 00:45:31,120 --> 00:45:33,400 SO WE CAN BE FLEXIBLE AND NIMBLE 1011 00:45:33,400 --> 00:45:35,400 AND FOCUS ON THE RESEARCH THAT 1012 00:45:35,400 --> 00:45:37,520 WE FEEL HAS THE MOST LEGS AND IS 1013 00:45:37,520 --> 00:45:39,840 MOST DIRECTLY CONNECTED TO 1014 00:45:39,840 --> 00:45:45,720 FINDING A CURE OR A TREATMENT. 1015 00:45:45,720 --> 00:45:50,960 SO OUR MISSION IS TO INCREASE 1016 00:45:50,960 --> 00:45:53,440 AWARENESS OF SPG4 HEREDITARY 1017 00:45:53,440 --> 00:45:55,320 SPASTIC PARAPLEGIA AND FUND 1018 00:45:55,320 --> 00:46:01,400 RESEARCH TO HELP FIND A CURE FOR 1019 00:46:01,400 --> 00:46:03,840 SPECIFICALLY SPG4 HEREDITARY 1020 00:46:03,840 --> 00:46:05,440 SPASTIC PARAPLEGIA. 1021 00:46:05,440 --> 00:46:10,720 WE'RE FOCUSSED ON TWO BROADER 1022 00:46:10,720 --> 00:46:12,520 RESEARCH PROJECTS AND THE FIRST 1023 00:46:12,520 --> 00:46:15,840 IS GENE THERAPY WE'RE HONORED TO 1024 00:46:15,840 --> 00:46:20,520 HAVE DR. MIGUEL ESTEVEZ ON THE 1025 00:46:20,520 --> 00:46:23,400 LINE WITH DR. BASS AND TEAM AT 1026 00:46:23,400 --> 00:46:23,720 DREXEL. 1027 00:46:23,720 --> 00:46:26,640 AND SO THIS IS GENE THERAPY 1028 00:46:26,640 --> 00:46:27,880 WHICH THEY'LL BE ABLE TO TALK 1029 00:46:27,880 --> 00:46:29,440 MORE ABOUT IN TERMS OF THE 1030 00:46:29,440 --> 00:46:34,240 CURRENT STATUS BUT WE DID FEEL 1031 00:46:34,240 --> 00:46:37,560 ONE OF OUR PRIORITIES WAS TO 1032 00:46:37,560 --> 00:46:39,800 ENSURE WE COMMUNICATED UPDATES 1033 00:46:39,800 --> 00:46:44,520 TO PATIENTS AFFECTED WITH SPG4 1034 00:46:44,520 --> 00:46:46,000 AND ALSO OUR DONATORS TO GIVE 1035 00:46:46,000 --> 00:46:47,840 THEM A BETTER UNDERSTANDING OF 1036 00:46:47,840 --> 00:46:49,160 EXACTLY HERE IS WHERE YOUR 1037 00:46:49,160 --> 00:46:51,160 DONATIONS AND DOLLARS ARE GOING. 1038 00:46:51,160 --> 00:46:54,320 SO WE DO TRY TO BE VERY 1039 00:46:54,320 --> 00:46:56,720 TRANSPARENT WITH UPDATES ON THE 1040 00:46:56,720 --> 00:46:57,320 PROJECT STATUS. 1041 00:46:57,320 --> 00:46:59,360 THAT'S ONE THING WE FOUND EVEN 1042 00:46:59,360 --> 00:47:01,320 DONATING TO OTHER FOUNDATIONS. 1043 00:47:01,320 --> 00:47:03,320 WE DO APPRECIATE WHEN WE KNOW 1044 00:47:03,320 --> 00:47:03,920 EXACTLY WHERE OUR DOLLARS ARE 1045 00:47:03,920 --> 00:47:06,320 GOING. 1046 00:47:06,320 --> 00:47:11,120 SO THE FIRST IS GENE THERAPY AND 1047 00:47:11,120 --> 00:47:15,760 THE SECOND IS NU9 FOR SPG4 1048 00:47:15,760 --> 00:47:20,840 SPECIFICALLY PARTNERING A DOCTOR 1049 00:47:20,840 --> 00:47:23,360 FROM NORTHWESTERN AND PIGGY 1050 00:47:23,360 --> 00:47:26,440 BACKING ON HER SUCCESS ON NU-9 1051 00:47:26,440 --> 00:47:30,680 FOR ALS AND LOOK AT THE DRUG 1052 00:47:30,680 --> 00:47:31,880 COMPOUND FOR SPG4 SPECIFICALLY 1053 00:47:31,880 --> 00:47:33,880 AND INCLUDING THE PROJECT 1054 00:47:33,880 --> 00:47:42,520 UPDATES AND STATUS AS OF MAR%H. 1055 00:47:42,520 --> 00:47:46,120 I THINK IN CONCLUSION WE ARE 1056 00:47:46,120 --> 00:47:47,880 HERE SPG4 HERE TO SUPPORT ALL 1057 00:47:47,880 --> 00:47:51,520 PATIENTS AND FAMILIES AFFECTED 1058 00:47:51,520 --> 00:47:53,160 WITH SPG4 AND ALSO TO SUPPORT 1059 00:47:53,160 --> 00:47:54,080 ALL RESEARCHERS. 1060 00:47:54,080 --> 00:47:56,240 I THINK OUR ROLE IS TO HELP 1061 00:47:56,240 --> 00:47:58,800 CONNECT THE DOTS THE BEST WE 1062 00:47:58,800 --> 00:47:59,080 CAN. 1063 00:47:59,080 --> 00:48:04,040 WE'RE NOT THE EXPERTS BUT WE CAN 1064 00:48:04,040 --> 00:48:05,360 ENSURE THINGS LIKE NATURAL 1065 00:48:05,360 --> 00:48:07,760 HISTORY STUDIES ARE ONGOING AND 1066 00:48:07,760 --> 00:48:09,640 IN PROGRESS BECAUSE WE KNOW 1067 00:48:09,640 --> 00:48:11,760 THAT'S AN IMPORTANT PART TO 1068 00:48:11,760 --> 00:48:13,480 FINDING A CURE OR HAVE THE 1069 00:48:13,480 --> 00:48:15,800 FOUNDATION IN PLACE TO BE ABLE 1070 00:48:15,800 --> 00:48:18,960 TO FIND A CURE OR FOR EXAMPLE WE 1071 00:48:18,960 --> 00:48:22,000 WERE ABLE TO HELP CONNECT 1072 00:48:22,000 --> 00:48:24,160 DR. ESTEVEZ OUT OF U-MASS WITH 1073 00:48:24,160 --> 00:48:29,160 THE DREXEL TEAM WITH SPG4 MOUSE 1074 00:48:29,160 --> 00:48:29,360 MODEL. 1075 00:48:29,360 --> 00:48:30,080 WE'RE A LITTLE BIT MORE BEHIND 1076 00:48:30,080 --> 00:48:35,320 THE SCENES IN DOING WHAT WE CAN 1077 00:48:35,320 --> 00:48:37,200 TO HELP MOVE RESEARCH AND 1078 00:48:37,200 --> 00:48:38,320 PROGRESS FORWARD AND THE 1079 00:48:38,320 --> 00:48:38,960 RESEARCHERS AND EXPERTS ON THE 1080 00:48:38,960 --> 00:48:40,840 LINE WE'RE HERE TO HELP AND 1081 00:48:40,840 --> 00:48:42,520 SUPPORT YOU IN ANY WAY WE CAN 1082 00:48:42,520 --> 00:48:47,400 AND ARE SO GRATEFUL FOR YOUR 1083 00:48:47,400 --> 00:48:55,200 DEDICATION ON SPG4. 1084 00:48:55,200 --> 00:48:59,400 >> THANK YOU SO MUCH, ANDREA AND 1085 00:48:59,400 --> 00:49:02,120 ERIN FOR YOUR PERSPECTIVES AND 1086 00:49:02,120 --> 00:49:02,520 THAT INFORMATION. 1087 00:49:02,520 --> 00:49:07,800 AND NEXT WE'LL MOVE ON TO 1088 00:49:07,800 --> 00:49:11,000 RE-DRR 1089 00:49:11,000 --> 00:49:11,640 RE-DRR 1090 00:49:11,640 --> 00:49:12,280 RE-DRR 1091 00:49:12,280 --> 00:49:15,800 RE-DRRE -- 1092 00:49:15,800 --> 00:49:17,200 DR. REBECCA SCHULE. 1093 00:49:17,200 --> 00:49:18,520 >> I'M HONORED TO BE PART OF 1094 00:49:18,520 --> 00:49:23,040 THIS AND I STRONGLY BELIEVE IF 1095 00:49:23,040 --> 00:49:27,000 WE ALL BAND TOGETHER AND 1096 00:49:27,000 --> 00:49:36,520 COLLABORATE TRANS-ATLANTICALLY 1097 00:49:36,520 --> 00:49:38,920 WE CAN MAKE PROGRESS. 1098 00:49:38,920 --> 00:49:41,640 I'M AN ADULT NEUROLOGIST SO I 1099 00:49:41,640 --> 00:49:43,760 SEE MAINLY ADULT PATIENTS. 1100 00:49:43,760 --> 00:49:45,480 I THINK WE ALL IN THIS 1101 00:49:45,480 --> 00:49:46,920 ENVIRONMENT ROOM ARE UNITED BY 1102 00:49:46,920 --> 00:49:49,000 THE GOAL THIS WE WANT TO 1103 00:49:49,000 --> 00:49:51,840 IMPLEMENT ACCESSIBLE AND 1104 00:49:51,840 --> 00:49:53,320 EFFECTIVE THERAPIES FOR SPG4. 1105 00:49:53,320 --> 00:49:56,280 WHAT WE HAVE ALSO LEARNED AND 1106 00:49:56,280 --> 00:50:01,520 KNOW THE WAY TO THERAPIES LEADS 1107 00:50:01,520 --> 00:50:02,920 BY CLINICAL TRIALS. 1108 00:50:02,920 --> 00:50:05,440 SO BEFORE I TALK ABOUT OUR SPG4 1109 00:50:05,440 --> 00:50:08,400 COHORT, I'D LIKE TO GIVE YOU A 1110 00:50:08,400 --> 00:50:11,440 LITTLE BACKGROUND ABOUT THE 1111 00:50:11,440 --> 00:50:11,640 AFRICA 1112 00:50:14,200 --> 00:50:17,440 INFRASTRUCTURE WE SET UP FOR HOW 1113 00:50:17,440 --> 00:50:20,320 WE COORDINATE OUR SPG4 CLINICAL 1114 00:50:20,320 --> 00:50:20,560 RESEARCH. 1115 00:50:20,560 --> 00:50:24,080 SO WE ESSENTIALLY NEED TO FIGURE 1116 00:50:24,080 --> 00:50:26,120 OUT TWO LARGE AND COMPLEX 1117 00:50:26,120 --> 00:50:27,000 PROBLEMS TO BE READY FOR A 1118 00:50:27,000 --> 00:50:28,920 CLINICAL TRIAL. 1119 00:50:28,920 --> 00:50:30,320 WE NEED TO FIGURE OUT CLINICAL 1120 00:50:30,320 --> 00:50:33,200 DEVELOPMENT AND THAT MEANS WE 1121 00:50:33,200 --> 00:50:35,000 NEED GOOD CLINICAL TRIAL OUTCOME 1122 00:50:35,000 --> 00:50:37,800 PARAMETERS THAT CAN MEASURE 1123 00:50:37,800 --> 00:50:38,840 THERAPY RESPONSE FOR QUESTIONS 1124 00:50:38,840 --> 00:50:40,480 AND OTHER THINGS AND THIS IS A 1125 00:50:40,480 --> 00:50:41,320 COMPLEX ISSUE. 1126 00:50:41,320 --> 00:50:45,160 ON THE OTHER HAND WE NEED GOOD 1127 00:50:45,160 --> 00:50:47,320 THERAPEUTIC TARGETS AND NEED TO 1128 00:50:47,320 --> 00:50:48,920 DEVELOP THE THERAPIES 1129 00:50:48,920 --> 00:50:51,240 PRE-CLINICALLY AND THIS IS ALSO 1130 00:50:51,240 --> 00:50:53,200 A PROCESS THAT INVOLVES MANY 1131 00:50:53,200 --> 00:50:55,720 STEPS AND VERY COMPLEX. 1132 00:50:55,720 --> 00:50:56,920 ONLY IF THE TRUE LINES OF WORK 1133 00:50:56,920 --> 00:50:59,480 ARE AT THE SAME TIME WE CAN 1134 00:50:59,480 --> 00:51:01,320 PROCEED TO CLINICAL TRIAL. 1135 00:51:01,320 --> 00:51:05,200 WHAT WE TRIED TO DO IN THE TREAT 1136 00:51:05,200 --> 00:51:05,920 HSP NETWORK WHICH I COORDINATE 1137 00:51:05,920 --> 00:51:09,720 AND IT'S A NETWORK OF CLINICIANS 1138 00:51:09,720 --> 00:51:11,840 AND RESEARCHERS AND TRY TO 1139 00:51:11,840 --> 00:51:13,520 COORDINATE OUR RESEARCH IN A 1140 00:51:13,520 --> 00:51:14,920 GOAL-ORIENTED WAY. 1141 00:51:14,920 --> 00:51:18,760 WE TRIED TO AVOID DUPLICATION OF 1142 00:51:18,760 --> 00:51:20,360 EFFORTS AND BE AS EFFICIENT AS 1143 00:51:20,360 --> 00:51:22,200 POSSIBLE ALWAYS WITH THE 1144 00:51:22,200 --> 00:51:23,240 TRANSLATIONAL TREATMENT GOAL IN 1145 00:51:23,240 --> 00:51:23,440 MIND. 1146 00:51:23,440 --> 00:51:26,120 AND WE TRY TO ALLOCATE OUR 1147 00:51:26,120 --> 00:51:28,560 RESOURCES WHERE NEED AND THE 1148 00:51:28,560 --> 00:51:30,120 RESOURCES WE TRIED TO COLLECT 1149 00:51:30,120 --> 00:51:33,920 ARE REALLY A CLINICAL AND 1150 00:51:33,920 --> 00:51:38,920 RESEARCH NETWORK ON THE ONE 1151 00:51:38,920 --> 00:51:39,720 HAND. 1152 00:51:39,720 --> 00:51:46,920 AND TO DISCUSS IDEAS AND THEN AN 1153 00:51:46,920 --> 00:51:49,320 INFRASTRUCTURE WHICH WE SHARE 1154 00:51:49,320 --> 00:51:52,480 WITH A CLINICAL DATABASE AND BIO 1155 00:51:52,480 --> 00:51:55,840 BANK AND COLLECT BIO SAMPLES 1156 00:51:55,840 --> 00:51:57,920 FROM PATIENTS INCLUDING SPG4 AND 1157 00:51:57,920 --> 00:52:04,160 A DEPOSITORY TO LINK DATA AND 1158 00:52:04,160 --> 00:52:07,800 DATA SETS THAT CAN BE USED FOR 1159 00:52:07,800 --> 00:52:08,840 MULTIPLE PROJECTS AND SHOULD BE 1160 00:52:08,840 --> 00:52:13,440 AS ACCESSIBLE AS MANY PEOPLE AS 1161 00:52:13,440 --> 00:52:13,760 POSSIBLE. 1162 00:52:13,760 --> 00:52:15,320 YOU CAN SEE THERE'S A STRONG 1163 00:52:15,320 --> 00:52:17,440 FOCUS IN EUROPE CURRENTLY AND I 1164 00:52:17,440 --> 00:52:19,520 HOPE WE ARE GOING TO GROW ALSO 1165 00:52:19,520 --> 00:52:22,200 ON THE OTHER SIDE OF THE 1166 00:52:22,200 --> 00:52:23,840 ATLANTIC AND JUST IN THE PAST 1167 00:52:23,840 --> 00:52:29,440 FEW DAYS I HAVE TALKED TO 1168 00:52:29,440 --> 00:52:31,800 SEVERAL PEOPLE IN THE 1169 00:52:31,800 --> 00:52:35,120 U.S. INCLUDING OTHERS THAT ARE 1170 00:52:35,120 --> 00:52:37,240 SPEAKERS TODAY THAT HAVE AGREED 1171 00:52:37,240 --> 00:52:39,760 TO JOIN OUR EFFORT SO THIS IS 1172 00:52:39,760 --> 00:52:41,920 REALLY A GROWING NETWORK OF 1173 00:52:41,920 --> 00:52:46,400 DEDICATED PEOPLE TRYING TO FIND 1174 00:52:46,400 --> 00:52:48,840 TREATMENT OPTIONS SPASTIC 1175 00:52:48,840 --> 00:52:49,120 PARAPLEGIA. 1176 00:52:49,120 --> 00:52:52,920 WE'RE TRYING TO HARMONIZE OUR 1177 00:52:52,920 --> 00:52:55,840 CLINICAL APPROACH AND HARMONIZE 1178 00:52:55,840 --> 00:52:57,560 DATA COLLECTION. 1179 00:52:57,560 --> 00:52:58,600 COLLECT PHENOTYPIC INFORMATION 1180 00:52:58,600 --> 00:53:00,720 IN A STANDARDIZED WAY AND 1181 00:53:00,720 --> 00:53:05,280 COLLABORATE ON PROJECT AND HAVE 1182 00:53:05,280 --> 00:53:06,800 A BROADER AGGRESSIVE SHARING 1183 00:53:06,800 --> 00:53:07,920 POLICY FOR DATA SAMPLES AND 1184 00:53:07,920 --> 00:53:18,680 RESOURCES. 1185 00:53:18,680 --> 00:53:20,800 AND THERE'S A WEB-BASED DATABASE 1186 00:53:20,800 --> 00:53:23,000 SO EVERY MEMBER OF THE NETWORK 1187 00:53:23,000 --> 00:53:25,400 CAN LOG ON AND DIRECTLY ENTER 1188 00:53:25,400 --> 00:53:31,800 DATA FOR THEIR PATIENTS. 1189 00:53:31,800 --> 00:53:35,440 PATIENTS ARE USING A GLOBAL 1190 00:53:35,440 --> 00:53:37,920 UNIQUE IDENTIFIER MAKING IT 1191 00:53:37,920 --> 00:53:41,440 IDENTIFIABLE AND WE CAN DIRECTLY 1192 00:53:41,440 --> 00:53:43,200 ALSO USE THAT FOR CLINICAL 1193 00:53:43,200 --> 00:53:43,400 TRIAL. 1194 00:53:43,400 --> 00:53:48,120 AND WHAT YOU IMPLEMENTED IS 1195 00:53:48,120 --> 00:53:50,680 EVERY USER CAN DOWNLOAD THE DATA 1196 00:53:50,680 --> 00:53:52,960 AND IF YOU WANT IT USE OTHER 1197 00:53:52,960 --> 00:53:54,560 PEOPLE'S DATA YOU HAVE TO ASK 1198 00:53:54,560 --> 00:53:56,560 AND THERE'S A COMMITTEE THAT 1199 00:53:56,560 --> 00:53:57,520 DECIDES ON THAT REQUEST. 1200 00:53:57,520 --> 00:53:59,480 THAT WAY YOU ALWAYS SEE WHAT 1201 00:53:59,480 --> 00:54:01,960 DATA IS THERE BECAUSE THAT 1202 00:54:01,960 --> 00:54:03,840 REALLY SIMULATES RESEARCH 1203 00:54:03,840 --> 00:54:07,280 BECAUSE YOU SEE OPPORTUNITIES. 1204 00:54:07,280 --> 00:54:10,960 THIS DATABASE IS CONNECTED TO A 1205 00:54:10,960 --> 00:54:14,120 BIO BANK THAT IS RATHER UNIQUE 1206 00:54:14,120 --> 00:54:16,320 BECAUSE IT IS DIRECTLY CONNECTED 1207 00:54:16,320 --> 00:54:17,720 TO THE CLINICAL DATA. 1208 00:54:17,720 --> 00:54:20,920 FOR EACH SAMPLE YOU HAVE A TIME 1209 00:54:20,920 --> 00:54:21,680 POINT IN WHICH CLINICAL 1210 00:54:21,680 --> 00:54:26,520 INFORMATION AND ALSO WE HAVE A 1211 00:54:26,520 --> 00:54:28,640 LARGE VARIETY OF SAMPLES AND 1212 00:54:28,640 --> 00:54:32,920 SAMPLE PATIENTS LONGITUDINALLY 1213 00:54:32,920 --> 00:54:38,520 AND HAVE PLASMA SAMPLES IN 1214 00:54:38,520 --> 00:54:38,880 INTERVALS. 1215 00:54:38,880 --> 00:54:39,800 WITHIN THE INFRASTRUCTURE WE 1216 00:54:39,800 --> 00:54:43,320 HAVE ALSO RECRUITED A QUITE A 1217 00:54:43,320 --> 00:54:45,520 SIZABLE SPG4 COHORT ALMOST 500 1218 00:54:45,520 --> 00:54:51,400 PATIENTS FROM 340 FAMILIES ABOUT 1219 00:54:51,400 --> 00:54:52,200 EQUAL PROPORTIONS OF FEMALES AND 1220 00:54:52,200 --> 00:54:54,160 MALES AND RECRUITED OVER 20 1221 00:54:54,160 --> 00:54:55,760 YEARS NOW. 1222 00:54:55,760 --> 00:54:59,520 JUST TO GIVE YOU AN IDEA ABOUT 1223 00:54:59,520 --> 00:55:01,840 THE PATIENTS I'LL BE TALKING 1224 00:55:01,840 --> 00:55:05,040 ABOUT IS THAT YOU SEE HERE THE 1225 00:55:05,040 --> 00:55:05,560 AGE DISTRIBUTION. 1226 00:55:05,560 --> 00:55:07,840 THERE'S A TIME POINT WHEN THEY 1227 00:55:07,840 --> 00:55:09,720 FIRST COME TO ONE OF THE CLINICS 1228 00:55:09,720 --> 00:55:13,320 AND YOU CAN SEE THEY HAVE A 1229 00:55:13,320 --> 00:55:14,920 MEDIUM AGE OF 50. 1230 00:55:14,920 --> 00:55:19,840 I THINK THIS SHIFT TOWARDS MORE 1231 00:55:19,840 --> 00:55:22,040 ADULT SPECTRUM IS HARDLY 1232 00:55:22,040 --> 00:55:25,200 REFLECTING THE BIOLOGY OF THE 1233 00:55:25,200 --> 00:55:27,800 DISEASE BECAUSE OFTEN SPG4 IS AN 1234 00:55:27,800 --> 00:55:31,200 ADULT ONSET DISEASE BUT IT MAY 1235 00:55:31,200 --> 00:55:34,320 ALSO PARTLY BE A RECRUITMENT 1236 00:55:34,320 --> 00:55:36,320 BIAS BECAUSE FOR A LONG PERIOD 1237 00:55:36,320 --> 00:55:39,080 THE RESEARCH NETWORKS IN SPG4 1238 00:55:39,080 --> 00:55:41,480 HAVE VERY MUCH BEEN DOMINATED BY 1239 00:55:41,480 --> 00:55:43,800 ADULT NEUROLOGY CLINICS AND ONLY 1240 00:55:43,800 --> 00:55:45,840 IN THE RECENT TWO OR THREE YEARS 1241 00:55:45,840 --> 00:55:49,120 HAVE THEY REALLY ACTIVELY 1242 00:55:49,120 --> 00:55:50,720 CONTACTED PEDIATRIC NEUROLOGISTS 1243 00:55:50,720 --> 00:55:54,560 TO OVERCOME THIS BIAS AND 1244 00:55:54,560 --> 00:55:57,120 COLLABORATE TOGETHER ACROSS THE 1245 00:55:57,120 --> 00:55:58,080 SPECTRUM. 1246 00:55:58,080 --> 00:55:59,880 IT USUALLY TAKES MORE THAN 10 1247 00:55:59,880 --> 00:56:02,640 YEARS FOR PATIENTS FROM THEIR 1248 00:56:02,640 --> 00:56:03,840 FIRST SYMPTOMS BEFORE THEY REACH 1249 00:56:03,840 --> 00:56:07,560 A SPECIALIZED OUT-PATIENT CLINIC 1250 00:56:07,560 --> 00:56:11,840 REFLECTING THE SLOW ONSET AND 1251 00:56:11,840 --> 00:56:15,840 ALSO THE DELAY IN RECEIVING A 1252 00:56:15,840 --> 00:56:17,520 DIAGNOSIS FOR THE SLOW PROGRESS 1253 00:56:17,520 --> 00:56:19,840 ADULT ONSET OF SPG4. 1254 00:56:19,840 --> 00:56:28,680 SO IF WE LOOK AT THIS WE SEE A 1255 00:56:28,680 --> 00:56:31,360 CURIOUS BIMODAL DISTRIBUTION A 1256 00:56:31,360 --> 00:56:34,000 PEAK IN THE EARLY YEARS OF LIFE 1257 00:56:34,000 --> 00:56:35,720 AND BROAD DISTRIBUTION ACROSS 1258 00:56:35,720 --> 00:56:37,440 THE LIFE SPAN WITH THE MEDIAN OF 1259 00:56:37,440 --> 00:56:37,840 38 YEARS. 1260 00:56:37,840 --> 00:56:40,600 FOR THE PURPOSE OF THE TALK I 1261 00:56:40,600 --> 00:56:43,800 TRIED TO SEPARATE THE TWO GROUPS 1262 00:56:43,800 --> 00:56:48,280 BECAUSE I HYPOTHESIZE THESE 1263 00:56:48,280 --> 00:56:50,360 REALLY ALMOST REFLECT TWO 1264 00:56:50,360 --> 00:56:54,760 DIFFERENT FLAVORS OF SPG4 IN AN 1265 00:56:54,760 --> 00:57:05,440 INFANTILE FORM AND DEGENERATIVE 1266 00:57:05,440 --> 00:57:13,000 ONSET WHERE THEY HAVE MOTOR 1267 00:57:13,000 --> 00:57:15,760 SKILLS THAT ARE NORMAL AND OVER 1268 00:57:15,760 --> 00:57:16,840 TIME SYMPTOMS APPEAR. 1269 00:57:16,840 --> 00:57:19,520 FOR WHAT THE REASONS MAY BE FOR 1270 00:57:19,520 --> 00:57:21,600 THE BIMODAL ONSET LET ME TELL 1271 00:57:21,600 --> 00:57:23,120 YOU MORE ABOUT THE GENETIC 1272 00:57:23,120 --> 00:57:24,920 MAKEUP OF OUR COHORT. 1273 00:57:24,920 --> 00:57:26,720 IF WE LOOK AT THE MUTATION TYPES 1274 00:57:26,720 --> 00:57:30,880 REPRESENTED IN OUR SPG4 COHORT, 1275 00:57:30,880 --> 00:57:33,960 YOU CAN SEE THAT SHY OF 20% OF 1276 00:57:33,960 --> 00:57:35,720 CASES ARE CAUSED BY MUTATIONS. 1277 00:57:35,720 --> 00:57:41,040 THEN WE HAVE ABOUT 20% EACH IN 1278 00:57:41,040 --> 00:57:45,880 GENOMIC DELETIONS AND THAT MEANS 1279 00:57:45,880 --> 00:57:50,120 THAT ABOUT 80% OF ALL MUTATIONS 1280 00:57:50,120 --> 00:57:53,480 WE OBSERVE IN SPG4 ALSO CALLED 1281 00:57:53,480 --> 00:57:56,320 TRUNCATING MUTATIONS AND ONLY 1282 00:57:56,320 --> 00:57:57,920 20% ARE THESE MUTATIONS. 1283 00:57:57,920 --> 00:57:58,840 IF WE LOOK AT THE DISTRIBUTION 1284 00:57:58,840 --> 00:58:05,440 OF THOSE MUTATIONS ACROSS THE 1285 00:58:05,440 --> 00:58:08,560 PROTEIN, HERE YOU SEE A 1286 00:58:08,560 --> 00:58:10,560 SCHEMATIC OF THE GENE WITH ALL 1287 00:58:10,560 --> 00:58:15,760 THE IMPORTANT BINDING DOMAINS 1288 00:58:15,760 --> 00:58:17,920 AND THE FUNCTIONAL DATA AND ON 1289 00:58:17,920 --> 00:58:21,520 TOP OF THE SCHEMATIC HERE, ALL 1290 00:58:21,520 --> 00:58:24,240 THE MISSING VARIANTS. 1291 00:58:24,240 --> 00:58:26,280 SO EACH LINE REPRESENTS A 1292 00:58:26,280 --> 00:58:27,720 VARIANT AND IF THE LINE GETS 1293 00:58:27,720 --> 00:58:30,360 THICKER IT MEANS THERE'S MORE 1294 00:58:30,360 --> 00:58:31,720 THAN ONE MUTATION AND CAUSES THE 1295 00:58:31,720 --> 00:58:33,960 LINES TO OVERLAP. 1296 00:58:33,960 --> 00:58:35,760 YOU CAN SEE REALLY ALMOST 1297 00:58:35,760 --> 00:58:38,920 EXCLUSIVELY THE MUTATIONS ARE 1298 00:58:38,920 --> 00:58:41,400 LOCATED IN THIS DOMAIN AND THE 1299 00:58:41,400 --> 00:58:43,760 TRUNCATED MUTATIONS BELOW THIS 1300 00:58:43,760 --> 00:58:45,400 ARE REALLY SPREAD ALL OVER THE 1301 00:58:45,400 --> 00:58:48,520 PROTEIN AND THE SAME IS TRUE 1302 00:58:48,520 --> 00:58:49,720 ALSO FOR THE EXOME DELETIONS 1303 00:58:49,720 --> 00:58:51,800 WITH LARGE PORTIONS OF THE 1304 00:58:51,800 --> 00:58:54,800 GENOME ARE MISSING AND HERE 1305 00:58:54,800 --> 00:58:55,800 REPRESENTED BY THE LONG 1306 00:58:55,800 --> 00:58:59,480 HORIZONTAL LINES AND AS THEY 1307 00:58:59,480 --> 00:59:02,200 ALSO SPAN THE WHOLE PROTEIN. 1308 00:59:02,200 --> 00:59:05,280 SO WHAT ARE POTENTIAL REASONS 1309 00:59:05,280 --> 00:59:11,560 FOR THIS BIMODAL ONSET OF SPG4? 1310 00:59:11,560 --> 00:59:15,000 I'LL GIVE YOU TWO VISUALIZATIONS 1311 00:59:15,000 --> 00:59:16,320 OF BASICALLY THE SAME FACT. 1312 00:59:16,320 --> 00:59:20,320 IF YOU LOOK AT THE TRUNCATIONS 1313 00:59:20,320 --> 00:59:27,760 DIVIDED OR GROUPED BY INFANTILE 1314 00:59:27,760 --> 00:59:31,760 VERSUS DEGENERATIVE AND THEY'RE 1315 00:59:31,760 --> 00:59:36,600 TWICE AS FREQUENT AS INFANTILE 1316 00:59:36,600 --> 00:59:39,760 CASES AND THIS MAY PREDISPOSE 1317 00:59:39,760 --> 00:59:39,960 THEM. 1318 00:59:39,960 --> 00:59:45,200 IF YOU LOOK AT THIS THE OTHER 1319 00:59:45,200 --> 00:59:48,120 WAY AROUND, WE HAVE THESE 1320 00:59:48,120 --> 00:59:50,920 MUTATIONS AND YOU SEE IT'S TRUE 1321 00:59:50,920 --> 00:59:54,800 THE MEDIAN DISEASE ONSET IS IN 1322 00:59:54,800 --> 00:59:56,840 THESE 5 YEARS EARLY IN THESE 1323 00:59:56,840 --> 00:59:58,320 CARRIERS THAN IN CARRIERS OF 1324 00:59:58,320 --> 01:00:00,600 TRUNCATING MUTATIONS. 1325 01:00:00,600 --> 01:00:02,440 BUT YOU CAN SEE IN BOTH GROUPS 1326 01:00:02,440 --> 01:00:05,160 WE HAVE VERY EARLY ONSET CASES 1327 01:00:05,160 --> 01:00:06,920 AND ALSO IN THIS MUTATION THERE 1328 01:00:06,920 --> 01:00:15,800 IS THE AGE OF ONSET REALLY CAN 1329 01:00:15,800 --> 01:00:22,960 REACH LATE ADULTS. 1330 01:00:22,960 --> 01:00:24,680 WHAT ABOUT DISEASE SEVERITY? 1331 01:00:24,680 --> 01:00:27,440 50 YEARS AGO WE HAD A RATING 1332 01:00:27,440 --> 01:00:33,720 SCALE TO MEASURE DISEASE 1333 01:00:33,720 --> 01:00:37,360 SEVERITY HSP AND CAN REACH A 1334 01:00:37,360 --> 01:00:39,120 MAXIMUM OF 52 POINTS AND 0 ARE 1335 01:00:39,120 --> 01:00:42,200 NO SYMPTOMS WHATSOEVER AND 52 IS 1336 01:00:42,200 --> 01:00:43,880 MAXIMUM DISEASE SEVERITY. 1337 01:00:43,880 --> 01:00:47,520 HERE YOU SEE THE DISEASE 1338 01:00:47,520 --> 01:00:50,760 DURATION AT BASELINE ON THE Y 1339 01:00:50,760 --> 01:00:51,840 AXIS THE TOTAL SCORE AS A 1340 01:00:51,840 --> 01:00:53,480 MEASURE OF DISEASE. 1341 01:00:53,480 --> 01:00:57,160 YOU CAN SEE THERE IS A HIGHLY 1342 01:00:57,160 --> 01:00:59,000 SIGNIFICANT CORRELATION BETWEEN 1343 01:00:59,000 --> 01:01:03,800 THOSE TWO PARAMETERS BUT THE 1344 01:01:03,800 --> 01:01:05,520 DISEASE DURATION IS 20% OF THE 1345 01:01:05,520 --> 01:01:07,680 VARIABILITY. 1346 01:01:07,680 --> 01:01:09,720 WHAT'S THE REASON FOR THIS WE 1347 01:01:09,720 --> 01:01:11,400 ARE PREDICTING? 1348 01:01:11,400 --> 01:01:14,200 WE LOOKED AT A MIXED MODEL AT 1349 01:01:14,200 --> 01:01:15,080 FACTORS INFLUENCING THE DISEASE 1350 01:01:15,080 --> 01:01:17,480 SEVERITY AND IN ADDITION TO THE 1351 01:01:17,480 --> 01:01:19,800 DISEASE DELETION WE FIND THE AGE 1352 01:01:19,800 --> 01:01:23,400 OF ON SET SIGNIFICANTLY 1353 01:01:23,400 --> 01:01:24,800 INFLUENCES DISEASE SEVERITY BUT 1354 01:01:24,800 --> 01:01:27,760 IN A KIND OF COUNTERINTUITIVE 1355 01:01:27,760 --> 01:01:29,440 WAY. 1356 01:01:29,440 --> 01:01:33,800 USUALLY WE ARE USED TO 1357 01:01:33,800 --> 01:01:34,920 ASSOCIATING EARLY ONSET DISEASE 1358 01:01:34,920 --> 01:01:38,880 BUT AS SPG4 AS A GROUP NOT THE 1359 01:01:38,880 --> 01:01:42,080 DE NOVOS BUT AS A GROUP LATER 1360 01:01:42,080 --> 01:01:44,120 ONSET SEEMS TO BE A BAD 1361 01:01:44,120 --> 01:01:48,160 PROGNOSTIC FACTOR BEING 1362 01:01:48,160 --> 01:01:49,720 ASSOCIATED WITH MORE SEVERE 1363 01:01:49,720 --> 01:01:49,920 DISEASE. 1364 01:01:49,920 --> 01:01:51,800 AND THE PRESENCE OF MUTATIONS IS 1365 01:01:51,800 --> 01:01:54,320 ALSO ASSOCIATED WITH MORE 1366 01:01:54,320 --> 01:01:58,920 DISEASE AS COMPARED TO FRTRUNCATED 1367 01:01:58,920 --> 01:01:59,160 MUTATIONS. 1368 01:01:59,160 --> 01:02:05,520 IN OUR COHORT OF LEADS WE DON'T 1369 01:02:05,520 --> 01:02:13,080 SEE AN EFFECT OF SEX ON DISEASE. 1370 01:02:13,080 --> 01:02:15,200 I SPLIT OUR COHORT IN THREE 1371 01:02:15,200 --> 01:02:17,360 GROUPS OF EQUAL SIZE BY AGE OF 1372 01:02:17,360 --> 01:02:21,200 ONSET SO YOU CAN SEE THERE'S AN 1373 01:02:21,200 --> 01:02:24,400 EARLY ONSET GROUP, THERE'S AN 1374 01:02:24,400 --> 01:02:27,800 INTERMEDIATE ONSET GROUP AND 1375 01:02:27,800 --> 01:02:31,280 LATE ONSET GROUP. 1376 01:02:31,280 --> 01:02:34,880 SEE ON THE Y AXIS GETTING AN 1377 01:02:34,880 --> 01:02:36,200 IDEA BY FORMING THE RATIO 1378 01:02:36,200 --> 01:02:39,760 BETWEEN THE RATING SCALE AND THE 1379 01:02:39,760 --> 01:02:43,640 DISEASE DURATION. 1380 01:02:43,640 --> 01:02:45,800 THIS GIVES AN INDICATION OF THE 1381 01:02:45,800 --> 01:02:47,520 PROGRESSION RATE. 1382 01:02:47,520 --> 01:02:51,040 IF YOU COMPARE THIS AND IF YOU 1383 01:02:51,040 --> 01:02:54,360 LOOK AT THE TOTAL SPG4 COHORT 1384 01:02:54,360 --> 01:02:56,760 THE PROGRESSION RATE IS ONE PER 1385 01:02:56,760 --> 01:02:56,960 YEAR. 1386 01:02:56,960 --> 01:03:01,320 YOU CAN SEE IN EARLY ONSET CASES 1387 01:03:01,320 --> 01:03:06,720 INDEED PROGRESSION IS SLOWER. 1388 01:03:06,720 --> 01:03:08,840 MEDIAN AND INTERMEDIATE CASES 1389 01:03:08,840 --> 01:03:11,120 BELEIF LIKE THE TOTAL COHORT AND 1390 01:03:11,120 --> 01:03:13,800 LATE ONSET CASES THE RATE IS 1391 01:03:13,800 --> 01:03:14,560 CONSIDERABLY FASTER THAN EARLY 1392 01:03:14,560 --> 01:03:21,720 ONSET CASES. 1393 01:03:21,720 --> 01:03:23,200 WE CAN ALSO LOOK AT THIS USING 1394 01:03:23,200 --> 01:03:26,280 THE CONTINUOUS VARIABLES AND SEE 1395 01:03:26,280 --> 01:03:28,400 THE SAME EFFECT HERE YOU CAN SEE 1396 01:03:28,400 --> 01:03:32,400 THE RED DOTS EARLY IN EARLY 1397 01:03:32,400 --> 01:03:38,280 ONSET CASES WITH LESS STEEP 1398 01:03:38,280 --> 01:03:38,720 PROGRESSION RATES. 1399 01:03:38,720 --> 01:03:44,440 SO WHICH EVERY WAY YOU LOOK AT 1400 01:03:44,440 --> 01:03:48,640 THIS WE SEE SIMILAR AFFECTS LIKE 1401 01:03:48,640 --> 01:03:50,320 FOR EXAMPLE, SPG5. 1402 01:03:50,320 --> 01:03:53,520 ALL RIGHT, ANOTHER WAY TO LOOK 1403 01:03:53,520 --> 01:03:57,000 AT AGE OF ONSET IS TO LOOK AT 1404 01:03:57,000 --> 01:04:01,240 THOSE VERY EARLY ONSET INFANTS. 1405 01:04:01,240 --> 01:04:02,320 IS THERE ANYTHING SPECIAL ABOUT 1406 01:04:02,320 --> 01:04:05,720 THOSE THAT START FROM THE 1407 01:04:05,720 --> 01:04:06,720 BEGINNING IN THE DEVELOPMENT? 1408 01:04:06,720 --> 01:04:09,000 HERE YOU SEE THE SAME DATA AS ON 1409 01:04:09,000 --> 01:04:09,640 THE LEFT. 1410 01:04:09,640 --> 01:04:11,520 YOU HAVE A GRAPH ON THE RIGHT. 1411 01:04:11,520 --> 01:04:16,320 THE ONLY DIFFERENCE IS THAT I 1412 01:04:16,320 --> 01:04:17,280 COLOR-CODED THE AGE. 1413 01:04:17,280 --> 01:04:19,280 THE RED GOT ARE INFAN TILE ONSET 1414 01:04:19,280 --> 01:04:21,640 CASES AND THE BLACK ARE THE 1415 01:04:21,640 --> 01:04:33,120 DEGENERATIVE ONSET CASES. 1416 01:04:33,120 --> 01:04:35,480 THERE'S A SMALL GROUP WITH EARLY 1417 01:04:35,480 --> 01:04:39,640 ONSET AND SEVERE DISEASE WHEREAS 1418 01:04:39,640 --> 01:04:42,520 MOST OF THE INFANTILE ONSET 1419 01:04:42,520 --> 01:04:43,960 CASES HAVE A LESS THAN AVERAGE 1420 01:04:43,960 --> 01:04:45,960 DISEASE PROGRESSION RATE. 1421 01:04:45,960 --> 01:04:50,240 SO THEY ARE ACTUALLY LESS SEVERE 1422 01:04:50,240 --> 01:04:52,440 THAN THE AVERAGE SPG4 CASES. 1423 01:04:52,440 --> 01:04:54,920 SO THERE'S TWO DISTINCT GROUPS. 1424 01:04:54,920 --> 01:04:58,400 ON A HUNCH I LABELLED THOSE 1425 01:04:58,400 --> 01:05:03,880 CASES IN OUR SPG4 COHORT WHERE 1426 01:05:03,880 --> 01:05:05,240 WE KNOW WE HAVE DE NOVO 1427 01:05:05,240 --> 01:05:06,760 INHERITANCE AND ALL THE CASES 1428 01:05:06,760 --> 01:05:09,520 THAT HAVE THE SEVERE PHENOTYPE 1429 01:05:09,520 --> 01:05:23,640 ARE INDEED DE NOVO SPG4. 1430 01:05:23,640 --> 01:05:26,920 WE HAVE A MEASURE I FIND USEFUL 1431 01:05:26,920 --> 01:05:28,520 WHEN CONSULTING PATIENTS OF 1432 01:05:28,520 --> 01:05:30,120 DAILY PRACTICE AND WE SEE THE 1433 01:05:30,120 --> 01:05:36,440 SAME EFFECT OF AGE OF ONSET AND 1434 01:05:36,440 --> 01:05:37,680 PROGRESSION HERE. 1435 01:05:37,680 --> 01:05:39,440 IF YOU CONCENTRATE ON THE RED 1436 01:05:39,440 --> 01:05:44,160 LINE YOU LOOK AT THE TIME FROM 1437 01:05:44,160 --> 01:05:45,920 ONSET OF THE DISEASE UNTIL A 1438 01:05:45,920 --> 01:05:47,520 PATIENT USES A WALKER OR 1439 01:05:47,520 --> 01:05:54,080 WHEELCHAIR ON A DAILY BASIS. 1440 01:05:54,080 --> 01:05:56,320 AND FOR THE TOTAL SPG4 COHORT IT 1441 01:05:56,320 --> 01:05:59,840 TAKES A MEDIAN OF 23 YEARS FROM 1442 01:05:59,840 --> 01:06:05,520 ONSET TO LOSS OF INDEPENDENT 1443 01:06:05,520 --> 01:06:06,280 WALKING. 1444 01:06:06,280 --> 01:06:08,840 YOU CAN SEE THE TIME IS 1445 01:06:08,840 --> 01:06:10,520 CONSIDERABLY LATER FOR THE EARLY 1446 01:06:10,520 --> 01:06:15,840 ONSET CASES SO MORE THAN 10 1447 01:06:15,840 --> 01:06:18,200 YEARS LATER AND WE SEE EXACTLY 1448 01:06:18,200 --> 01:06:23,840 THE SAME PATTERN FOR 1449 01:06:23,840 --> 01:06:27,840 INDEPENDENCE HERE. 1450 01:06:27,840 --> 01:06:30,760 THERE'S THERE'S A CONSISTENT 1451 01:06:30,760 --> 01:06:31,520 ONSET. 1452 01:06:31,520 --> 01:06:35,000 WE'RE WORK TO LOOK AT THE DATA 1453 01:06:35,000 --> 01:06:36,720 FROM OUR COHORT AND WE HAVE 1454 01:06:36,720 --> 01:06:42,320 VISITS FROM MORE THAN 400 1455 01:06:42,320 --> 01:06:51,480 PATIENTS SPAN INING THE TIME AND 1456 01:06:51,480 --> 01:06:53,480 LOOKING AT INDIVIDUAL DISEASE 1457 01:06:53,480 --> 01:06:55,080 PROGRESSION RATES. 1458 01:06:55,080 --> 01:06:57,720 NOW WE HAVE IDENTIFIED MUTATIONS 1459 01:06:57,720 --> 01:07:01,640 AND AGE IN ONSET AS MODIFIERS 1460 01:07:01,640 --> 01:07:05,400 MUCH THE PHENOTYPE IN SPG4 BUT 1461 01:07:05,400 --> 01:07:09,000 STILL THE TWO FACTORS HAVE A 1462 01:07:09,000 --> 01:07:11,440 SMALL PROPORTION OF THE ENORMOUS 1463 01:07:11,440 --> 01:07:19,280 VARIABILITY WE SEE. 1464 01:07:19,280 --> 01:07:20,720 HOW CAN WE EXPLAIN THIS AND FOR 1465 01:07:20,720 --> 01:07:26,120 THIS WE LAUNCHED A PROJECT WHICH 1466 01:07:26,120 --> 01:07:27,920 I'VE HELPED COORDINATE WITH THE 1467 01:07:27,920 --> 01:07:33,160 UNIVERSITY OF MIAMI AND THEY'RE 1468 01:07:33,160 --> 01:07:34,520 COLLECTING SPG4 CASES TO 1469 01:07:34,520 --> 01:07:35,760 UNDERSTAND WHY THE DISEASE MAN 1470 01:07:35,760 --> 01:07:41,120 TESTS IN SO MANY WAYS. 1471 01:07:41,120 --> 01:07:42,120 WE'RE FOLLOWING THREE HOPEFULLY 1472 01:07:42,120 --> 01:07:43,040 COMPLIMENTARY APPROACHES. 1473 01:07:43,040 --> 01:07:47,360 THE FIRST APPROACH IS TO COLLECT 1474 01:07:47,360 --> 01:07:48,680 THE LARGEST POSSIBLE SPG4 COHORT 1475 01:07:48,680 --> 01:07:51,560 WITH A TARGET OF AT LEAST 1,000 1476 01:07:51,560 --> 01:07:55,840 CASE AND NICK EXTREME CASES FROM 1477 01:07:55,840 --> 01:07:57,560 THE MILDEST AND MOST SEVERE AND 1478 01:07:57,560 --> 01:07:59,520 TRY TO FUND THE FACTORS THEY 1479 01:07:59,520 --> 01:08:05,000 HAVE IN COMMON THE SECOND 1480 01:08:05,000 --> 01:08:07,280 APPROACH IS A FAMILY-BASED 1481 01:08:07,280 --> 01:08:10,400 APPROACH AND THE AGE OF ONSET 1482 01:08:10,400 --> 01:08:15,360 CAN VARY BY DECADES. 1483 01:08:15,360 --> 01:08:19,760 WE'RE COLLECTING THESE WE CALL 1484 01:08:19,760 --> 01:08:21,440 DISCORDANT FAMILIES AND WE HAVE 1485 01:08:21,440 --> 01:08:24,080 A LARGE FAMILY IN SWITZERLAND 1486 01:08:24,080 --> 01:08:27,360 WITH MORE THAN 60 AFFECTED 1487 01:08:27,360 --> 01:08:29,480 FAMILY MEMBERS IDEAL FOR 1488 01:08:29,480 --> 01:08:33,160 STUDYING THE ADDITIONAL GENETIC 1489 01:08:33,160 --> 01:08:35,080 INFLUENCES THAT CAN MODIFY THAT 1490 01:08:35,080 --> 01:08:35,320 PHENOTYPE. 1491 01:08:35,320 --> 01:08:39,760 MANY OF THE PEOPLE HERE IN THE 1492 01:08:39,760 --> 01:08:41,520 ROOM HAVE ACTUALLY ALREADY 1493 01:08:41,520 --> 01:08:42,560 PLEDGED THEIR COLLABORATION FOR 1494 01:08:42,560 --> 01:08:43,720 THE PROJECT AND I'M EXCITED 1495 01:08:43,720 --> 01:08:47,880 BECAUSE THIS IS AN EXAMPLE OF A 1496 01:08:47,880 --> 01:08:50,360 PROJECT WE CAN ONLY PULL OFF IF 1497 01:08:50,360 --> 01:08:54,800 WE COLLABORATE GLOBALLY TO FIND 1498 01:08:54,800 --> 01:08:55,800 ENOUGH PATIENTS. 1499 01:08:55,800 --> 01:09:00,760 THIS RECRUITMENT FOR THE LARGEST 1500 01:09:00,760 --> 01:09:03,800 COHORT IS A TRUE CHALLENGE AND 1501 01:09:03,800 --> 01:09:07,720 THIS IS WHY WE LAUNCHED THE EDGE 1502 01:09:07,720 --> 01:09:11,520 TRY AND I HAVE SHOWN A COMPANION 1503 01:09:11,520 --> 01:09:15,800 REGISTRY THE SPG4 PATIENT 1504 01:09:15,800 --> 01:09:19,000 REGISTRY LINKED TO THE HSP 1505 01:09:19,000 --> 01:09:20,320 REGISTRY TO COMBINE THE DATA 1506 01:09:20,320 --> 01:09:21,120 FROM BOTH DATABASES. 1507 01:09:21,120 --> 01:09:23,840 SO WHAT IS THE PATIENT REGISTRY 1508 01:09:23,840 --> 01:09:27,640 DO? 1509 01:09:27,640 --> 01:09:30,400 PATIENTS CAN SIGN UP THEMSELVES 1510 01:09:30,400 --> 01:09:33,920 AND REGISTER THEIR INTEREST FOR 1511 01:09:33,920 --> 01:09:38,000 CLINICAL TRIALS AND CAN ENTER 1512 01:09:38,000 --> 01:09:39,760 HEALTH-RELATED INFORMATION AND 1513 01:09:39,760 --> 01:09:41,040 REPORT LONGITUDINAL OUTCOMES 1514 01:09:41,040 --> 01:09:42,960 THAT ALLOW US TO DETERMINE 1515 01:09:42,960 --> 01:09:43,600 PROGRESSION RATES. 1516 01:09:43,600 --> 01:09:47,440 OF COURSE THIS NEEDS TO BE 1517 01:09:47,440 --> 01:09:50,960 IMPLEMENTED IN A MULTI-LANGUAGE. 1518 01:09:50,960 --> 01:09:55,760 WE HAVE ENGLISH, ITALIAN, DUTCH, 1519 01:09:55,760 --> 01:09:57,040 GERMAN AND TURKISH AND WE HAVE 1520 01:09:57,040 --> 01:09:59,520 COME A LONG WAY BUT A LONG WAY 1521 01:09:59,520 --> 01:10:00,520 TO GO. 1522 01:10:00,520 --> 01:10:01,440 WE'RE TESTING THE PILOT VERSION 1523 01:10:01,440 --> 01:10:03,720 WITH THE HELP OF PATIENTS 1524 01:10:03,720 --> 01:10:05,520 COLLECTING THEIR FEEDBACK AND I 1525 01:10:05,520 --> 01:10:07,720 HOPE THIS WILL BE ONLINE BY 1526 01:10:07,720 --> 01:10:14,120 AUGUST 2022. 1527 01:10:14,120 --> 01:10:15,720 THIS BRINGS ME TO ONE LAST 1528 01:10:15,720 --> 01:10:19,360 ASPECT I WANT TO SHARE WITH YOU 1529 01:10:19,360 --> 01:10:25,200 AND THAT'S A QUESTION OF OUTCOME 1530 01:10:25,200 --> 01:10:27,360 PARAMETERS. 1531 01:10:27,360 --> 01:10:32,520 THIS IS A LARGE CHALLENGE STILL. 1532 01:10:32,520 --> 01:10:36,440 WE NEED MUCH BETTER OUTCOMES AND 1533 01:10:36,440 --> 01:10:39,000 NEED TO UNDERSTAND WHICH 1534 01:10:39,000 --> 01:10:39,720 OUTCOMES HAVE MEANING FOR 1535 01:10:39,720 --> 01:10:43,280 PATIENT. 1536 01:10:43,280 --> 01:10:44,480 WE STARTED A PROJECT TOGETHER 1537 01:10:44,480 --> 01:10:45,480 WITH MANY PATIENT ORGANIZATIONS 1538 01:10:45,480 --> 01:10:48,520 AND YOU SEE THE LOGOS ON THE 1539 01:10:48,520 --> 01:10:50,720 RIGHT TO UNDERSTAND WHAT ARE THE 1540 01:10:50,720 --> 01:10:52,960 MEANINGFUL ASPECTS OF HEALTH 1541 01:10:52,960 --> 01:10:54,520 THAT ARE AFFECTED BY HSP. 1542 01:10:54,520 --> 01:10:59,520 I MEAN ASPECT OF HEALTH IN THE 1543 01:10:59,520 --> 01:11:04,640 BROADEST SENSE BECAUSE THEY CAN 1544 01:11:04,640 --> 01:11:10,160 COMPRISE SOCIAL INTERACTION AND 1545 01:11:10,160 --> 01:11:10,640 LOTS OF PARTICIPATION. 1546 01:11:10,640 --> 01:11:16,320 I MEAN THIS IN A BROAD SENSE. 1547 01:11:16,320 --> 01:11:20,480 ONLY IF WE UNDERSTAND THE 1548 01:11:20,480 --> 01:11:23,520 HOLISTIC DISABILITY WE CAN 1549 01:11:23,520 --> 01:11:25,520 EXTRACT CONCEPTS WE CAN MEASURE 1550 01:11:25,520 --> 01:11:26,760 THAT REPRESENT THE DISABILITY 1551 01:11:26,760 --> 01:11:28,320 CAUSED BY THE DISEASE AND ONCE 1552 01:11:28,320 --> 01:11:34,000 WE HAVE EXTRACTED THOSE CONCEPTS 1553 01:11:34,000 --> 01:11:35,240 WE NEED TO FIND MEASURES AND 1554 01:11:35,240 --> 01:11:37,640 THOSE ARE CALLED OUTCOME 1555 01:11:37,640 --> 01:11:37,920 PARAMETERS. 1556 01:11:37,920 --> 01:11:39,760 THERE WE HAVE DIFFERENT 1557 01:11:39,760 --> 01:11:42,760 MODALITIES THAT WE CAN PULL FROM 1558 01:11:42,760 --> 01:11:45,360 TO MEASURE OUR CONCEPT OF 1559 01:11:45,360 --> 01:11:45,640 INTEREST. 1560 01:11:45,640 --> 01:11:50,560 WE HAVE A NUMBER OF PROJECTS AND 1561 01:11:50,560 --> 01:11:53,120 I LISTED A FEW TO WORK ON THE 1562 01:11:53,120 --> 01:11:54,320 OUTCOME PARAMETERS. 1563 01:11:54,320 --> 01:11:56,880 ONE DEDICATED PARTICULARLY THE 1564 01:11:56,880 --> 01:11:59,000 CHILDREN BECAUSE I THINK WITH 1565 01:11:59,000 --> 01:12:03,600 CHILDREN THE SITUATION IS VEEP 1566 01:12:03,600 --> 01:12:07,800 MORE CHALLENGING AND I'D LIKE TO 1567 01:12:07,800 --> 01:12:10,120 DRAW PARTICULAR ATTENTION TO THE 1568 01:12:10,120 --> 01:12:11,760 OBSERVE THE PATIENT-REPORTED 1569 01:12:11,760 --> 01:12:13,760 OUTCOMES AND THIS IS A LINK TO 1570 01:12:13,760 --> 01:12:18,720 THE REGISTRY AND THE OUTCOMES 1571 01:12:18,720 --> 01:12:20,880 THAT WILL POPULATE AND GIVE 1572 01:12:20,880 --> 01:12:22,000 CONTENT TO THE PATIENT REGISTRY. 1573 01:12:22,000 --> 01:12:23,840 WE HAVE A FRAMEWORK FOR THE WORK 1574 01:12:23,840 --> 01:12:25,840 BECAUSE IT IS VERY CHALLENGING 1575 01:12:25,840 --> 01:12:30,000 TO VALIDATE NOVEL OUTCOME 1576 01:12:30,000 --> 01:12:31,800 PARAMETERS IN THE TIMELY FASHION 1577 01:12:31,800 --> 01:12:35,800 AND WE'RE TRYING TO BUILD A 1578 01:12:35,800 --> 01:12:39,760 PLATFORM MODELLED AFTER THE IDEA 1579 01:12:39,760 --> 01:12:42,960 OF ADAPTIVE TRIALS USED IN 1580 01:12:42,960 --> 01:12:44,200 RESEARCH TO TEST NOVEL PRECISION 1581 01:12:44,200 --> 01:12:48,080 THERAPIES AND MUCH OF THIS 1582 01:12:48,080 --> 01:12:48,920 THINKING AND INFRASTRUCTURE CAN 1583 01:12:48,920 --> 01:12:52,280 BE USED FOR OUTCOME NAVIGATION. 1584 01:12:52,280 --> 01:12:56,400 WITH THAT I'D LIKE TO ENCOURAGE 1585 01:12:56,400 --> 01:12:59,520 ALL OF YOU THAT IF YOU SEE 1586 01:12:59,520 --> 01:13:00,000 POTENTIAL POINTS OF 1587 01:13:00,000 --> 01:13:02,440 COLLABORATION AND IF YOU HAVE 1588 01:13:02,440 --> 01:13:05,520 QUESTIONS, DON'T HESITATE TO 1589 01:13:05,520 --> 01:13:06,720 SEND ME AN E-MAIL AND WOULD LIKE 1590 01:13:06,720 --> 01:13:08,600 TO THANK ALL THE GROUPS OF 1591 01:13:08,600 --> 01:13:09,320 PEOPLE BECAUSE THE NAMES 1592 01:13:09,320 --> 01:13:11,040 WOULDN'T FIT ON A SLIDE THAT 1593 01:13:11,040 --> 01:13:15,320 HAVE SUPPORTED AND CONTINUED TO 1594 01:13:15,320 --> 01:13:17,200 SUPPORT THIS WORK INCLUDING FUND 1595 01:13:17,200 --> 01:13:18,360 FROM INSTITUTIONS. 1596 01:13:18,360 --> 01:13:19,920 THANK YOU VERY MUCH. 1597 01:13:19,920 --> 01:13:22,680 >> THANK YOU VERY MUCH. 1598 01:13:22,680 --> 01:13:24,720 >> WE'RE GOING TO SHIFT OUR 1599 01:13:24,720 --> 01:13:27,800 BREAK BY A FEW MINUTES AND TAKE 1600 01:13:27,800 --> 01:13:31,080 OUR BREAK NOW AND REJOIN 1601 01:13:31,080 --> 01:13:34,320 EVERYONE AND RESTART AT 11:25 1602 01:13:34,320 --> 01:13:54,840 EASTERN STANDARD TIME. 1603 01:13:54,840 --> 01:14:01,080 >> WE'LL HAVE A PRESENTATION BY 1604 01:14:01,080 --> 01:14:08,920 DR. TORO AND THEN HEAR FROM 1605 01:14:08,920 --> 01:14:11,720 DARIUS EBRAHIMI-FAKHARI AND THEN 1606 01:14:11,720 --> 01:14:13,320 HEAR FROM MICHELLE CHRISTIE AND 1607 01:14:13,320 --> 01:14:17,600 I'LL INTRODUCE ARIANE HAS BEEN 1608 01:14:17,600 --> 01:14:21,840 LEADING THE CHARGE FOR THE 1609 01:14:21,840 --> 01:14:22,040 MEETING. 1610 01:14:22,040 --> 01:14:23,760 SHE'S A PHYSICIAN SCIENTIST AT 1611 01:14:23,760 --> 01:14:27,760 THE NIH AND INVESTIGATOR IN 1612 01:14:27,760 --> 01:14:32,960 CLINICAL TRIALS INCLUDING THE 1613 01:14:32,960 --> 01:14:39,040 THERAPIES FOR ULTRA RARE 1614 01:14:39,040 --> 01:14:43,800 DISEASES AND WE'LL HAVE POLICY 1615 01:14:43,800 --> 01:15:19,760 AND RSP AND I WELCOME THEIR 1616 01:15:19,760 --> 01:15:25,160 INPUT. 1617 01:15:25,160 --> 01:15:31,760 WE HAVE A NEURO OLOLOGY DISORDER AND 1618 01:15:31,760 --> 01:15:35,360 RESEARCH INTERESTS AND TARGET ON 1619 01:15:35,360 --> 01:15:41,400 DE GENE -- DEGENERATIVE 1620 01:15:41,400 --> 01:15:45,280 DISEASES AND LOOKS AT CHILD 1621 01:15:45,280 --> 01:15:50,440 ONSET FORM OF PATHWAYS. 1622 01:15:50,440 --> 01:15:56,440 THE CURRENT WORK IS A NATURAL 1623 01:15:56,440 --> 01:16:11,800 HISTORIES STUDIES AND 1624 01:16:11,800 --> 01:16:21,480 DR. CHRISTIE LEADS A PRACTICE 1625 01:16:21,480 --> 01:16:23,480 FOR NEURAL PHYSIOLOGY AND LOOKS 1626 01:16:23,480 --> 01:16:31,760 AT GENETICS FOR CHILD MLS WITH 1627 01:16:31,760 --> 01:16:43,840 NEURO GENETIC CONDITIONS ANDAGE 1628 01:16:43,840 --> 01:16:48,760 LOOKING AT OTHER DISORDER AND 1629 01:16:48,760 --> 01:16:54,680 LOOKING AT OTHER PROTOCOLS. 1630 01:16:54,680 --> 01:17:00,840 I'LL LET ARIANE. 1631 01:17:00,840 --> 01:17:02,480 >> I'LL PRESENT BRIEFLY SO WE'RE 1632 01:17:02,480 --> 01:17:04,600 BACK ON TIME AND I'M PRESENTING 1633 01:17:04,600 --> 01:17:06,400 ON BEHALF OF DR. SCHOR AND ALTER 1634 01:17:06,400 --> 01:17:08,560 WHO ALSO EVALUATED THE PATIENTS 1635 01:17:08,560 --> 01:17:10,880 AND TO EXPLAIN HOW THIS CAME 1636 01:17:10,880 --> 01:17:13,040 ABOUT IN TERMS OF OUR 1637 01:17:13,040 --> 01:17:14,880 INVOLVEMENT IN THE SPACE. 1638 01:17:14,880 --> 01:17:16,240 SO MANY YEAR AGO MY COLLEAGUE 1639 01:17:16,240 --> 01:17:19,760 DR. SCHOR AND ALTER SAW SPENCER 1640 01:17:19,760 --> 01:17:22,760 WOULD IS NOW A 34-YEAR-OLD YOUNG 1641 01:17:22,760 --> 01:17:25,960 MAN EVALUATED IN 2012 WHEN HE 1642 01:17:25,960 --> 01:17:29,360 WAS 25 YEARS OF AGE AND HAD A 1643 01:17:29,360 --> 01:17:32,760 HISTORY OF GROSS MOTOR 1644 01:17:32,760 --> 01:17:39,480 MILESTONES AND CHILD ONSET 1645 01:17:39,480 --> 01:17:51,360 RIGIDITY AND A WALKER AND LENG N 1646 01:17:51,600 --> 01:17:54,640 -- LENGTHENING AND HAD CLEANING 1647 01:17:54,640 --> 01:18:01,320 OF THE SPINAL CORD ON IMAGING AS 1648 01:18:01,320 --> 01:18:09,440 WELL AS SPASTIC QUADRIPARESIS 1649 01:18:09,440 --> 01:18:11,720 AND WE EVALUATED MATTHEW AND WE 1650 01:18:11,720 --> 01:18:13,040 EVALUATED HIM WITH HIS BROTHER 1651 01:18:13,040 --> 01:18:14,840 WHO ALSO HAD A NEUROLOGICAL 1652 01:18:14,840 --> 01:18:18,120 DISEASE BUT ENDED UP HAVING 1653 01:18:18,120 --> 01:18:19,640 SEPARATE NEUROLOGICAL DISEASES 1654 01:18:19,640 --> 01:18:22,400 WHICH SOMETIMES HAPPENED IN THE 1655 01:18:22,400 --> 01:18:23,720 UDP. 1656 01:18:23,720 --> 01:18:27,760 HE BASICALLY HAD SPASTIC 1657 01:18:27,760 --> 01:18:29,600 QUADRIPARESIS AND HAD A SIMILAR 1658 01:18:29,600 --> 01:18:31,760 HISTORY AND DIAGNOSED WITH DE 1659 01:18:31,760 --> 01:18:36,040 NOVO MUTATION OF SPG4. 1660 01:18:36,040 --> 01:18:37,000 THERE WAS ANOTHER PATIENT WHEN 1661 01:18:37,000 --> 01:18:37,720 WE LOOKED BACK IN THE PROGRAM 1662 01:18:37,720 --> 01:18:45,960 WHO HAD A MUTATION AT THE SAME 1663 01:18:45,960 --> 01:18:54,360 REGION BUT A DIFFERENT AMINO 1664 01:18:54,360 --> 01:18:55,640 ACID SUBSTITUTION AND THERE WAS 1665 01:18:55,640 --> 01:18:57,480 SOME IN VITRO ASSAYS TO TRY TO 1666 01:18:57,480 --> 01:19:01,680 SEE WHAT THE DIFFERENTIAL IMPACT 1667 01:19:01,680 --> 01:19:02,880 OF THE AMINO SUBSTITUTION WAS. 1668 01:19:02,880 --> 01:19:04,800 SO WE WROTE UP THE TWO PATIENTS 1669 01:19:04,800 --> 01:19:08,080 IN A POSTER A FEW YEARS AGO AT 1670 01:19:08,080 --> 01:19:10,320 THE AMERICAN COLLEGE OF GENOMIC 1671 01:19:10,320 --> 01:19:13,120 MEETING BECAUSE IT SEEMED LIKE 1672 01:19:13,120 --> 01:19:15,440 AN UNUSUAL PHENOTYPE AND SHORTLY 1673 01:19:15,440 --> 01:19:16,840 AFTER THE LITERATURE THEY 1674 01:19:16,840 --> 01:19:19,680 PUBLISHED A LETTER TO THE EDITOR 1675 01:19:19,680 --> 01:19:22,240 DETAILING HOW THE MUTATION COULD 1676 01:19:22,240 --> 01:19:23,400 COST THIS COMPLEX SPG4 PHENOTYPE 1677 01:19:23,400 --> 01:19:25,880 SIMILAR TO WHETHER WE HAD BEEN 1678 01:19:25,880 --> 01:19:27,360 SEEING IN THE PATIENTS IN THE 1679 01:19:27,360 --> 01:19:28,520 SERIES HAD SEEN A MUTATION WE 1680 01:19:28,520 --> 01:19:34,280 HAD SEEN IN OUR PATIENTS. 1681 01:19:34,280 --> 01:19:38,000 SO LAST YEAR A LOCAL GENETICISTS 1682 01:19:38,000 --> 01:19:41,400 REFERRED THE TWO LITTLE GIRLS WE 1683 01:19:41,400 --> 01:19:46,800 HEARD FROM EARLIER BLAIR AND 1684 01:19:46,800 --> 01:19:47,520 LILLY AND AWAY WHAT'S 1685 01:19:47,520 --> 01:19:49,120 INTERESTING IS THEY WERE NOT 1686 01:19:49,120 --> 01:19:54,200 SEEKING OUT SPECIFIC PATIENTS 1687 01:19:54,200 --> 01:19:57,760 WITH A CERTAIN FEENLT 1688 01:20:02,760 --> 01:20:05,440 IT'S UNUSUAL TO HAVE THE SAME 1689 01:20:05,440 --> 01:20:06,760 PATIENTS RECRUITED OVER YEARS 1690 01:20:06,760 --> 01:20:08,480 WITHOUT EMPHASIS ON A SPECIFIC 1691 01:20:08,480 --> 01:20:08,720 PHENOTYPE. 1692 01:20:08,720 --> 01:20:13,600 IT SEEMED QUITE UNUSUAL TO US 1693 01:20:13,600 --> 01:20:19,720 AND BASED ON THE TWO LITTLE 1694 01:20:19,720 --> 01:20:21,880 GIRLS WE SAW WE FELT TO GET THE 1695 01:20:21,880 --> 01:20:23,240 COMMUNITY TOGETHER TO SEE WHY 1696 01:20:23,240 --> 01:20:27,720 THE DE NOVO CONDITIONS MAY 1697 01:20:27,720 --> 01:20:39,120 PRESENT DIFFERENTLY AND WHAT THE 1698 01:20:39,120 --> 01:20:40,320 NATURAL HISTORY MAY OCCUR AND 1699 01:20:40,320 --> 01:20:43,360 I'LL PASS IT TO DARIUS WHO CAN 1700 01:20:43,360 --> 01:20:44,160 DETAIL MORE ABOUT HIS COHORT HE 1701 01:20:44,160 --> 01:21:02,880 FOLLOWED. 1702 01:21:02,880 --> 01:21:10,400 >> THANK YOU, ARIANE. 1703 01:21:10,400 --> 01:21:14,640 THANK YOU FOR THE INVITATION TO 1704 01:21:14,640 --> 01:21:15,280 BE HERE. 1705 01:21:15,280 --> 01:21:18,280 I'M DARIUS EBRAHIMI-FAKHARI AND 1706 01:21:18,280 --> 01:21:19,280 A SPECIALIST AT BOSTON'S 1707 01:21:19,280 --> 01:21:21,240 CHILDREN HOSPITAL WHERE I LEAD A 1708 01:21:21,240 --> 01:21:25,760 RESEARCH PROGRAM FOR EARLY ONSET 1709 01:21:25,760 --> 01:21:27,440 FORMS OF SPASTIC PARAPLEGIA. 1710 01:21:27,440 --> 01:21:29,040 IT'S NICE TO SEE THE COMMUNITY 1711 01:21:29,040 --> 01:21:29,840 COME TOGETHER AROUND THIS 1712 01:21:29,840 --> 01:21:32,840 QUESTION AND I'M DELIGHTED TO 1713 01:21:32,840 --> 01:21:36,040 SHARE SOME OF OUR WORK IN THE 1714 01:21:36,040 --> 01:21:36,240 SPACE. 1715 01:21:36,240 --> 01:21:37,320 THESE ARE MY DISCLOSURES. 1716 01:21:37,320 --> 01:21:39,160 BEFORE I GO INTO FINDINGS I WANT 1717 01:21:39,160 --> 01:21:41,280 TO GIVE CREDIT TO MY TEAM 1718 01:21:41,280 --> 01:21:46,480 MEMBERS WHO PUT THIS TOGETHER 1719 01:21:46,480 --> 01:21:53,080 AND WHO WORKED ON THIS THIS 1720 01:21:53,080 --> 01:21:57,480 INCLUDES ALISA AND CATHERINE WHO 1721 01:21:57,480 --> 01:22:01,880 MANY FAMILIES HAVE MET AND 1722 01:22:01,880 --> 01:22:07,760 AFSHIN WHO HELPS WITH THE 1723 01:22:07,760 --> 01:22:08,400 MOLECULAR ANALYSES I'LL PRESENT 1724 01:22:08,400 --> 01:22:11,080 TODAY. 1725 01:22:11,080 --> 01:22:12,800 IN THE NEXT 15 TO 20 MINUTES I 1726 01:22:12,800 --> 01:22:15,040 HOPE TO COVER FOUR AREAS. 1727 01:22:15,040 --> 01:22:17,080 I'LL TALK ABOUT THE CHALLENGES 1728 01:22:17,080 --> 01:22:19,280 OF STUDYING ULTRA RARE DISEASE 1729 01:22:19,280 --> 01:22:19,920 AND I REALIZE I'M PREACHING TO 1730 01:22:19,920 --> 01:22:21,400 THE CHOIR TODAY. 1731 01:22:21,400 --> 01:22:23,040 IN THE SECOND PART I'LL SPEAK 1732 01:22:23,040 --> 01:22:26,200 ABOUT OUR APPROACH TO 1733 01:22:26,200 --> 01:22:27,440 ESTABLISHING CLINICAL TRIAL 1734 01:22:27,440 --> 01:22:36,600 READINESS FOR ONSET FORMS OF 1735 01:22:36,600 --> 01:22:37,440 HEREDITARY SPASTIC PARAPLEGIA 1736 01:22:37,440 --> 01:22:40,480 AND TALK ABOUT OUR PATIENTS WITH 1737 01:22:40,480 --> 01:22:42,400 DE NOVO SPG4 WE'VE MED AND IN 1738 01:22:42,400 --> 01:22:43,800 THE LAST PART I'LL TALK ABOUT 1739 01:22:43,800 --> 01:22:45,040 FUTURE DIRECTIONS. 1740 01:22:45,040 --> 01:22:47,040 I HOPE THIS WILL STIMULATE 1741 01:22:47,040 --> 01:22:52,440 DISCUSSION WE'LL HAVE LATER ON. 1742 01:22:52,440 --> 01:22:53,680 THE FIRST NOTE AND I JUST WANT 1743 01:22:53,680 --> 01:22:56,200 TO REVIEW SOME OF THE FRAMEWORK 1744 01:22:56,200 --> 01:22:58,640 THAT WE OPERATE IN AND I THINK 1745 01:22:58,640 --> 01:23:00,600 DR. SCHOR HIT ON A LOT OF THE 1746 01:23:00,600 --> 01:23:03,480 POINTS THAT WE ALL THINK ABOUT 1747 01:23:03,480 --> 01:23:09,480 IN THE RARE DISEASE SPACE. 1748 01:23:09,480 --> 01:23:11,520 FIRST WE HAVE TO ACKNOWLEDGE 1749 01:23:11,520 --> 01:23:17,280 RARE DISEASE AFFECTS A SMALL 1750 01:23:17,280 --> 01:23:19,760 NUMBER BUT WORLDWIDE IT AFFECTS 1751 01:23:19,760 --> 01:23:22,280 A LARGE NUMBER AND MOST PRESENT 1752 01:23:22,280 --> 01:23:23,760 DURING CHILDHOOD AND THE VAST 1753 01:23:23,760 --> 01:23:27,440 MAJORITY DOES NOT HAVE A 1754 01:23:27,440 --> 01:23:33,040 SPECIFIC TREATMENT. 1755 01:23:33,040 --> 01:23:35,440 I THINK THE PROBLEM IS 1756 01:23:35,440 --> 01:23:39,480 ILLUSTRATED IN THE GRAPH THE 1757 01:23:39,480 --> 01:23:41,000 RARE DISEASES IN THE BLUE LINE 1758 01:23:41,000 --> 01:23:43,040 AND THERAPIES AND YOU SEE THE 1759 01:23:43,040 --> 01:23:45,680 POSITIVE TREND BUT THE GAP 1760 01:23:45,680 --> 01:23:46,920 REMAINS QUITE WIDE. 1761 01:23:46,920 --> 01:23:48,680 THAT I THINK HAS IN PART TO DO 1762 01:23:48,680 --> 01:23:51,480 WITH THE FACT THAT WE'VE SEEN 1763 01:23:51,480 --> 01:23:53,240 REMARKABLE SUCCESS IN GENE 1764 01:23:53,240 --> 01:23:53,480 DISCOVERY. 1765 01:23:53,480 --> 01:23:55,800 WE'RE NOW ABLE TO UNCOVER THE 1766 01:23:55,800 --> 01:23:57,880 GENETIC ETIOLOGY OF MANY RARE 1767 01:23:57,880 --> 01:24:00,360 DISEASES BUT BEYOND GENE 1768 01:24:00,360 --> 01:24:01,520 DISCOVERY, ARE MOLECULAR 1769 01:24:01,520 --> 01:24:01,960 UNDERSTANDING. 1770 01:24:01,960 --> 01:24:03,480 THE UNDERSTANDING OF THE 1771 01:24:03,480 --> 01:24:07,760 PATHWAYS AND MOLECULES REMAINS 1772 01:24:07,760 --> 01:24:15,040 QUITE LIMITED. 1773 01:24:15,040 --> 01:24:17,200 DISEASE MODELS AND REAGENTS 1774 01:24:17,200 --> 01:24:19,280 STILL NEED TO BE DEVELOPED AND 1775 01:24:19,280 --> 01:24:21,480 LOOKING AT NATURAL HISTORY DATA 1776 01:24:21,480 --> 01:24:23,240 AND HISTORICALLY THERE'S LIMITED 1777 01:24:23,240 --> 01:24:25,280 INTEREST IN FUNDING THE RESEARCH 1778 01:24:25,280 --> 01:24:26,800 AND LIMITED COMMERCIAL INTEREST 1779 01:24:26,800 --> 01:24:30,360 IN DEVELOPING THERAPIES. 1780 01:24:30,360 --> 01:24:31,480 THOUGH THIS HAS CHANGED IN 1781 01:24:31,480 --> 01:24:32,760 RECENT YEARS. 1782 01:24:32,760 --> 01:24:35,400 AS A PHYSICIAN SCIENTIST I THINK 1783 01:24:35,400 --> 01:24:39,680 TWO KEY AREAS WHERE WE CAN HELP 1784 01:24:39,680 --> 01:24:43,520 THE RARE DISEASE COMMUNITY. 1785 01:24:43,520 --> 01:24:44,560 I'M SUMMARIZE THEM. 1786 01:24:44,560 --> 01:24:46,000 ONE IS CLINICAL TRIAL READINESS. 1787 01:24:46,000 --> 01:24:51,040 I'LL EXPLAIN THAT IN A MOMENT 1788 01:24:51,040 --> 01:24:58,680 AND SECOND MOLECULAR TREATMENTS. 1789 01:24:58,680 --> 01:25:00,400 WHEN I THINK OF CLINICAL TRIAL 1790 01:25:00,400 --> 01:25:03,200 READINESS I THINK OF THE 1791 01:25:03,200 --> 01:25:03,440 NETWORK. 1792 01:25:03,440 --> 01:25:05,840 YOU NEED TO BUILD A COMMUNITY TO 1793 01:25:05,840 --> 01:25:08,920 DEVELOP A SUSTAINABLE AND 1794 01:25:08,920 --> 01:25:10,480 SUCCESSFUL RARE DISEASE RESEARCH 1795 01:25:10,480 --> 01:25:11,760 PROGRAM AND IT INCLUDES THE 1796 01:25:11,760 --> 01:25:13,680 PATIENTS AND FAMILIES AND 1797 01:25:13,680 --> 01:25:15,480 ADVOCATES AND RESEARCHERS AND 1798 01:25:15,480 --> 01:25:17,240 THERE ARE KEY PIECES OF 1799 01:25:17,240 --> 01:25:19,040 INFRASTRUCTURE THAT NEED TO BE 1800 01:25:19,040 --> 01:25:22,960 BUILT TO REALLY TAKE DEVELOPMENT 1801 01:25:22,960 --> 01:25:26,480 THROUGH DIFFERENT STAGES THAT 1802 01:25:26,480 --> 01:25:27,480 INCLUDES EARLY INVESTMENT IN 1803 01:25:27,480 --> 01:25:29,120 NATURAL HISTORY STUDIES AND 1804 01:25:29,120 --> 01:25:32,160 INCLUDES BIOMARKER DISCOVERY AND 1805 01:25:32,160 --> 01:25:33,320 DEFINING OUTCOME MEASURES, 1806 01:25:33,320 --> 01:25:35,760 LOOKING AT QUALITY OF LIFE WHICH 1807 01:25:35,760 --> 01:25:38,400 I THINK IS A VERY IMPORTANT AREA 1808 01:25:38,400 --> 01:25:41,280 AND IN TERMS OF PRE-CLINICAL 1809 01:25:41,280 --> 01:25:42,880 DEVELOPMENT THE DISEASE MODELS 1810 01:25:42,880 --> 01:25:47,680 AND TOOLS AND LINING UP 1811 01:25:47,680 --> 01:25:49,480 TOXICOLOGY STUDIES AND SOME OF 1812 01:25:49,480 --> 01:25:50,080 THESE FACTORS NEED TO BE IN 1813 01:25:50,080 --> 01:25:52,680 PLACE AND I THINK THIS IS TRUE 1814 01:25:52,680 --> 01:25:59,800 FOR MANY RARE DISEASES AND A 1815 01:25:59,800 --> 01:26:00,280 COMMON THEME. 1816 01:26:00,280 --> 01:26:02,320 AND THIS TABLE BREAKS DOWN THE 1817 01:26:02,320 --> 01:26:05,040 QUESTION OF THERAPY DEVELOPMENT 1818 01:26:05,040 --> 01:26:06,920 INTO VERY SIMPLE CATEGORIES. 1819 01:26:06,920 --> 01:26:09,480 IF YOU THINK ABOUT IT, WE ONLY 1820 01:26:09,480 --> 01:26:11,800 HAVE REALLY 5 DIFFERENT 1821 01:26:11,800 --> 01:26:13,000 TREATMENT MODALITIES AVAILABLE. 1822 01:26:13,000 --> 01:26:15,800 FIRST IS SMALL MOLECULES WHICH 1823 01:26:15,800 --> 01:26:17,240 IS STILL THE MAINSTAY OF 1824 01:26:17,240 --> 01:26:18,720 TREATMENT FOR MANY DISEASES. 1825 01:26:18,720 --> 01:26:25,640 WE HAVE PROTEIN REPLACEMENT 1826 01:26:25,640 --> 01:26:26,880 STRATEGIES FOR AND 1827 01:26:26,880 --> 01:26:28,480 ANTIBODY-BASED TREATMENTS FOR 1828 01:26:28,480 --> 01:26:29,920 IMMUNE MEDIATED DISORDERS AND 1829 01:26:29,920 --> 01:26:34,880 TWO EMERGING CATEGORIES OF 1830 01:26:34,880 --> 01:26:36,080 MOLECULAR TREATMENTS THAT 1831 01:26:36,080 --> 01:26:45,240 SUMMARIZE OLIGO NUCLEOTIDES AND 1832 01:26:45,240 --> 01:26:47,280 MOLECULAR TREATMENTS AND THE 1833 01:26:47,280 --> 01:26:47,960 APPROACH WE TOOK AT BOSTON 1834 01:26:47,960 --> 01:26:49,040 CHILDREN'S HOSPITAL IS TO SAY 1835 01:26:49,040 --> 01:26:51,760 WE'RE GOING TO TRY TO FILL SOME 1836 01:26:51,760 --> 01:26:53,600 OF THESE GAPS FOR THIS GROUP OF 1837 01:26:53,600 --> 01:26:53,880 DISORDERS. 1838 01:26:53,880 --> 01:27:03,280 WE CAME UP OVER THE LAST YEARS 1839 01:27:03,280 --> 01:27:04,080 WITH A PROGRAM IN CLINIC 1840 01:27:04,080 --> 01:27:05,920 RESEARCH AND WE STARTED A 1841 01:27:05,920 --> 01:27:09,480 NATURAL HISTORY STUDY 1842 01:27:09,480 --> 01:27:10,960 SPECIFICALLY FOR CHILD ONSET SPG 1843 01:27:10,960 --> 01:27:13,880 BECAUSE WE NOTED THERE WAS A GAP 1844 01:27:13,880 --> 01:27:16,040 FOR THAT KIND OF RESEARCH AND 1845 01:27:16,040 --> 01:27:18,680 THAT NOW INCLUDES A LONGITUDINAL 1846 01:27:18,680 --> 01:27:20,800 NATURAL HISTORY STUDY LOOKING AT 1847 01:27:20,800 --> 01:27:26,240 CLINICAL OUTCOME PARAMETERS, 1848 01:27:26,240 --> 01:27:27,760 NEUROIMAGING AND QUALITY OF LIFE 1849 01:27:27,760 --> 01:27:28,360 AND BIOMARKERS. 1850 01:27:28,360 --> 01:27:31,760 AND THIS COMES FROM MY OWN 1851 01:27:31,760 --> 01:27:37,200 CLINICAL PRACTICE, MANY ARE NOW 1852 01:27:37,200 --> 01:27:39,480 ABLE TO RECEIVE SOME FORM OF 1853 01:27:39,480 --> 01:27:41,480 SEQUENCING BUT DON'T ALWAYS FIND 1854 01:27:41,480 --> 01:27:43,760 A DIAGNOSIS AND WE USE MORE 1855 01:27:43,760 --> 01:27:47,760 ADVANCED MOLECULAR TESTING IN 1856 01:27:47,760 --> 01:27:50,160 THESE CASES TO DETERMINE THE 1857 01:27:50,160 --> 01:27:51,400 ETIOLOGY AND ON THE BASIC 1858 01:27:51,400 --> 01:27:52,920 SCIENCE SIDE WE'RE CONDUCTING 1859 01:27:52,920 --> 01:27:56,480 SMALL MOLECULE SCREENS AND 1860 01:27:56,480 --> 01:27:59,680 WORKING WITH MANY COLLABORATORS 1861 01:27:59,680 --> 01:28:03,440 ON THERAPIES WITH GENE 1862 01:28:03,440 --> 01:28:04,520 REPLACEMENT APPROACHES. 1863 01:28:04,520 --> 01:28:06,680 WE HAVE THE TWO PARTS OF OUR 1864 01:28:06,680 --> 01:28:09,640 PROGRAM MOST OF THE BASIC 1865 01:28:09,640 --> 01:28:10,120 SIGNI 1866 01:28:10,120 --> 01:28:11,280 SCIENCE WORK IS DIRECTED AT 1867 01:28:11,280 --> 01:28:13,560 OTHER FORMS OF HSP BUT IN 1868 01:28:13,560 --> 01:28:14,040 PRINCIPLE THE SAME 1869 01:28:14,040 --> 01:28:16,240 INFRASTRUCTURE I THINK WE AS A 1870 01:28:16,240 --> 01:28:20,800 COMMUNITY NEED TO BUILD FOR 1871 01:28:20,800 --> 01:28:21,320 SPG4. 1872 01:28:21,320 --> 01:28:22,880 I WANT TO SPEND TWO MINUTES 1873 01:28:22,880 --> 01:28:26,000 QUICKLY TALKING ABOUT THE WAY WE 1874 01:28:26,000 --> 01:28:27,160 CONDUCT OUR NATURAL CASE STUDY 1875 01:28:27,160 --> 01:28:34,520 AND MOVE TO OUR FINDINGS. 1876 01:28:34,520 --> 01:28:35,720 IN OUR NATURAL HISTORY STUDY WE 1877 01:28:35,720 --> 01:28:39,120 HAVE THE INITIAL VISIT AND WE 1878 01:28:39,120 --> 01:28:44,080 TAKE A BROAD CLINICAL APPROACH 1879 01:28:44,080 --> 01:28:45,880 THROUGH 169 IN A CLINICAL 1880 01:28:45,880 --> 01:28:47,120 QUESTIONNAIRE AND THE GOAL IS TO 1881 01:28:47,120 --> 01:28:48,200 HAVE A BROAD REPRESENTATION OF 1882 01:28:48,200 --> 01:28:48,840 ALL POSSIBLE SYMPTOMS. 1883 01:28:48,840 --> 01:28:50,880 WE TAKE THIS APPROACH BECAUSE WE 1884 01:28:50,880 --> 01:28:53,160 ACKNOWLEDGED THAT IN MANY CASES 1885 01:28:53,160 --> 01:28:57,480 OUR INDUSTRYING OF THE 1886 01:28:57,480 --> 01:28:59,760 PHENOTYPIC SPECTRUM OF THE 1887 01:28:59,760 --> 01:29:00,720 DISEASE HAS LIMIT. 1888 01:29:00,720 --> 01:29:03,480 SO WE WANT TO BE AS BROAD AS 1889 01:29:03,480 --> 01:29:05,760 POSSIBLE AT THIS EARLY STAGE. 1890 01:29:05,760 --> 01:29:08,080 THEN AS REBECCA INTRODUCED, WE 1891 01:29:08,080 --> 01:29:13,480 USED A NUMBER OF RATING SCALES 1892 01:29:13,480 --> 01:29:16,120 INCLUDING THE SPASTIC PARAPLEGIA 1893 01:29:16,120 --> 01:29:19,720 SCALES AND INCLUDE A 1894 01:29:19,720 --> 01:29:20,360 HEALTH-RELATED QUALITY OF LIFE 1895 01:29:20,360 --> 01:29:21,560 ASSESSMENT. 1896 01:29:21,560 --> 01:29:24,280 WE ALSO REVIEW BRAIN MRI SCANS 1897 01:29:24,280 --> 01:29:26,040 OBTAINED ON A CLINICAL AND 1898 01:29:26,040 --> 01:29:27,840 COLLECT BLOOD SAMPLES AS PART OF 1899 01:29:27,840 --> 01:29:31,680 A BIO REPOSITORY AND THEN SELECT 1900 01:29:31,680 --> 01:29:33,440 CASES OF FIBROBLASTS. 1901 01:29:33,440 --> 01:29:36,360 THEN WE MOVE TO OUR FOLLOW-UP 1902 01:29:36,360 --> 01:29:38,880 AND LONGITUDINAL PHASE AS A MORE 1903 01:29:38,880 --> 01:29:41,320 CLINICAL QUESTIONNAIRE AND WE 1904 01:29:41,320 --> 01:29:45,480 USED THE SAME AND COLLECT BLOOD 1905 01:29:45,480 --> 01:29:47,280 SAMPLES. 1906 01:29:47,280 --> 01:29:49,000 THAT'S THE FRAMEWORK AND IN OUR 1907 01:29:49,000 --> 01:29:50,440 WORK WITH THE NATURAL HISTORY 1908 01:29:50,440 --> 01:29:56,360 STUDY WE CAME ACROSS A NUMBER OF 1909 01:29:56,360 --> 01:29:59,760 YOUNG PATIENTS WITH SPG4 AND 1910 01:29:59,760 --> 01:30:01,040 NOTED THAT MANY HAD DE NOVO 1911 01:30:01,040 --> 01:30:03,040 VARIANTS AND THAT LED US SIMILAR 1912 01:30:03,040 --> 01:30:04,760 TO THE NIH TEAM TO THIS 1913 01:30:04,760 --> 01:30:06,760 PUBLICATION THAT FIRST 1914 01:30:06,760 --> 01:30:08,480 PRESCRIBED THAT CHILDREN WITH DE 1915 01:30:08,480 --> 01:30:09,880 NOVO MUTATIONS OR INDIVIDUALS 1916 01:30:09,880 --> 01:30:11,720 WITH DE NOVO MUTATIONS TEND TO 1917 01:30:11,720 --> 01:30:16,600 HAVE FEATURES NOT AS COMMONLY 1918 01:30:16,600 --> 01:30:18,680 SEEN IN THE CLASSIC FAMILIAL 1919 01:30:18,680 --> 01:30:20,360 FORMS AND BROUGHT US TOGETHER. 1920 01:30:20,360 --> 01:30:23,240 I'LL BE PRESENTING IN OUR 1921 01:30:23,240 --> 01:30:24,800 EXPERIENCE FROM 17 INDIVIDUALS 1922 01:30:24,800 --> 01:30:26,880 WITH DE NOVO SPG4 VARIANTS. 1923 01:30:26,880 --> 01:30:29,680 SO THIS IS JUST A BASIC OVERVIEW 1924 01:30:29,680 --> 01:30:30,720 OF THE DEMOGRAPHIC INFORMATION 1925 01:30:30,720 --> 01:30:35,720 HERE AND I SHOULD SAY THIS IS 1926 01:30:35,720 --> 01:30:37,720 CROSS-SECTIONAL ANALYSIS. 1927 01:30:37,720 --> 01:30:38,960 THERE ARE LIMITATIONS TO 1928 01:30:38,960 --> 01:30:40,320 CONCLUSIONS ONE CAN DRAW FROM 1929 01:30:40,320 --> 01:30:42,040 THE DATA. 1930 01:30:42,040 --> 01:30:43,720 THESE 17 PARTICIPANTS CAME 1931 01:30:43,720 --> 01:30:46,680 MOSTLY FROM THE U.S. ABOUT 1932 01:30:46,680 --> 01:30:49,080 TWO-THIRDS AND A THIRD FROM 1933 01:30:49,080 --> 01:30:51,240 OUTSIDE THE UNITED STATES. 1934 01:30:51,240 --> 01:30:55,760 YOU SEE WE HAD ROUGHLY EQUAL 1935 01:30:55,760 --> 01:30:57,480 REPRESENTATION OF MALE AND 1936 01:30:57,480 --> 01:30:59,760 FEMALE AND I WANT TO DRAW YOUR 1937 01:30:59,760 --> 01:31:02,760 ATTENTION TO THE AGE AT LAST 1938 01:31:02,760 --> 01:31:03,680 FOLLOW UP REPRESENTING THE AGE 1939 01:31:03,680 --> 01:31:06,120 SPECTRUM AND THE COHORT. 1940 01:31:06,120 --> 01:31:07,520 THE AGE OF SYMPTOM ONSET. 1941 01:31:07,520 --> 01:31:10,040 WHAT WAS THE FIRST REPORTED 1942 01:31:10,040 --> 01:31:10,440 SYSTEM? 1943 01:31:10,440 --> 01:31:11,040 PARENT REPORTED. 1944 01:31:11,040 --> 01:31:14,320 THEN LASTLY, THE AGE AT A 1945 01:31:14,320 --> 01:31:15,040 MOLECULAR DIAGNOSIS. 1946 01:31:15,040 --> 01:31:16,400 I THINK A LOT OF INFORMATION CAN 1947 01:31:16,400 --> 01:31:17,640 BE GAINED FROM THE THREE 1948 01:31:17,640 --> 01:31:17,880 NUMBERS. 1949 01:31:17,880 --> 01:31:20,480 SO FIRST THE AGE OF FOLLOW UP 1950 01:31:20,480 --> 01:31:21,960 AND VICTORY AGE OF 9 YEARS. 1951 01:31:21,960 --> 01:31:25,000 YOU SEE THE DISTRIBUTION OF AGES 1952 01:31:25,000 --> 01:31:26,360 HERE RANGING FROM TWO YEARS OF 1953 01:31:26,360 --> 01:31:28,080 AGE TO 19 YEARS OF AGE AT THE 1954 01:31:28,080 --> 01:31:31,720 TIME OF ENROLLMENT. 1955 01:31:31,720 --> 01:31:35,520 THE AGE AT SYMPTOM OUTSET IS 1956 01:31:35,520 --> 01:31:37,640 MUCH EARLIER. 1957 01:31:37,640 --> 01:31:39,120 ALL PATIENTS PRESENT IN THE 1958 01:31:39,120 --> 01:31:42,560 FIRST TWO YEARS OF LIFE USUALLY 1959 01:31:42,560 --> 01:31:44,720 WITH MOTOR DELAY AND IN CONTRAST 1960 01:31:44,720 --> 01:31:47,480 YOU SEE THE AGE AT THE MOLECULAR 1961 01:31:47,480 --> 01:31:49,680 DIAGNOSIS WHICH IN THIS COHORT 1962 01:31:49,680 --> 01:31:51,800 GRANTED MOSTLY PATIENTS WITH 1963 01:31:51,800 --> 01:31:53,680 ACCESS TO HEALTH CARE AND 1964 01:31:53,680 --> 01:31:55,760 TERTIARY CARE THE MEAN AGE WAS 1965 01:31:55,760 --> 01:31:58,960 STILL 6 YEARS SO THERE'S A 1966 01:31:58,960 --> 01:31:59,560 SIGNIFICANT DIAGNOSTIC DELAY 1967 01:31:59,560 --> 01:32:00,200 STILL AND THAT'S SOMETHING WE 1968 01:32:00,200 --> 01:32:13,400 NEED TO WORK ON. 1969 01:32:13,400 --> 01:32:15,760 WHEN WE LOOKED AT THE MOLECULAR 1970 01:32:15,760 --> 01:32:20,000 SPECTRUM THE VAST MAJORITY OF DE 1971 01:32:20,000 --> 01:32:23,200 NOVO ARE CAUSED BY MUTATIONS AND 1972 01:32:23,200 --> 01:32:24,360 IT'S IMPORTANT TO DISCUSS TODAY 1973 01:32:24,360 --> 01:32:28,840 AND TOMORROW BECAUSE IT DOES 1974 01:32:28,840 --> 01:32:31,720 RAISE THE QUESTION WHETHER 1975 01:32:31,720 --> 01:32:41,800 CLASSIC FAMILIAL FORMS AND THE 1976 01:32:41,800 --> 01:32:46,160 NOBLE VARIANTS SHARE THE SAME 1977 01:32:46,160 --> 01:32:49,520 ETIOLOGY AND YOU SEE BASED ON 1978 01:32:49,520 --> 01:32:51,480 THE COMPUTER MODELLING MISSING 1979 01:32:51,480 --> 01:32:54,640 VARIANTS ARE TOLERATED VERSUS 1980 01:32:54,640 --> 01:32:55,760 NOT TOLERATED IN THE COMPUTER 1981 01:32:55,760 --> 01:32:58,680 MODELS AGREE WITH OUR FINDINGS 1982 01:32:58,680 --> 01:33:01,400 IN THAT MOST OF THE MISSING 1983 01:33:01,400 --> 01:33:03,480 VARIANTS AND THE TRIPLE A DOMAIN 1984 01:33:03,480 --> 01:33:04,760 IS PREDICTED TO BE DISEASE. 1985 01:33:04,760 --> 01:33:09,440 IN ITS COHORT WE ONLY HAVE ONE 1986 01:33:09,440 --> 01:33:11,280 TRUNCATED VARIANTS. 1987 01:33:11,280 --> 01:33:13,480 ALL OTHERS ARE MISSING VARIANTS 1988 01:33:13,480 --> 01:33:15,760 AND IN A PARTICULAR VARIANT WAS 1989 01:33:15,760 --> 01:33:16,560 RELATIVELY COMMON OCCURRING IN 1990 01:33:16,560 --> 01:33:20,800 FIVE INDIVIDUALS IN THIS COHORT. 1991 01:33:20,800 --> 01:33:23,120 SO WHAT DID LEARN ABOUT THE 1992 01:33:23,120 --> 01:33:24,680 CLINICAL SPECTRUM AND AGAIN THIS 1993 01:33:24,680 --> 01:33:27,440 IS A CROSS-SECTIONAL ANALYSIS SO 1994 01:33:27,440 --> 01:33:29,360 THERE'S A LOT OF LIMITATIONS 1995 01:33:29,360 --> 01:33:30,040 HERE. 1996 01:33:30,040 --> 01:33:33,000 THE FIRST SYMPTOM IS USUALLY 1997 01:33:33,000 --> 01:33:33,280 MOTOR DELAY. 1998 01:33:33,280 --> 01:33:37,720 YOU SEE ON THE LEFT YOU SEE THE 1999 01:33:37,720 --> 01:33:41,480 MILESTONES AND THE PERCENTAGE OF 2000 01:33:41,480 --> 01:33:43,000 INDIVIDUALS THAT ACHIEVE THESE 2001 01:33:43,000 --> 01:33:43,800 MILESTONES AND SEE THE AVERAGE 2002 01:33:43,800 --> 01:33:47,360 AGE AT WHICH THEY'RE ACHIEVED. 2003 01:33:47,360 --> 01:33:50,880 YOU SEE, FOR EXAMPLE, A MAJORITY 2004 01:33:50,880 --> 01:33:53,880 OF PATIENTS ACHIEVE ASSISTED 2005 01:33:53,880 --> 01:33:56,640 WALK AND AT A SIGNIFICANTLY 2006 01:33:56,640 --> 01:33:57,200 DELAYED AGE. 2007 01:33:57,200 --> 01:33:59,600 SO MOTOR DELAY REALLY IS THE 2008 01:33:59,600 --> 01:34:01,880 FIRST SYMPTOM IN THE SYNDROME. 2009 01:34:01,880 --> 01:34:06,320 AND I THINK IT'S ONE THAT 2010 01:34:06,320 --> 01:34:07,680 NEUROLOGISTS NEED TO PICK UP 2011 01:34:07,680 --> 01:34:09,840 EARLY AND REFER TO GENETIC 2012 01:34:09,840 --> 01:34:10,280 TESTING FOR. 2013 01:34:10,280 --> 01:34:11,760 THE SECOND LESSON WE LEARNED 2014 01:34:11,760 --> 01:34:13,160 ABOUT MORE DEVELOPMENT CAME FROM 2015 01:34:13,160 --> 01:34:14,880 A CROSS-SECTIONAL ANALYSIS OF 2016 01:34:14,880 --> 01:34:18,840 THE LEVEL OF AMBULATION AT 2017 01:34:18,840 --> 01:34:20,960 ENROLLMENT AND WHAT WE LEARNED 2018 01:34:20,960 --> 01:34:25,320 IS THAT THE MAJORITY OF PATIENTS 2019 01:34:25,320 --> 01:34:27,000 REQUIRE WHEELCHAIR FOR LONGER 2020 01:34:27,000 --> 01:34:28,160 DISTANCES AND YOU SEE THE 2021 01:34:28,160 --> 01:34:31,160 AVERAGE AGE AT WHICH WALKING OR 2022 01:34:31,160 --> 01:34:32,600 WHEELCHAIR WERE MORE COMMONLY 2023 01:34:32,600 --> 01:34:34,880 USED AND THAT'S QUITE EARLY. 2024 01:34:34,880 --> 01:34:36,240 THERE SEEMS TO BE A LOT OF 2025 01:34:36,240 --> 01:34:39,520 PROGRESSION EARLY ON AND THAT'S 2026 01:34:39,520 --> 01:34:43,800 ALSO REFLECTED IN THIS 2027 01:34:43,800 --> 01:34:46,280 RETROSPECTIVE ANALYSIS OF MOTOR 2028 01:34:46,280 --> 01:34:47,800 DISABILITY. 2029 01:34:47,800 --> 01:34:58,360 THIS IS A 7 POINT SCALE THAT 2030 01:34:58,360 --> 01:35:01,600 BASICALLY QUANTIFIES THE DEGREE 2031 01:35:01,600 --> 01:35:06,000 AND CHANGES WITH AGE QUICKLY AT 2032 01:35:06,000 --> 01:35:11,360 STAGE 6 IT'S WHEELCHAIR 2033 01:35:11,360 --> 01:35:11,760 DEPENDENT. 2034 01:35:11,760 --> 01:35:15,000 THAT'S OFTEN PRESENTED EARLY. 2035 01:35:15,000 --> 01:35:18,080 THE DEFINING FEATURE OF THIS 2036 01:35:18,080 --> 01:35:23,800 DISEASE IS SPASTICITY AND WE 2037 01:35:23,800 --> 01:35:27,840 FOUND UPPER LIMB SPASTICITY WAS 2038 01:35:27,840 --> 01:35:29,680 PRESENT IN A QUARTER OF THE 2039 01:35:29,680 --> 01:35:31,760 PATIENTS AND THE AVERAGE AGE AND 2040 01:35:31,760 --> 01:35:33,480 THIS IS CROSS SECTIONAL WAS 2041 01:35:33,480 --> 01:35:35,760 HIGHER THAN THE AVERAGE AGE OF 2042 01:35:35,760 --> 01:35:46,880 PATIENTS WHO ONLY HAD LOWER LIMB 2043 01:35:46,880 --> 01:35:50,560 SPACTICITY AND WE SEE THE 2044 01:35:50,560 --> 01:35:52,960 TYPICAL SIGNS TO LOOK FOR AND WE 2045 01:35:52,960 --> 01:35:57,520 SAW HYPERREFLEXIA AND IN A 2046 01:35:57,520 --> 01:36:01,480 MAJORITY OF PATIENTS, 2047 01:36:01,480 --> 01:36:03,360 CONTRACTURES AND THIS MAY BE 2048 01:36:03,360 --> 01:36:07,760 BECAUSE WE'RE ATTUNE TO LOOKING 2049 01:36:07,760 --> 01:36:10,680 AND WE FOUND EVIDENCE OF 2050 01:36:10,680 --> 01:36:13,800 MOVEMENT DISORDERS INCLUDING 2051 01:36:13,800 --> 01:36:19,480 DYSTONIA IN 40% OF PATIENTS. 2052 01:36:19,480 --> 01:36:21,360 LOOK BEING AT OTHER DOMAINS OF 2053 01:36:21,360 --> 01:36:23,280 DEVELOPMENT WE FOUND SPEECH 2054 01:36:23,280 --> 01:36:25,000 DELAY WAS ALMOST UNIVERSAL. 2055 01:36:25,000 --> 01:36:29,280 ABOUT A QUARTER OF PATIENTS WERE 2056 01:36:29,280 --> 01:36:34,880 MOSTLY NON-VERBAL AND PATIENTS 2057 01:36:34,880 --> 01:36:39,520 WITH VERBAL COMMUNICATION WE 2058 01:36:39,520 --> 01:36:42,760 FOUND DYS-PAIGE 2059 01:36:50,280 --> 01:36:53,640 DISPAGIA WAS COMMON AND THIS WAS 2060 01:36:53,640 --> 01:36:55,040 CLINICIAN RATED AND AT A 2061 01:36:55,040 --> 01:36:57,120 DISTRIBUTION OF A THIRD, A THIRD 2062 01:36:57,120 --> 01:36:57,920 AND A THIRD. 2063 01:36:57,920 --> 01:37:00,080 MEANING A THIRD OF PATIENTS HAD 2064 01:37:00,080 --> 01:37:01,480 NO COGNITIVE DEFICITS AND A 2065 01:37:01,480 --> 01:37:04,680 THIRD OF PATIENTS WERE JUDGED TO 2066 01:37:04,680 --> 01:37:09,480 HAVE MILD COGNITIVE DEFICITS AND 2067 01:37:09,480 --> 01:37:12,280 A THIRD JUDGED FOR AWHILE 2068 01:37:12,280 --> 01:37:12,760 DEFICITS. 2069 01:37:12,760 --> 01:37:14,720 THEY ASKED DO THEY THINK THE 2070 01:37:14,720 --> 01:37:16,000 DEFICITS HAVE PROGRESSED OVER 2071 01:37:16,000 --> 01:37:18,360 THE YEARS AND A THIRD OF 2072 01:37:18,360 --> 01:37:19,800 FAMILIES SAID THEY FELT THE 2073 01:37:19,800 --> 01:37:21,640 DEFICITS WERE INDEED 2074 01:37:21,640 --> 01:37:24,680 PROGRESSIVE. 2075 01:37:24,680 --> 01:37:26,880 NOW, IN TERMS OF OTHER SYMPTOMS 2076 01:37:26,880 --> 01:37:31,800 THAT WE LOOKED FOR WE FOUND THE 2077 01:37:31,800 --> 01:37:33,480 NEURO GENETIC BLADDER DISORDER 2078 01:37:33,480 --> 01:37:35,760 WAS COMMON AND INCONTINENCE AND 2079 01:37:35,760 --> 01:37:38,120 AT SOME STAGE OF THE DISEASE IT 2080 01:37:38,120 --> 01:37:39,760 WAS PRESENT AND PATIENTS WHERE 2081 01:37:39,760 --> 01:37:42,200 THIS WAS PRESENT A THIRD HAS 2082 01:37:42,200 --> 01:37:45,480 EVIDENCE OF ABNORMAL SWELLING 2083 01:37:45,480 --> 01:37:49,640 AND IN CONTRAST TO THE CLASSIC 2084 01:37:49,640 --> 01:37:54,920 FAMILIAL FORM AND TO ME SPEAKS 2085 01:37:54,920 --> 01:37:56,880 TO ME AS SOMETHING THAT POINTS A 2086 01:37:56,880 --> 01:37:58,880 DIFFERENCE IN ETIOLOGY ABOUT A 2087 01:37:58,880 --> 01:38:01,280 THIRD OF PATIENTS WITH DE NOVO 2088 01:38:01,280 --> 01:38:05,680 SPG4 HAD SEIZURES WHICH IS QUITE 2089 01:38:05,680 --> 01:38:08,920 UNCOMMON IN THE FAMILIAL FORM 2090 01:38:08,920 --> 01:38:11,720 AND A QUARTER QUALIFIED FOR A 2091 01:38:11,720 --> 01:38:13,840 DIAGNOSIS OF EPILEPSY BASED ON 2092 01:38:13,840 --> 01:38:19,720 TWO UNPROVOKED SEIZURES OR TREAT 2093 01:38:19,720 --> 01:38:30,800 TREATED WITH ANTIEPILEPTIC DRUGS 2094 01:38:30,800 --> 01:38:32,400 AND TREATMENT INCLUDED THE USUAL 2095 01:38:32,400 --> 01:38:35,680 SYMPTOMATIC TREATMENT APPROACHES 2096 01:38:35,680 --> 01:38:38,520 TO SPACTICITY INCLUDING 2097 01:38:38,520 --> 01:38:43,760 MEDICATIONS AND IN SOME CASES 2098 01:38:43,760 --> 01:38:50,040 BOTOX INJECTIONS WITH A BACLOFEN 2099 01:38:50,040 --> 01:38:52,480 PUMP AND RATED ON THE SPASTIC 2100 01:38:52,480 --> 01:38:55,680 PARAPLEGIA RATING SCALE WE FOUND 2101 01:38:55,680 --> 01:38:57,480 A MODERATE LEVEL OF DYSFUNCTION 2102 01:38:57,480 --> 01:38:59,000 BY AN AVERAGE SCORE OF 30. 2103 01:38:59,000 --> 01:39:06,920 I'M PLOTTING OUT HERE THE SPR 2104 01:39:06,920 --> 01:39:10,360 ITEMS TO SHOW 11, 12 AND 13 HAD 2105 01:39:10,360 --> 01:39:12,760 LOWER SCORES, CONTRACTURES AND 2106 01:39:12,760 --> 01:39:16,680 PAIN AND BLADDER DYSFUNCTION. 2107 01:39:16,680 --> 01:39:17,320 A LITTLE BIT OF A DIFFERENCE IN 2108 01:39:17,320 --> 01:39:19,280 THE DE NOVO AND FAMILIAR CASES 2109 01:39:19,280 --> 01:39:19,720 POTENTIALLY. 2110 01:39:19,720 --> 01:39:23,040 I ALSO WANT TO POINT OUT AND 2111 01:39:23,040 --> 01:39:25,680 THIS IS SOMETHING THE SPASTIC 2112 01:39:25,680 --> 01:39:30,840 PARAPLEGIA RATING SCALE IS A 2113 01:39:30,840 --> 01:39:34,240 GREAT OUTCOME SCALE AND HAS NOD 2114 01:39:34,240 --> 01:39:37,240 BEEN VALIDATED IN CHILDREN UNDER 2115 01:39:37,240 --> 01:39:39,680 AND THAT'S AN IMPORTANT 2116 01:39:39,680 --> 01:39:42,040 LIMITATION HERE. 2117 01:39:42,040 --> 01:39:43,240 AND IN THE LAST MINUTE I WANT TO 2118 01:39:43,240 --> 01:39:44,440 TALK ABOUT FUTURE DIRECTIONS FOR 2119 01:39:44,440 --> 01:39:45,480 OUR TEAM. 2120 01:39:45,480 --> 01:39:50,560 FOR THE CURRENT CROSS-SECTIONAL 2121 01:39:50,560 --> 01:39:51,720 ANALYSIS WE'RE HOPING TO PULL 2122 01:39:51,720 --> 01:39:54,240 INFORMATION FROM SEVERAL 2123 01:39:54,240 --> 01:39:54,600 COHORTS. 2124 01:39:54,600 --> 01:39:59,880 WE HAD DISCUSSIONS WITH OUR 2125 01:39:59,880 --> 01:40:01,240 COLLABORATE E 2126 01:40:01,240 --> 01:40:03,560 COLLABORATORS THE QUESTION IS 2127 01:40:03,560 --> 01:40:04,920 CAN WE DERIVE MORE GENERAL 2128 01:40:04,920 --> 01:40:07,120 TRENDS FROM THE CROSS-SECTIONAL 2129 01:40:07,120 --> 01:40:08,800 ANALYSIS AND HOPING TO ANSWER 2130 01:40:08,800 --> 01:40:09,680 THAT QUESTION. 2131 01:40:09,680 --> 01:40:14,840 WE'RE ALSO REACHING OUT TO 2132 01:40:14,840 --> 01:40:16,440 COLLECT BLOOD SAMPLES FOR 2133 01:40:16,440 --> 01:40:18,760 BIOMARKER DISCOVERY AND I THINK 2134 01:40:18,760 --> 01:40:20,520 IT WILL BE IMPORTANT FOR US IN 2135 01:40:20,520 --> 01:40:22,160 THE ROOM TRYING TO ANSWER HOW 2136 01:40:22,160 --> 01:40:22,920 MUCH OF THE EARLY PRESENTATION 2137 01:40:22,920 --> 01:40:27,240 IS INDEED PART OF THE PHENOTYPES 2138 01:40:27,240 --> 01:40:30,880 AND WANTING TO LOOK AT MARKERS 2139 01:40:30,880 --> 01:40:34,040 IN BLOOD SAMPLES AND THAT'S AN 2140 01:40:34,040 --> 01:40:35,720 ONGOING EFFORT AND WE'RE HOPING 2141 01:40:35,720 --> 01:40:39,360 TO USE A QUESTIONNAIRE WE USED 2142 01:40:39,360 --> 01:40:41,080 IN OTHER FORMS OF ONSET TO GET A 2143 01:40:41,080 --> 01:40:42,080 SENSE OF WHAT AREAS ARE 2144 01:40:42,080 --> 01:40:44,320 IMPORTANT TO FAMILIES ON A DAY 2145 01:40:44,320 --> 01:40:45,680 TO DAY BASIS AND TO PROVIDE THIS 2146 01:40:45,680 --> 01:40:47,760 AS A QUANTITATIVE OUTCOME 2147 01:40:47,760 --> 01:40:50,280 MACHINE. 2148 01:40:50,280 --> 01:40:51,680 -- MEASURE AND WE'RE HOPING TO 2149 01:40:51,680 --> 01:40:53,320 EXTEND TO A LONGITUDINAL PHASE 2150 01:40:53,320 --> 01:40:55,160 AND CONTINUE ENROLLMENT AND 2151 01:40:55,160 --> 01:40:58,400 AGAIN THE GOAL IS TO PROMOTE AND 2152 01:40:58,400 --> 01:41:00,720 SUPPORT CLINICAL TRIAL READINESS 2153 01:41:00,720 --> 01:41:03,480 TO DESCRIBE THE SYMPTOMS AND WE 2154 01:41:03,480 --> 01:41:04,440 CAN RATE THEIR IMPORTANCE AND 2155 01:41:04,440 --> 01:41:05,760 MAKE THE CASE THAT WE NEED TO 2156 01:41:05,760 --> 01:41:07,760 DEVELOP THERAPIES FOR THIS 2157 01:41:07,760 --> 01:41:09,680 CONDITION QUICKLY. 2158 01:41:09,680 --> 01:41:11,760 WITH THIS I'LL COME TO MY 2159 01:41:11,760 --> 01:41:14,640 SUMMARY AND I HOPE I WAS ABLE TO 2160 01:41:14,640 --> 01:41:18,280 SHOW YOU DE NOVO SPG4 IS A 2161 01:41:18,280 --> 01:41:20,040 COMPLEX DISEASE IN CHILDREN AND 2162 01:41:20,040 --> 01:41:23,720 IT HAS A BROAD RANGE WHEN IT 2163 01:41:23,720 --> 01:41:24,880 COMES TO SYSTEMS DIFFERENT FROM 2164 01:41:24,880 --> 01:41:28,680 SPG4 AND I HOPE I WAS ABLE TO 2165 01:41:28,680 --> 01:41:33,200 SHOW AN INTERNATIONAL EFFORT A 2166 01:41:33,200 --> 01:41:35,000 REGISTRY OF NATIONAL HISTORY 2167 01:41:35,000 --> 01:41:36,640 STUDY CAN HELP THE END POINTS OF 2168 01:41:36,640 --> 01:41:37,680 FUTURE TRIALS AND A WANT TO 2169 01:41:37,680 --> 01:41:39,080 THANK MY TEAM AND THE MANY 2170 01:41:39,080 --> 01:41:41,640 COLLABORATORS WHO CONTRIBUTED TO 2171 01:41:41,640 --> 01:41:45,000 THIS AND FUNDING SOURCES AND OUR 2172 01:41:45,000 --> 01:41:45,360 CONTACT DETAILS. 2173 01:41:45,360 --> 01:41:57,160 SO THANKS FOR YOUR ATTENTION. 2174 01:41:57,160 --> 01:42:02,000 >> THANKS MUCH, DARIUS. 2175 01:42:02,000 --> 01:42:03,280 UP NEXT IS MICHELLE CHRISTIE. 2176 01:42:03,280 --> 01:42:04,840 >> THANK YOU, I'M HONORED TO BE 2177 01:42:04,840 --> 01:42:06,520 PART OF THIS. 2178 01:42:06,520 --> 01:42:07,920 I KNOW I'M PROBABLY A NEW FACE 2179 01:42:07,920 --> 01:42:09,280 FOR MANY. 2180 01:42:09,280 --> 01:42:09,960 LET ME GO AHEAD AND SHARE MY 2181 01:42:09,960 --> 01:42:28,480 SCREEN. 2182 01:42:28,480 --> 01:42:30,480 SO DARIUS HAD REACHED OUT TO ME 2183 01:42:30,480 --> 01:42:34,080 AND I'M SO GRATEFUL THAT HE DID. 2184 01:42:34,080 --> 01:42:35,720 DOWN IN TEXAS WE ACTUALLY FOLLOW 2185 01:42:35,720 --> 01:42:42,520 A LARGE NUMBER OF PATIENTS WITH 2186 01:42:42,520 --> 01:42:49,480 HEREDITARY SPASTIC PARESIS AND I 2187 01:42:49,480 --> 01:42:55,760 HAVE NO FINANCIAL DISCLOSURES. 2188 01:42:55,760 --> 01:43:00,600 I HAVE A SECONDARY BOARD 2189 01:43:00,600 --> 01:43:06,560 CERTIFIED IN CHILD NEUROLOGY AND 2190 01:43:06,560 --> 01:43:09,120 CLINICAL NEUROPHYSIOLOGY AND MY 2191 01:43:09,120 --> 01:43:11,280 DAUGHTER'S ILL TODAY SO SHE'S IN 2192 01:43:11,280 --> 01:43:12,480 MY LAP. 2193 01:43:12,480 --> 01:43:17,120 I HAVE AN ASSISTANT 2194 01:43:17,120 --> 01:43:18,960 PROFESSORSHIP WITH UT 2195 01:43:18,960 --> 01:43:20,600 SOUTHWESTERN IN A SMALL ROLE BUT 2196 01:43:20,600 --> 01:43:25,160 IN THE GENE THERAPY PROGRAM. 2197 01:43:25,160 --> 01:43:31,720 WE ARE TALKING TO TRY TO CREATE 2198 01:43:31,720 --> 01:43:58,680 A GENE THERAPY. 2199 01:43:58,680 --> 01:43:59,800 AND THIS WAS PRESENTED AND 2200 01:43:59,800 --> 01:44:02,080 THAT'S BEEN MY ROLE TO DO THE 2201 01:44:02,080 --> 01:44:07,200 NERVE STUDIES FOR THE DATA. 2202 01:44:07,200 --> 01:44:11,640 I WORK FOR AN ORTHOPEDIC 2203 01:44:11,640 --> 01:44:11,880 HOSPITAL. 2204 01:44:11,880 --> 01:44:15,160 WE'RE IN DALLAS, TEXAS. 2205 01:44:15,160 --> 01:44:17,720 WE HAVE A LAB AND JUST SO YOU 2206 01:44:17,720 --> 01:44:31,760 KNOW ABOUT PEDIATRIC HSP WHERE I 2207 01:44:31,760 --> 01:44:40,600 WORK AND IT'S ONE OF THE LARGEST 2208 01:44:40,600 --> 01:44:43,800 CLINICS WE FOLLOWED PATIENTS FOR 2209 01:44:43,800 --> 01:45:00,720 GREATER THAN 25 YEARS. 2210 01:45:00,720 --> 01:45:03,160 AND WE HAVE 13 PATIENTS WHO HAVE 2211 01:45:03,160 --> 01:45:15,240 AN INFANTILE ONSET WITH 8 HAVING 2212 01:45:15,240 --> 01:45:20,360 THE DE NOVO MUTATIONS AND WE 2213 01:45:20,360 --> 01:45:23,760 DON'T SEE IN THE COHORT A LARGE 2214 01:45:23,760 --> 01:45:25,160 DIFFERENCE BETWEEN DE NOVO 2215 01:45:25,160 --> 01:45:27,680 MUTATIONS AND INHERITED IN A 2216 01:45:27,680 --> 01:45:34,440 PURE FORM ORCALLY -- OR 2217 01:45:34,440 --> 01:45:35,680 COMPLICATED FORM. 2218 01:45:35,680 --> 01:45:48,800 WE HAVE ONE PATIENT WHO HAD AN 2219 01:45:48,800 --> 01:45:51,720 AND MUTATIONS HAVE BEEN BROUGHT 2220 01:45:51,720 --> 01:45:54,880 UP BY OTHER SPEAKERS. 2221 01:45:54,880 --> 01:45:56,560 I KNEW DARIUS WAS GOING TO DO 2222 01:45:56,560 --> 01:45:58,480 SUCH A GREAT JOB TALKING ABOUT 2223 01:45:58,480 --> 01:46:02,200 THE COHORT IN GENERAL AND THE 2224 01:46:02,200 --> 01:46:03,600 INFORMATION SHARES A LOT OF THE 2225 01:46:03,600 --> 01:46:04,880 SAME THING WE SEE IN OUR 2226 01:46:04,880 --> 01:46:06,480 PATIENTS SO I WANT TO FOCUS ON 2227 01:46:06,480 --> 01:46:12,640 THE LONG-TERM DATA WE HAD. 2228 01:46:12,640 --> 01:46:14,680 SO I WANTED TO LOOK AT THE 2229 01:46:14,680 --> 01:46:15,800 HEREDITARY AND THE DE NOVO. 2230 01:46:15,800 --> 01:46:21,880 WE HAVE THREE PATIENTS PRESENTED 2231 01:46:21,880 --> 01:46:24,680 WITH HEREDITARY ONSET SPG4. 2232 01:46:24,680 --> 01:46:27,200 SOME INTERESTING PARTS AND THE 2233 01:46:27,200 --> 01:46:30,560 END VERY SMALL BUT THERE WAS 2234 01:46:30,560 --> 01:46:32,280 MATERNAL INHERITANCE WITH ALL OF 2235 01:46:32,280 --> 01:46:32,480 THEM. 2236 01:46:32,480 --> 01:46:33,960 SYMPTOMS WERE FIRST NOTED ABOUT 2237 01:46:33,960 --> 01:46:38,280 THE SAME TIME AS THE DE NOVO. 2238 01:46:38,280 --> 01:46:43,160 BETWEEN 4 AND 16 AND 18 MONTHS. 2239 01:46:43,160 --> 01:46:47,800 SO SCORES WERE 2 TO 3 FOR ALL OF 2240 01:46:47,800 --> 01:46:51,080 THEM AND ALL REQUIRED HAMSTRING 2241 01:46:51,080 --> 01:46:58,440 LENGTHENING AND ACHILLES 2242 01:46:58,440 --> 01:46:59,280 STRETCHING AND WITH GROWTH YOU 2243 01:46:59,280 --> 01:47:00,440 NOTE INCREASED CROUCHING OVER 2244 01:47:00,440 --> 01:47:01,640 THE YEARS. 2245 01:47:01,640 --> 01:47:04,640 WE DIDN'T SEE MAJOR DIFFERENCES 2246 01:47:04,640 --> 01:47:09,880 WITHIN THEIR AMBULATION. 2247 01:47:09,880 --> 01:47:12,280 I WANTED TO SHOW THIS BECAUSE 2248 01:47:12,280 --> 01:47:14,680 IT'S MORE THAN ANYTHING AND THIS 2249 01:47:14,680 --> 01:47:18,880 IS A PATIENT WITH AN INHERITED 2250 01:47:18,880 --> 01:47:21,680 FORM AND YOU SEE A SPASTIC GAIT 2251 01:47:21,680 --> 01:47:26,800 AS WE START WALKING. 2252 01:47:26,800 --> 01:47:28,720 AGAIN ALL THESE PATIENTS WILL BE 2253 01:47:28,720 --> 01:47:31,800 GREATER THAN 10-YEAR FOLLOW-UP 2254 01:47:31,800 --> 01:48:02,080 ON THE VIDEOS. 2255 01:48:02,080 --> 01:48:06,120 TO ME IT APPEARS LOWER BUT ARE 2256 01:48:06,120 --> 01:48:07,280 STILL WALKING WITHOUT ASSISTING 2257 01:48:07,280 --> 01:48:09,640 DEVICES AND THIS PATIENT HAS OUR 2258 01:48:09,640 --> 01:48:10,680 LONGEST FOLLOW-UP OF ACTUALLY 2259 01:48:10,680 --> 01:48:56,240 ALMOST 30 YEARS. 2260 01:48:56,240 --> 01:49:54,960 HERE'S ONE THAT NEEDED A WALKER. 2261 01:49:54,960 --> 01:50:01,480 AND THEN HIS GREATER THAN 2262 01:50:01,480 --> 01:50:03,680 10-YEAR FOLLOW-UP AND HE GOES 2263 01:50:03,680 --> 01:50:07,120 BETWEEN HIS WHEELCHAIR AND 2264 01:50:07,120 --> 01:50:09,680 CRUTCHES BUT DOES STILL MOVE 2265 01:50:09,680 --> 01:50:19,200 WITH HIS CRUTCH USE. 2266 01:50:19,200 --> 01:50:21,680 HE ENJOYS PLAYING BASKETBALL AND 2267 01:50:21,680 --> 01:51:00,920 IS A REAL PLEASURE. 2268 01:51:00,920 --> 01:51:03,200 ONE OTHER HEREDITARY LONG-TERM 2269 01:51:03,200 --> 01:51:03,680 FOLLOW-UP. 2270 01:51:03,680 --> 01:51:05,680 YOU CAN SEE VERY MILD GAIT 2271 01:51:05,680 --> 01:51:07,760 DISTURBANCE WHEN THEY INITIALLY 2272 01:51:07,760 --> 01:51:20,560 PRESENTED TO US. 2273 01:51:20,560 --> 01:51:35,440 AND AGAIN THESE ARE ALL SPG4s. 2274 01:51:35,440 --> 01:51:42,880 FOR MORE THAN A 10-YEAR PERIOD 2275 01:51:42,880 --> 01:51:50,720 MAINTAINED A SPASTIC BUT DIDN'T 2276 01:51:50,720 --> 01:51:51,680 NEED DEVICES OVER A LONG-TERM 2277 01:51:51,680 --> 01:52:07,880 PERIOD. 2278 01:52:07,880 --> 01:52:13,600 SO THIS IS OUR DE NOVO COHORT 2279 01:52:13,600 --> 01:52:15,800 AND WE HAVE LONG-TERM FOLLOW-UP 2280 01:52:15,800 --> 01:52:19,760 OF PATIENTS 10 TO 19 YEARS WORTH 2281 01:52:19,760 --> 01:52:22,160 OF FOLLOW-UP ON PATIENTS WITH DE 2282 01:52:22,160 --> 01:52:24,160 NOVO SPG4 MUTATIONS. 2283 01:52:24,160 --> 01:52:28,880 AND WHAT WE SEE SO WE SEE A MIX 2284 01:52:28,880 --> 01:52:32,120 OF BOTH CURE AND COMPLICATED 2285 01:52:32,120 --> 01:52:32,440 PHENOTYPES. 2286 01:52:32,440 --> 01:52:34,840 THEY ALL HAVE MUTATIONS IN 2287 01:52:34,840 --> 01:52:39,680 DIFFERENT AREAS. 2288 01:52:39,680 --> 01:52:46,680 THE PURE FORM WAS AN EYE 2289 01:52:46,680 --> 01:52:47,800 PREDICTIONS DELETION WHERE 2290 01:52:47,800 --> 01:52:53,960 OTHERS WERE UP IN OTHER 2291 01:52:53,960 --> 01:52:55,760 DISCUSSIONS AS WELL. 2292 01:52:55,760 --> 01:52:57,680 AND I THINK THE POINT I WOULD 2293 01:52:57,680 --> 01:53:03,040 LOVE TO BE CHALLENGED ON IT AND 2294 01:53:03,040 --> 01:53:05,080 SEE VIDEOS TOO BUT IF WE 2295 01:53:05,080 --> 01:53:07,080 ACTUALLY DIDN'T SEE A LARGE IN A 2296 01:53:07,080 --> 01:53:09,160 GOOD WAY, A LARGE PROGRESSION IN 2297 01:53:09,160 --> 01:53:11,400 THE PATIENTS SO SOME OF THEM 2298 01:53:11,400 --> 01:53:14,080 WOULD CHOOSE AS THEY GROW TO 2299 01:53:14,080 --> 01:53:16,880 SPEND MORE TIME IN THEIR 2300 01:53:16,880 --> 01:53:19,080 WHEELCHAIR TO INCREASE THEIR 2301 01:53:19,080 --> 01:53:23,080 INDEPENDENCE AND THEIR SPEED. 2302 01:53:23,080 --> 01:53:28,920 HOWEVER, WE DID NOT SEE A GREAT 2303 01:53:28,920 --> 01:53:31,680 CHANGE WITHIN THEIR AMBULATION 2304 01:53:31,680 --> 01:53:34,720 WHEN YOU WATCH THEIR VIDEOS FOR 2305 01:53:34,720 --> 01:53:35,280 A SPLIT SECOND. 2306 01:53:35,280 --> 01:53:36,080 SO HERE'S ONE OF OUR FIRST 2307 01:53:36,080 --> 01:54:10,320 PATIENTS. 2308 01:54:10,320 --> 01:54:11,760 I DO THINK IT WOULD BE NECESSARY 2309 01:54:11,760 --> 01:54:14,080 TO GET TIME TO WALK TEST ON OUR 2310 01:54:14,080 --> 01:54:19,680 PATIENTS TO SEE ARE THEY SLOWER, 2311 01:54:19,680 --> 01:54:21,680 WHAT'S HAPPENING BUT THEY 2312 01:54:21,680 --> 01:54:23,680 OVERALL REQUIRE THE SAME 2313 01:54:23,680 --> 01:54:27,680 ASSISTIVE DEVICES THAT THEY HAVE 2314 01:54:27,680 --> 01:54:39,720 BEEN SINCE EARLY CHILDHOOD. 2315 01:54:39,720 --> 01:55:03,880 HERE'S AND THIS IS A PATIENT 2316 01:55:03,880 --> 01:55:11,760 WITH DE NOVO AGAIN. 2317 01:55:11,760 --> 01:55:42,480 LONG-TERM FOLLOW-UP. 2318 01:55:42,480 --> 01:56:09,120 A PATIENT 3 DE NOVO OVERALL. 2319 01:56:09,120 --> 01:56:13,680 YOU CAN SEE SHE'S STILL WALKING, 2320 01:56:13,680 --> 01:56:15,080 STILL AMBULATING WITHOUT THE USE 2321 01:56:15,080 --> 01:56:16,480 OF ASSISTIVE DEVICES. 2322 01:56:16,480 --> 01:56:18,680 I THINK WE CAN ALL APPRECIATE 2323 01:56:18,680 --> 01:56:23,760 THERE IS A SLIGHT CHANGE IN HER 2324 01:56:23,760 --> 01:56:27,720 GAIT BUT THERE'S NO EXTRA 2325 01:56:27,720 --> 01:56:35,320 DEVICES BEING USED. 2326 01:56:35,320 --> 01:56:36,080 AND IN OUR LAST PATIENT IS 2327 01:56:36,080 --> 01:57:07,800 SIMILAR. 2328 01:57:07,800 --> 01:57:11,280 SIMILAR ON OVER 10 YEARS OF 2329 01:57:11,280 --> 01:57:11,800 FOLLOW-UP. 2330 01:57:11,800 --> 01:57:14,280 WE'RE NOT REQUIRING ADDITIONAL 2331 01:57:14,280 --> 01:57:15,800 ASSISTIVE DEVICES ON OUR SHORT 2332 01:57:15,800 --> 01:57:22,960 AMBULATION STUDIES. 2333 01:57:22,960 --> 01:57:25,480 SO AGAIN THIS IS A SMALL VALUE 2334 01:57:25,480 --> 01:57:29,080 AND IT'S IMPORTANT TO HAVE 2335 01:57:29,080 --> 01:57:30,480 CONFERENCES LIKE THIS AND PULL 2336 01:57:30,480 --> 01:57:32,440 ALL OF OUR PATIENTS TOGETHER. 2337 01:57:32,440 --> 01:57:35,760 ONE THING I NOTICED IS AND IT 2338 01:57:35,760 --> 01:57:39,480 WAS WRITTEN ABOUT BEFORE AND 2339 01:57:39,480 --> 01:57:43,480 PUBLISHED IN ONE CASE WITHIN 2340 01:57:43,480 --> 01:57:45,720 FAMILIES THERE JUST SEEMED TO BE 2341 01:57:45,720 --> 01:57:48,040 AN ELEMENT OF ANTICIPATION WITH 2342 01:57:48,040 --> 01:57:49,400 SPG4s WHERE PARENTS WOULD 2343 01:57:49,400 --> 01:57:52,400 PRESENT MUCH LATER ON AND AS 2344 01:57:52,400 --> 01:57:53,800 GENERATIONS GO BY THEIR CHILDREN 2345 01:57:53,800 --> 01:57:58,280 PRESENT VERY EARLY. 2346 01:57:58,280 --> 01:58:00,800 THIS WOULD BE VERY NEW. 2347 01:58:00,800 --> 01:58:02,440 WE USUALLY LOOK AT THE DISORDERS 2348 01:58:02,440 --> 01:58:05,200 AND SO I WOULD BE FASCINATED BY 2349 01:58:05,200 --> 01:58:08,760 PEOPLE WHO UNDERSTAND GENETICS 2350 01:58:08,760 --> 01:58:12,800 FULLY WHY ARE THESE MUTATIONS 2351 01:58:12,800 --> 01:58:16,280 SHOWING AN ELEMENT OF 2352 01:58:16,280 --> 01:58:17,960 ANTICIPATION AND CAN THAT THEN 2353 01:58:17,960 --> 01:58:19,480 HELP US UNDERSTAND WHY SOME OF 2354 01:58:19,480 --> 01:58:21,680 OUR DE NOVO PATIENTS ARE 2355 01:58:21,680 --> 01:58:24,560 PRESENTING SO EARLY. 2356 01:58:24,560 --> 01:58:26,320 IS THERE SOMETHING ELSE GOING ON 2357 01:58:26,320 --> 01:58:28,080 WITH TRANSCRIPTION OR 2358 01:58:28,080 --> 01:58:30,920 TRANSLATION OR WITH THE PROTEIN 2359 01:58:30,920 --> 01:58:35,680 ITSELF THAT IS AFFECTING THEM SO 2360 01:58:35,680 --> 01:58:36,080 EARLY. 2361 01:58:36,080 --> 01:58:37,880 I HAVE A SECOND QUESTION WHICH I 2362 01:58:37,880 --> 01:58:39,720 KNOW WILL GENERATE A LOT OF 2363 01:58:39,720 --> 01:58:41,080 DISCUSSION AND HOME IT DOES 2364 01:58:41,080 --> 01:58:44,280 LATER ON BUT IS OUR INFANTILE 2365 01:58:44,280 --> 01:58:47,480 FORM OF HSP PROGRESSIVE AT A 2366 01:58:47,480 --> 01:58:49,160 FUNCTIONAL LEVEL FOR LONG 2367 01:58:49,160 --> 01:58:49,480 DISTANCES? 2368 01:58:49,480 --> 01:58:52,040 YES, WE DO SEE A SLIGHT CHANGE 2369 01:58:52,040 --> 01:58:55,000 BUT IS THIS DIFFERENT THAN WHAT 2370 01:58:55,000 --> 01:58:57,560 WE WOULD DUE TO GROWTH IN 2371 01:58:57,560 --> 01:58:59,760 PATIENTS WITH SOMETHING LIKE 2372 01:58:59,760 --> 01:59:03,400 CEREBRAL PALSY WHERE WE KNOW THE 2373 01:59:03,400 --> 01:59:06,280 NEUROLOGIC INJURY IS STAFFIC AND 2374 01:59:06,280 --> 01:59:11,160 FROM OUR CHILDREN'S POINT OF 2375 01:59:11,160 --> 01:59:15,280 VIEW IT WON'T MATTER WHY BUT AS 2376 01:59:15,280 --> 01:59:17,880 WE HAVE WHICH THERAPIES TO USE 2377 01:59:17,880 --> 01:59:19,160 FOR WONDERFUL PATIENTS AND 2378 01:59:19,160 --> 01:59:21,560 BECAUSE GENE THERAPIES ARE 2379 01:59:21,560 --> 01:59:23,360 AMAZING AND I WANT TO ADVANCE 2380 01:59:23,360 --> 01:59:26,600 THEM VERY MUCH I'M PROUD TO BE 2381 01:59:26,600 --> 01:59:29,440 PART OF THE GENE THERAPY 2382 01:59:29,440 --> 01:59:29,680 PROGRAM. 2383 01:59:29,680 --> 01:59:33,160 CURRENTLY THOUGH ALL THE AAB9s 2384 01:59:33,160 --> 01:59:35,360 WE'RE STUDYING ARE FOR FATAL 2385 01:59:35,360 --> 01:59:37,480 DISEASE AND I JUST WANT TO BE 2386 01:59:37,480 --> 01:59:40,200 EXTRA CAREFUL AS A MOTHER MYSELF 2387 01:59:40,200 --> 01:59:42,680 THAT WE'RE SAFE WITH OUR 2388 01:59:42,680 --> 01:59:44,640 PATIENTS WITH HSP BECAUSE 2389 01:59:44,640 --> 01:59:45,720 THEY'RE BEAUTIFUL PATIENTS. 2390 01:59:45,720 --> 01:59:48,040 THEY'RE WONDERFUL AND WE WANT TO 2391 01:59:48,040 --> 01:59:50,480 MAKE SURE WE BALANCE THE SIDE 2392 01:59:50,480 --> 01:59:52,160 EFFECT PROFILES WE'RE GIVING 2393 01:59:52,160 --> 01:59:53,880 THEM TO MAKE SURE WE'RE 2394 01:59:53,880 --> 01:59:56,280 PROLONGING AND IMPROVING THEIR 2395 01:59:56,280 --> 01:59:56,480 LIVES. 2396 01:59:56,480 --> 01:59:58,240 THAT'S MY MAIN POINT. 2397 01:59:58,240 --> 01:59:59,760 I HOPE ALL THOSE POINTS GENERATE 2398 01:59:59,760 --> 02:00:01,080 A LOT OF DISCUSSION LATER ON 2399 02:00:01,080 --> 02:00:03,040 WHEN WE CAN OPENLY TALK AND 2400 02:00:03,040 --> 02:00:07,720 THANK YOU SO MUCH FOR ALLOWING 2401 02:00:07,720 --> 02:00:08,200 US TO BE PART OF THIS 2402 02:00:08,200 --> 02:00:14,280 DISCUSSION. 2403 02:00:14,280 --> 02:00:15,640 >> THANK YOU FOR THE BEAUTIFUL 2404 02:00:15,640 --> 02:00:18,280 PRESENTATION AND THANKS FOR 2405 02:00:18,280 --> 02:00:19,680 PARTICIPATING UNDER THE 2406 02:00:19,680 --> 02:00:20,000 CIRCUMSTANCES. 2407 02:00:20,000 --> 02:00:21,680 SO WE'RE GOING TO HAVE A LUNCH 2408 02:00:21,680 --> 02:00:22,440 BREAK. 2409 02:00:22,440 --> 02:00:35,160 AND IF WE CAN TRY TO BE BACK FOR 2410 02:00:35,160 --> 02:00:38,200 12:35 THAT WOULD BE WONDERFUL. 2411 02:00:38,200 --> 02:00:46,440 THE VIDEOCAST CAN'T BE PAUSED. 2412 02:00:46,440 --> 02:00:49,280 BE MINDFUL IF YOU TURN YOUR 2413 02:00:49,280 --> 02:00:50,880 CAMERA ON IT WILL BROADCAST BUT 2414 02:00:50,880 --> 02:00:53,080 I'LL MUTE THE VIDEOCAST IN A FEW 2415 02:00:53,080 --> 02:00:56,280 MINUTES IN CASE ANYBODY WANTS TO 2416 02:00:56,280 --> 02:00:58,840 CHITCHAT OVER LUNCH AND 2417 02:00:58,840 --> 02:01:00,160 OTHERWISE WE'LL BE BACK AT 12:35 2418 02:01:00,160 --> 02:01:01,880 >> SO I'M GOING TO INTRODUCING 2419 02:01:01,880 --> 02:01:04,400 OUR MODERATOR FOR THE SECOND 2420 02:01:04,400 --> 02:01:04,640 SESSION. 2421 02:01:04,640 --> 02:01:05,640 THE SECOND SESSION WILL BE ON 2422 02:01:05,640 --> 02:01:07,360 THE TOPIC OF GENETICS. 2423 02:01:07,360 --> 02:01:14,360 THE MODERATOR IS CAMILO TORO A 2424 02:01:14,360 --> 02:01:17,840 NEUROLOGIST SPECIALIZED IN 2425 02:01:17,840 --> 02:01:21,840 MOVEMENT DISORDER AND HAS BEEN 2426 02:01:21,840 --> 02:01:25,840 THE CLINIC DIRECTOR UP HIS 2427 02:01:25,840 --> 02:01:29,840 DEPARTMENT AND ACQUIRED 2428 02:01:29,840 --> 02:01:40,200 INFORMATION ON BIOINFORMETIC 2429 02:01:40,200 --> 02:01:41,800 TOOLS AND HAS SEEN MORE CLASSIC 2430 02:01:41,800 --> 02:01:43,240 HSPs. 2431 02:01:43,240 --> 02:01:45,080 I'LL PASS IT LONG TO INTRODUCE 2432 02:01:45,080 --> 02:01:48,760 OUR SPEAKERS FOR THE AFTERNOON. 2433 02:01:48,760 --> 02:01:53,040 >> THANK YOU VERY MUCH FOR THE 2434 02:01:53,040 --> 02:01:53,360 INTRODUCTION. 2435 02:01:53,360 --> 02:01:55,320 NOT ONLY THE INTRODUCTION BUT 2436 02:01:55,320 --> 02:01:59,360 FOR PUTTING TOGETHER THE 2437 02:01:59,360 --> 02:01:59,640 SYMPOSIUM. 2438 02:01:59,640 --> 02:02:05,280 I THINK WE OWE THE INCREDIBLE 2439 02:02:05,280 --> 02:02:10,080 EFFORT TO YOU I'M TO INTRODUCE 2440 02:02:10,080 --> 02:02:12,760 OUR TWO SPEAKERS FOR THE 2441 02:02:12,760 --> 02:02:17,600 AFTERNOON AND THEY'RE PERFECT ON 2442 02:02:17,600 --> 02:02:24,520 THE TOPIC TO ADDRESS THE DAY AND 2443 02:02:24,520 --> 02:02:27,240 WHAT IS THE DIFFERENCE BETWEEN 2444 02:02:27,240 --> 02:02:28,960 DE NOVO AND INHERITED SPG4 AND 2445 02:02:28,960 --> 02:02:38,200 IS THERE GAI EXPLANATION OR WAYS 2446 02:02:38,200 --> 02:02:39,640 AND WE CAN UNDERSTAND THE 2447 02:02:39,640 --> 02:02:41,320 DIFFERENCE AND UNDERSTANDING THE 2448 02:02:41,320 --> 02:02:42,800 DISEASE AND BETTER THE DE NOVO 2449 02:02:42,800 --> 02:02:47,640 VERSION OF THE DISEASE AND WITH 2450 02:02:47,640 --> 02:02:51,040 THAT KNOWLEDGE TO BE TRANSLATED 2451 02:02:51,040 --> 02:02:52,320 TO MODERATE THE DISEASE. 2452 02:02:52,320 --> 02:02:55,680 THE TWO SPEAKERS WE'RE FORTUNATE 2453 02:02:55,680 --> 02:03:00,800 TO HAVE DR. JENNIFER POSEY 2454 02:03:00,800 --> 02:03:01,360 ASSISTANT PROFESSOR IN THE 2455 02:03:01,360 --> 02:03:04,080 DEPARTMENT OF MOLECULAR AND 2456 02:03:04,080 --> 02:03:08,160 HUMAN GENETICS AT BAYLOR AND HAS 2457 02:03:08,160 --> 02:03:09,760 INCREDIBLE EXPERIENCE IN THE USE 2458 02:03:09,760 --> 02:03:13,160 OF MOLECULAR GENETICS AS IT 2459 02:03:13,160 --> 02:03:17,840 RELATES TO CORRELATING WITH 2460 02:03:17,840 --> 02:03:29,840 PATIENT'S CLINICAL PRESENTATIONS 2461 02:03:29,840 --> 02:03:34,120 AND WHERE THERE CAN BE 2462 02:03:34,120 --> 02:03:36,680 VARIATIONS IN THE SAME TEAM. 2463 02:03:36,680 --> 02:03:38,440 THE NEXT SPEAKER WILL BE HEATHER 2464 02:03:38,440 --> 02:03:44,280 McLAUGHLIN AND IS ALSO A BOARD 2465 02:03:44,280 --> 02:03:49,800 CERTIFIED CLINICAL MOLECULAR 2466 02:03:49,800 --> 02:03:50,280 GENETICIST. 2467 02:03:50,280 --> 02:03:52,440 HAS A REALLY INTERESTING VANTAGE 2468 02:03:52,440 --> 02:03:56,560 POINT THAT IS INFORMATIVE TO ALL 2469 02:03:56,560 --> 02:04:04,920 OF US AND THE FACT SHE WORKS NOW 2470 02:04:04,920 --> 02:04:09,880 A PLACE THAT DOES A LARGE AMOUNT 2471 02:04:09,880 --> 02:04:11,440 OF MOLECULAR SEQUENCING AND 2472 02:04:11,440 --> 02:04:17,840 SHE'LL BE ABLE TO TELL US IN HER 2473 02:04:17,840 --> 02:04:23,680 EXPERIENCE WITH THIS LARGE DATA 2474 02:04:23,680 --> 02:04:29,840 SETS THE INCIDENT OF SPG4 2475 02:04:29,840 --> 02:04:31,480 MUTATIONS DIAGNOSES IN THE 2476 02:04:31,480 --> 02:04:37,080 SAMPLES IN AN ACTIVE MOLECULAR 2477 02:04:37,080 --> 02:04:40,160 SEQUENCING GROUP. 2478 02:04:40,160 --> 02:04:45,120 WITHOUT FURTHER ADO I WILL GO 2479 02:04:45,120 --> 02:04:47,160 FORTH AND WE HAVE OPEN SESSION 2480 02:04:47,160 --> 02:04:50,320 FOR DISCUSSION IN WHICH WE ARE 2481 02:04:50,320 --> 02:04:52,520 GEE TO ADDRESS QUESTIONS 2482 02:04:52,520 --> 02:04:56,960 REGARDING BOTH THE MORNING AND 2483 02:04:56,960 --> 02:04:57,760 THE AFTERNOON SESSION AND I 2484 02:04:57,760 --> 02:04:59,880 THINK THIS IS GOING TO GENERATE 2485 02:04:59,880 --> 02:05:01,880 A FAIR AMOUNT OF INTERESTING 2486 02:05:01,880 --> 02:05:02,200 CONVERSATIONS. 2487 02:05:02,200 --> 02:05:06,960 THANK YOU. 2488 02:05:06,960 --> 02:05:09,560 >> THANK YOU VERY MUCH DR. TORO 2489 02:05:09,560 --> 02:05:11,200 AND FOR THE OPPORTUNITY TO SPEAK 2490 02:05:11,200 --> 02:05:11,920 TO THE GROUP TODAY. 2491 02:05:11,920 --> 02:05:14,480 I FOUND AS I WAS PREPARING MY 2492 02:05:14,480 --> 02:05:16,120 SLIDES THERE WAS MORE I WANTED 2493 02:05:16,120 --> 02:05:18,440 TO TALK ABOUT AND SAY THAN 2494 02:05:18,440 --> 02:05:19,760 PERHAPS THERE WOULD BE TIME 2495 02:05:19,760 --> 02:05:20,640 DURING THE INITIAL MEETING. 2496 02:05:20,640 --> 02:05:22,320 I TRIED TO PUT TOGETHER A 2497 02:05:22,320 --> 02:05:23,840 PRESENTATION THAT HOPEFULLY 2498 02:05:23,840 --> 02:05:25,760 PROVIDES A LITTLE BIT OF AN 2499 02:05:25,760 --> 02:05:27,240 OVERVIEW OR FRAMEWORK FOR MAYBE 2500 02:05:27,240 --> 02:05:28,360 HOW TO THINK ABOUT SOME OF THE 2501 02:05:28,360 --> 02:05:31,760 QUESTIONS WE HAVE ABOUT THE ROLE 2502 02:05:31,760 --> 02:05:33,840 OF DE NOVO MUTATIONS AND SPG4 2503 02:05:33,840 --> 02:05:40,120 AND MORE COMPLEX DISEASE. 2504 02:05:40,120 --> 02:05:42,400 SO I WANTED TO BACK UP AND KIND 2505 02:05:42,400 --> 02:05:44,440 OF QUICKLY REMIND THE GROUP AND 2506 02:05:44,440 --> 02:05:47,840 MANY ON THE CALL WILL ALREADY BE 2507 02:05:47,840 --> 02:05:51,640 FAMILIAR WITH THIS BUT FROM A 2508 02:05:51,640 --> 02:05:53,160 RARE DISEASE GENOMIC STANDPOINT 2509 02:05:53,160 --> 02:05:55,360 WHICH IS WHERE I'M COMING FROM 2510 02:05:55,360 --> 02:05:57,200 AS A PHYSICIAN SCIENTIST AND 2511 02:05:57,200 --> 02:05:58,480 RARE DISEASE RESEARCHER WE LIKE 2512 02:05:58,480 --> 02:06:00,880 TO STEP BACK AND LOOK AT THEM IN 2513 02:06:00,880 --> 02:06:02,360 TERMS OF THE MECHANISMS IN WHICH 2514 02:06:02,360 --> 02:06:05,160 THEY FORM AND THEIR 2515 02:06:05,160 --> 02:06:05,960 CHARACTERISTICS AND LEARN FROM 2516 02:06:05,960 --> 02:06:07,800 THERE FOR THE MEANS OF THE 2517 02:06:07,800 --> 02:06:09,320 EXPECTED DISEASE AND THE 2518 02:06:09,320 --> 02:06:10,800 EXPECTED PHENOTYPIC EXPRESSION. 2519 02:06:10,800 --> 02:06:12,200 SO I WANTED TO JUST FRAME SOME 2520 02:06:12,200 --> 02:06:15,160 OF THE TALK IN TERMS OF WE OFTEN 2521 02:06:15,160 --> 02:06:16,560 THINK ABOUT DE NOVO MUTATIONS AS 2522 02:06:16,560 --> 02:06:19,200 BEING INFLUENCED BY SOME OF THE 2523 02:06:19,200 --> 02:06:20,560 STATIC PROPERTIES OF OUR GENE 2524 02:06:20,560 --> 02:06:24,480 POEM I THINK A GREAT EXAMPLE IS 2525 02:06:24,480 --> 02:06:27,360 CPG NUCLEOTIDES WHICH HAVE A 2526 02:06:27,360 --> 02:06:28,920 HIGHER LIKELIHOOD OF BEING 2527 02:06:28,920 --> 02:06:34,360 MUTATED AND I THINK THE R499 A 2528 02:06:34,360 --> 02:06:40,160 AMINO ACID RESIDUE OCCURS IN THE 2529 02:06:40,160 --> 02:06:41,760 CPG NUCLEOTIDES NOT SURPRISING 2530 02:06:41,760 --> 02:06:44,960 WE SEE THAT AS A RECURRENT NEW 2531 02:06:44,960 --> 02:06:48,240 MUTATION PRESENTED IN RELATED 2532 02:06:48,240 --> 02:06:48,520 FAMILIES. 2533 02:06:48,520 --> 02:06:51,560 WE KNOW DURING DNA REPLICATION 2534 02:06:51,560 --> 02:07:01,840 YOU CAN HAVE ERRONEOUS 2535 02:07:01,840 --> 02:07:05,840 NUCLEOTIDES AND CERTAIN GENOMES 2536 02:07:05,840 --> 02:07:07,960 CAN BE EXPOSED AND WE HAVE 2537 02:07:07,960 --> 02:07:09,840 EXAMPLES AND WE KNOW THE SPAST 2538 02:07:09,840 --> 02:07:12,480 GENE ITSELF SITS VERY PROXIMAL 2539 02:07:12,480 --> 02:07:17,760 TO SEVERAL REPEATS THAT CAN 2540 02:07:17,760 --> 02:07:22,840 MEDIATE NON-ALLELIC EVENTS AND 2541 02:07:22,840 --> 02:07:23,760 THERE'S CELL SPECIFIC PROPERTY 2542 02:07:23,760 --> 02:07:27,040 MAY INCREASE THE LIKELY HHS THE 2543 02:07:27,040 --> 02:07:29,160 MUTATION OR HOW IT'S EXPRESSED 2544 02:07:29,160 --> 02:07:30,800 AND CHROMATIN STATE AND GENE 2545 02:07:30,800 --> 02:07:31,920 EXPRESSION AND THINGS LIKE THIS. 2546 02:07:31,920 --> 02:07:33,560 I PROBABLY DON'T HAVE TO REMIND 2547 02:07:33,560 --> 02:07:34,680 THIS GROUP BUT WHEN WE'RE 2548 02:07:34,680 --> 02:07:36,960 THINKING ABOUT INHERITED VERSUS 2549 02:07:36,960 --> 02:07:38,160 DE NOVO FROM A BIG PICTURE 2550 02:07:38,160 --> 02:07:41,160 PERSPECTIVE OF COURSE EACH OF US 2551 02:07:41,160 --> 02:07:42,520 HAVE FAR FEWER DE NOVO MUTATIONS 2552 02:07:42,520 --> 02:07:45,760 THAN WE HAVE INHERITED VARIANTS. 2553 02:07:45,760 --> 02:07:48,400 WE OFTEN CONCEPTUALIZE FROM A 2554 02:07:48,400 --> 02:07:49,800 POPULATION STANDPOINT MOST 2555 02:07:49,800 --> 02:07:51,400 INHERITED VARIANTS WILL HAVE A 2556 02:07:51,400 --> 02:07:55,000 SMALL IF ANY EFFECT SIZE ON OUR 2557 02:07:55,000 --> 02:07:57,640 HEALTH ON OUR CLINICAL PHENOTYPE 2558 02:07:57,640 --> 02:07:58,880 WHEREAS WE EXPECT THAT DE NOVO 2559 02:07:58,880 --> 02:08:01,080 MUTATIONS IN GENERAL ARE MORE 2560 02:08:01,080 --> 02:08:01,960 LIKELY TO IMPACT HEALTH IN ALL 2561 02:08:01,960 --> 02:08:09,840 OF US AND WITH THAT, ONE OF THE 2562 02:08:09,840 --> 02:08:13,840 THINGS THAT WE BEGAN TO CONSIDER 2563 02:08:13,840 --> 02:08:16,280 IN THE CLINICAL REALM WORKING 2564 02:08:16,280 --> 02:08:18,640 WITH ONE OF THE DIAGNOSTIC 2565 02:08:18,640 --> 02:08:20,840 LABORATORIES AT BAYLOR GENETICS, 2566 02:08:20,840 --> 02:08:23,800 WE WANTED TO GET A LITTLE BIT OF 2567 02:08:23,800 --> 02:08:27,520 A SENSE FOR HOW FREQUENT ARE 2568 02:08:27,520 --> 02:08:29,160 MUTATIONS AND RARE DISEASE AND 2569 02:08:29,160 --> 02:08:31,160 THIS HAS BEEN IN STUDIES OVER A 2570 02:08:31,160 --> 02:08:33,200 DECADE NOW AND WE STEPPED BACK 2571 02:08:33,200 --> 02:08:35,400 AND ASK FOR INDIVIDUALS REFERRED 2572 02:08:35,400 --> 02:08:36,640 BY THEIR PHYSICIANS FOR RARE 2573 02:08:36,640 --> 02:08:38,960 DISEASE OF ANY KIND, MANY OF 2574 02:08:38,960 --> 02:08:40,240 THESE INDIVIDUALS WILL HAVE 2575 02:08:40,240 --> 02:08:41,960 NEUROLOGIC CONDITIONS. 2576 02:08:41,960 --> 02:08:43,360 SOME WILL NOT. 2577 02:08:43,360 --> 02:08:46,760 BUT FOR THOSE INDIVIDUALS 2578 02:08:46,760 --> 02:08:48,240 REFERRED FOR DIAGNOSTIC XM 2579 02:08:48,240 --> 02:08:49,840 SEQUENCING WHICH I ARGUE IS IN 2580 02:08:49,840 --> 02:08:54,000 SOME WAYS AN UNBIASSED ANALYSIS 2581 02:08:54,000 --> 02:08:56,080 OF THE GENOME TO SOME EXTENT. 2582 02:08:56,080 --> 02:08:59,000 WE'RE LOOKING AT THE MAJORITY OF 2583 02:08:59,000 --> 02:09:01,160 THE DISEASE GENES, THE CODING 2584 02:09:01,160 --> 02:09:01,400 REGIONS. 2585 02:09:01,400 --> 02:09:07,880 HOW FREEBLQUENTLY DO YOU IDENTIFY 2586 02:09:07,880 --> 02:09:09,120 NEW MUTATIONS AND THIS IS 2587 02:09:09,120 --> 02:09:13,160 IMPORTANT FOR THOSE WHO COME 2588 02:09:13,160 --> 02:09:16,160 AWAY WITH THE DIAGNOSIS MEANING 2589 02:09:16,160 --> 02:09:20,360 AN AUTOSOMAL VARIANT ON ONE OR 2590 02:09:20,360 --> 02:09:33,120 TWO COPIES OR AFFECTING THE GENE 2591 02:09:33,120 --> 02:09:38,400 ON THE FEMALE ALLELE AFFECTED 2592 02:09:38,400 --> 02:09:42,360 AND LOOK AT TO THE TOTAL OF 2593 02:09:42,360 --> 02:09:44,720 DIAGNOSES FROM FULL SEQUENCING 2594 02:09:44,720 --> 02:09:48,080 COHORTS AND WE CALCULATOR COUNT 2595 02:09:48,080 --> 02:09:52,160 THE NUMBER DE NOVO WHERE WE WERE 2596 02:09:52,160 --> 02:09:54,840 ABLE TO DEMONSTRATE AND IT WAS 2597 02:09:54,840 --> 02:09:57,840 NOT INHERITED FROM EITHER PARENT 2598 02:09:57,840 --> 02:10:00,800 AND IN PRIMARILY PEDIATRIC 2599 02:10:00,800 --> 02:10:03,520 COHORTS, ALMOST-QUARTERS OF 2600 02:10:03,520 --> 02:10:04,840 THOSE INDIVIDUALS HAVE DE NOVO 2601 02:10:04,840 --> 02:10:05,120 MUTATIONS. 2602 02:10:05,120 --> 02:10:07,720 IN ADULT COHORTS SO INDIVIDUALS 2603 02:10:07,720 --> 02:10:10,360 WHO ARE OVER 18 YEARS OF AGE, 2604 02:10:10,360 --> 02:10:11,560 THAT GETS CLOSER TO A LITTLE 2605 02:10:11,560 --> 02:10:13,240 MORE THAN HALF OF INDIVIDUALS 2606 02:10:13,240 --> 02:10:14,720 WILL HAVE A DE NOVO MUTATION. 2607 02:10:14,720 --> 02:10:17,160 OF THOSE, IF YOU LOOK AT THE AGE 2608 02:10:17,160 --> 02:10:19,160 BREAKDOWN THE INDIVIDUALS IN 2609 02:10:19,160 --> 02:10:21,440 THIS PARTICULAR COHORT THAT HAD 2610 02:10:21,440 --> 02:10:23,000 A DE NOVO MUTATION POSITIVE OF 2611 02:10:23,000 --> 02:10:24,960 THEIR CONDITION, THEY WERE ALL 2612 02:10:24,960 --> 02:10:26,560 BETWEEN 18 YEARS AND 30 YEARS. 2613 02:10:26,560 --> 02:10:28,840 THESE WERE ADULTS NO HOLDER THAN 2614 02:10:28,840 --> 02:10:30,360 30 YEARS OF AGE AND THERE'S 2615 02:10:30,360 --> 02:10:31,960 PROBABLY A COUPLE REASONS FOR 2616 02:10:31,960 --> 02:10:32,160 THAT. 2617 02:10:32,160 --> 02:10:35,360 ONE VERY PRACTICAL REASON IS 2618 02:10:35,360 --> 02:10:39,880 THAT ADULTS COME TO MY GENETICS 2619 02:10:39,880 --> 02:10:41,560 CLINIC THE OLDER THEY ARE THE 2620 02:10:41,560 --> 02:10:50,240 LESS LIKE LIE WE'RE ABLE TO GET 2621 02:10:50,240 --> 02:10:53,800 SAMPLES FROM THEIR PARENTS AND 2622 02:10:53,800 --> 02:10:54,760 THERE'S VERY MUCH IN THE FIELD 2623 02:10:54,760 --> 02:10:57,560 IN ADULT GENETICS THE IDEA THAT 2624 02:10:57,560 --> 02:10:59,400 A LOT OF ADULT ONSET GENETIC 2625 02:10:59,400 --> 02:11:02,040 DISEASE IS LESS LIKELY TO BE DE 2626 02:11:02,040 --> 02:11:03,240 NOVO BECAUSE DE NOVO MUTATION 2627 02:11:03,240 --> 02:11:05,280 LIKELY TO BE CONFERRING A MORE 2628 02:11:05,280 --> 02:11:07,800 SEVERE PHENOTYPE. 2629 02:11:07,800 --> 02:11:12,080 AGAIN, THIS IS VERY BROAD 2630 02:11:12,080 --> 02:11:13,840 STROKES NOT SPECIFIC TO SPG4 BUT 2631 02:11:13,840 --> 02:11:15,440 I WANTED TO PROVIDE A LAY OF THE 2632 02:11:15,440 --> 02:11:17,240 LAND HOW WE THINK CLINICALLY 2633 02:11:17,240 --> 02:11:21,840 FROM THE MEDICAL GENETIC 2634 02:11:21,840 --> 02:11:23,520 STANDPOINT ABOUT MUTATION. 2635 02:11:23,520 --> 02:11:24,920 THE OTHER THING I WANTED TO 2636 02:11:24,920 --> 02:11:27,160 BEGIN TO TALK ABOUT WITH THIS 2637 02:11:27,160 --> 02:11:28,960 GROUP TODAY WAS TO FRAME SOME OF 2638 02:11:28,960 --> 02:11:32,880 THIS THINKING WITHIN HOW WE 2639 02:11:32,880 --> 02:11:35,640 APPROACH THE GENOMIC ARCHITECT 2640 02:11:35,640 --> 02:11:36,560 ARCHITECTURE OF DISEASE. 2641 02:11:36,560 --> 02:11:38,560 YOU CAN SEE A FAMILY PEDIGREE. 2642 02:11:38,560 --> 02:11:42,360 SO WE HAVE AN INDIVIDUAL SHOWN 2643 02:11:42,360 --> 02:11:43,760 HERE IN GREEN AND FATHER AND 2644 02:11:43,760 --> 02:11:45,480 MOTHER HERE AND THEN ADDITIONAL 2645 02:11:45,480 --> 02:11:46,760 FAMILY MEMBERS FURTHER UP THE 2646 02:11:46,760 --> 02:11:48,560 FAMILY TREE. 2647 02:11:48,560 --> 02:11:50,040 AND WHEN WE THINK ABOUT NEW 2648 02:11:50,040 --> 02:11:51,880 MUTATION WE THINK OF THE DE NOVO 2649 02:11:51,880 --> 02:11:53,000 MUTATION OR ONE THAT OCCURRED 2650 02:11:53,000 --> 02:11:54,800 RECENTLY IN A FAMILY TREE OR 2651 02:11:54,800 --> 02:11:57,280 PEDIGREE AND WE EXPECT THAT TO 2652 02:11:57,280 --> 02:12:01,000 HAVE A LARGE PHENOTYPIC EFFECT 2653 02:12:01,000 --> 02:12:06,120 SIZE WHEREAS FOR MORE COMMON 2654 02:12:06,120 --> 02:12:06,520 VAS 2655 02:12:06,520 --> 02:12:13,200 VARIANTS PERHAPS THE PARENTAL OR 2656 02:12:13,200 --> 02:12:14,640 GRANDPARENTAL WE EXPECT A LESS 2657 02:12:14,640 --> 02:12:17,240 INFLUENCE AND IT'S IMPACTING 2658 02:12:17,240 --> 02:12:19,640 ONLY THIS INDIVIDUAL NEITHER OF 2659 02:12:19,640 --> 02:12:21,680 HIS OR HER PARENTS HAVE THE 2660 02:12:21,680 --> 02:12:23,600 VARIANT AND THIS IS WHAT I WAS 2661 02:12:23,600 --> 02:12:25,360 JUST TALKING ABOUT WE SEE 2662 02:12:25,360 --> 02:12:25,960 FREQUENTLY IN OUR DIAGNOSTIC 2663 02:12:25,960 --> 02:12:28,880 LABORATORY COHORT. 2664 02:12:28,880 --> 02:12:33,360 THESE TYPES OF OBSERVATIONS 2665 02:12:33,360 --> 02:12:36,640 ACTUALLY PROMPTED THE CLAN 2666 02:12:36,640 --> 02:12:37,840 GENOMIC HYPOTHESIS AND PUBLISHED 2667 02:12:37,840 --> 02:12:41,760 MORE THAN A DECADE AGO AND 2668 02:12:41,760 --> 02:12:42,440 POSITED THERE'S A CONTRIBUTION 2669 02:12:42,440 --> 02:12:46,240 OF NEW METATIONS TO HUMAN RARE 2670 02:12:46,240 --> 02:12:46,480 DISEASE. 2671 02:12:46,480 --> 02:12:49,560 WHILE THIS IS VERY MUCH THOUGHT 2672 02:12:49,560 --> 02:12:53,880 OF IN ALLELE VARIANTS WE'VE BEEN 2673 02:12:53,880 --> 02:12:58,720 ABLE TO DEMONSTRATE RECENTLY 2674 02:12:58,720 --> 02:13:12,200 SOME ARE BROUGHT TO HOMO 2675 02:13:12,200 --> 02:13:12,760 ZYGOCI 2676 02:13:12,760 --> 02:13:13,000 ZYGOCITY. 2677 02:13:13,000 --> 02:13:14,360 I WANT TO MOVE ON AND TALK ABOUT 2678 02:13:14,360 --> 02:13:18,760 THE CHALLENGE OF INCOMPLETE 2679 02:13:18,760 --> 02:13:19,040 PENETRANTS. 2680 02:13:19,040 --> 02:13:23,440 I'M GOING TO USE CONGENITAL 2681 02:13:23,440 --> 02:13:25,480 SCOLIOSIS TO MAKE SOME POINTS I 2682 02:13:25,480 --> 02:13:28,920 THINK COULD BE RELEVANT FOR THE 2683 02:13:28,920 --> 02:13:29,120 GROUP. 2684 02:13:29,120 --> 02:13:32,480 SO A TEAM AT ORTHOPEDIC SURGEONS 2685 02:13:32,480 --> 02:13:35,400 ARE CLOSE COLLABORATORS OF OURS 2686 02:13:35,400 --> 02:13:37,560 AND THEY'VE BEEN STUDYING 2687 02:13:37,560 --> 02:13:39,960 CHILDREN WITH THIS EARLY ONSET 2688 02:13:39,960 --> 02:13:41,000 CONGENITAL SCOLIOSIS. 2689 02:13:41,000 --> 02:13:42,960 THEY SEE THE INDIVIDUALS AFFECT 2690 02:13:42,960 --> 02:13:47,360 INTERESTED A DELETION OF 16P.1.2 2691 02:13:47,360 --> 02:13:49,960 SHOWN BY THE INTERRUPTED RED 2692 02:13:49,960 --> 02:13:50,360 LINE. 2693 02:13:50,360 --> 02:13:51,560 WHAT WAS FRUSTRATING TO THEM 2694 02:13:51,560 --> 02:13:54,720 INITIALLY WAS IN MANY CASES THE 2695 02:13:54,720 --> 02:13:55,680 DELETION AND LOSS OF FUNCTION 2696 02:13:55,680 --> 02:14:00,160 EXPERIENCE WAS INHERITED FROM AN 2697 02:14:00,160 --> 02:14:01,880 UNAFFECTED PARENT LIKE THIS 2698 02:14:01,880 --> 02:14:02,560 FATHER HERE. 2699 02:14:02,560 --> 02:14:05,720 THEY EVENTUALLY FIGURED OUT WHAT 2700 02:14:05,720 --> 02:14:08,120 WAS CAUSING THIS INCOMPLETE 2701 02:14:08,120 --> 02:14:10,680 PENETRANTS AND TURNED OUT THE 2702 02:14:10,680 --> 02:14:13,880 INDIVIDUALS AFFECTED WITH 2703 02:14:13,880 --> 02:14:18,000 CONGENITAL SCOLIOSIS HAD A LOSS 2704 02:14:18,000 --> 02:14:24,960 OF ALLELE AND THE OTHER HAD A 2705 02:14:24,960 --> 02:14:28,480 HYPOMORPHIC GENE SO SOME 2706 02:14:28,480 --> 02:14:30,960 EXPRESSION BUT NOT FULL AND YOU 2707 02:14:30,960 --> 02:14:35,680 NEED THAT VARIANT AND THE 2708 02:14:35,680 --> 02:14:37,760 HYPOMORPHIC EXPRESSION ON THE 2709 02:14:37,760 --> 02:14:40,200 ALLELE TO HAVE CONGENITAL 2710 02:14:40,200 --> 02:14:40,600 SCOLIOSIS. 2711 02:14:40,600 --> 02:14:45,840 THAT VARIANT IS ACTUALLY A 2712 02:14:45,840 --> 02:14:53,680 COMMON ALLELE IN THE CHINESE HUN 2713 02:14:53,680 --> 02:14:53,960 POPULATION. 2714 02:14:53,960 --> 02:14:58,760 AND THE HYPOTHESIS WAS ULT FATLY 2715 02:14:58,760 --> 02:15:03,520 IF YOU HAD TWO WILD TYPE ALLELE 2716 02:15:03,520 --> 02:15:06,520 WITH THIS ALLELE IN BLUE YOU 2717 02:15:06,520 --> 02:15:10,360 STILL HAVE THE TBX EXPRESSION 2718 02:15:10,360 --> 02:15:13,200 THAT YOUR RISK OF CONGENITAL 2719 02:15:13,200 --> 02:15:15,720 SCOLIOSIS IS LOW. 2720 02:15:15,720 --> 02:15:18,760 THAT'S TRUE EVEN WITH TWO 2721 02:15:18,760 --> 02:15:19,360 HYPOMORPHIC EXPRESSION OR ONE 2722 02:15:19,360 --> 02:15:21,600 VARIANT AND ONE LOSS OF FUNCTION 2723 02:15:21,600 --> 02:15:23,920 VARIANT, YOU STILL HAVE JUST 2724 02:15:23,920 --> 02:15:25,560 ENOUGH TBX6 EXPRESSION TO 2725 02:15:25,560 --> 02:15:29,040 SQUEEZE BY AND PROBABLY NOT HAVE 2726 02:15:29,040 --> 02:15:29,720 CONGENITAL SCOLIOSIS. 2727 02:15:29,720 --> 02:15:33,160 BUT YOUR PENETRANTS FOR 2728 02:15:33,160 --> 02:15:35,520 SCOLIOSIS IS SPECIALLY INCREASED 2729 02:15:35,520 --> 02:15:41,120 ONCE HAVE YOU HAVE A COPY ON ONE 2730 02:15:41,120 --> 02:15:43,560 ALLELE OPPOSITE WHERE YOUR TBX6 2731 02:15:43,560 --> 02:15:45,680 EXPRESSION IS STILL DETECTABLE 2732 02:15:45,680 --> 02:15:47,400 BUT SUBSTANTIALLY REDUCED. 2733 02:15:47,400 --> 02:15:51,440 THIS IS AN IMPORTANT KIND OF 2734 02:15:51,440 --> 02:15:54,760 LESSON FOR US BECAUSE IT TAUGHT 2735 02:15:54,760 --> 02:15:57,360 US TO THINK CRITICALLY NOT ONLY 2736 02:15:57,360 --> 02:15:58,840 ABOUT THE GENE CAUSING WHAT 2737 02:15:58,840 --> 02:16:00,920 APPEARS TO BE A DOMINANT 2738 02:16:00,920 --> 02:16:04,720 CONDITION WITH INCOMPLETE 2739 02:16:04,720 --> 02:16:05,840 PENETRANTS BUT TO UNDERSTAND HOW 2740 02:16:05,840 --> 02:16:07,720 OTHER VARIANTS EITHER THIS LOCUS 2741 02:16:07,720 --> 02:16:09,680 OR OTHER EXAMPLES I WON'T HAVE 2742 02:16:09,680 --> 02:16:11,880 TIME TO DISCUSS TODAY WHERE 2743 02:16:11,880 --> 02:16:17,440 THERE'S OTHER LOCI TO UNDERSTAND 2744 02:16:17,440 --> 02:16:20,720 GENE DOSAGE AND WHAT'S HAPPENING 2745 02:16:20,720 --> 02:16:23,360 BEHIND THE SCENES IN RELATION TO 2746 02:16:23,360 --> 02:16:25,280 THE SEVERITY OF THE PHENOTYPE OR 2747 02:16:25,280 --> 02:16:26,720 PENETRANTS OF THE PHENOTYPE. 2748 02:16:26,720 --> 02:16:28,000 I WON'T BELABOR THIS POINT 2749 02:16:28,000 --> 02:16:31,240 BECAUSE IT WAS MENTIONED EARLIER 2750 02:16:31,240 --> 02:16:33,800 WITH REBECCA SCHOLES TALK BUT IN 2751 02:16:33,800 --> 02:16:39,240 COLLABORATION WITH BAYLOR, OUR 2752 02:16:39,240 --> 02:16:42,760 GROUP HAS BEEN LOOKING AT THE 2753 02:16:42,760 --> 02:16:47,160 BURDEN OF THIS AND ONE DRIVING 2754 02:16:47,160 --> 02:16:53,520 REASON IS HE HAD SEEN IN HIS OWN 2755 02:16:53,520 --> 02:16:55,880 PEDIATRIC NEUROLOGY CLINIC WHERE 2756 02:16:55,880 --> 02:16:57,720 SOME INDIVIDUALS IN THE SAME 2757 02:16:57,720 --> 02:16:59,480 FAMILY HAVE THE SAME MUTATION AT 2758 02:16:59,480 --> 02:17:04,640 THE REST OF THE FAMILY MEMBERS 2759 02:17:04,640 --> 02:17:07,600 PRESENTED MUCH GREATER THAN 2760 02:17:07,600 --> 02:17:08,680 EXPECTED AND THE QUESTIONS IS 2761 02:17:08,680 --> 02:17:10,160 WHY ARE THEY HAVING MORE SEVERE 2762 02:17:10,160 --> 02:17:11,920 DISEASE AND HOW CAN WE HELP 2763 02:17:11,920 --> 02:17:13,400 FAMILIES TO KNOW WHAT TO EXPECT 2764 02:17:13,400 --> 02:17:15,160 FOR A NEW MEMBER OF THE FAMILY 2765 02:17:15,160 --> 02:17:16,520 WHO HAS THE VARIANT. 2766 02:17:16,520 --> 02:17:17,840 HOW SEVERE IS THIS GOING TO BE 2767 02:17:17,840 --> 02:17:20,320 AND HOW CAN THEY PLAN? 2768 02:17:20,320 --> 02:17:24,600 WHAT HE LEARNED WAS THAT THERE 2769 02:17:24,600 --> 02:17:27,720 ARE MANY VARIANTS AND GENES 2770 02:17:27,720 --> 02:17:33,000 ASSOCIATED WITH NEUROON -- 2771 02:17:33,000 --> 02:17:35,840 NEUROPATHY AND MANY TIMES 2772 02:17:35,840 --> 02:17:38,440 UNAFFECTED INDIVIDUALS WOULD 2773 02:17:38,440 --> 02:17:41,440 HAVE VARIANTS IN THE FAMILY BUT 2774 02:17:41,440 --> 02:17:44,200 ARE UNAFFECTED PARENTS AND HAVE 2775 02:17:44,200 --> 02:17:46,760 VARIANTS BUT WHEN YOU LOOK AT 2776 02:17:46,760 --> 02:17:49,560 THE CHILDREN SEVERELY AFFECTS 2777 02:17:49,560 --> 02:17:51,120 YOU WOULD SEE A DRIVING MUTATION 2778 02:17:51,120 --> 02:17:53,120 AND THIS YOUNG MALE HAS AN 2779 02:17:53,120 --> 02:17:54,880 VARIANT AND HAD MUCH MUCH MORE 2780 02:17:54,880 --> 02:17:56,240 SEVERE DISEASE THAN YOU WOULD 2781 02:17:56,240 --> 02:18:00,160 EXPECT FOR INDIVIDUALS WITH THIS 2782 02:18:00,160 --> 02:18:05,560 VARIANT IN MFN2 AND WHAT JIM WAS 2783 02:18:05,560 --> 02:18:08,040 ABLE TO SHOW IS THE VARIANT 2784 02:18:08,040 --> 02:18:11,280 INHERITED FROM PARENTS MODERATE 2785 02:18:11,280 --> 02:18:17,640 THE SEVERITY OF THE PHENOTYPE. 2786 02:18:17,640 --> 02:18:19,360 THIS NEW MUTATIONAL BURDEN. 2787 02:18:19,360 --> 02:18:21,600 ONE THING PROPOSED BUT NOT 2788 02:18:21,600 --> 02:18:22,880 DEMONSTRATED IN THE HUMAN RARE 2789 02:18:22,880 --> 02:18:25,360 DISEASE RESEARCH WORLD AT LEAST 2790 02:18:25,360 --> 02:18:27,120 NOT DEFINITIVELY IN ANY WAY I 2791 02:18:27,120 --> 02:18:29,840 CAN FIND IN THE LITERATURE IS 2792 02:18:29,840 --> 02:18:33,440 THE POSSIBILITY WITH NEW 2793 02:18:33,440 --> 02:18:37,160 MUTATIONS VERSUS INHERITED YOU 2794 02:18:37,160 --> 02:18:39,560 CAN HAVE COMPENSATORY LOCI 2795 02:18:39,560 --> 02:18:40,480 RATHER THAN DIALING UP THE 2796 02:18:40,480 --> 02:18:42,240 SEVERITY COULD DIAL DOWN THE 2797 02:18:42,240 --> 02:18:43,320 SEVERITY OF THE CONDITION AND IN 2798 02:18:43,320 --> 02:18:45,840 A SETTING WHERE YOU HAVE AN 2799 02:18:45,840 --> 02:18:49,760 INHERITED VARIANT OVER MULTIPLE 2800 02:18:49,760 --> 02:18:52,120 GENERATIONS THERE'S THE 2801 02:18:52,120 --> 02:18:53,080 THEORETICAL POSSIBILITY 2802 02:18:53,080 --> 02:18:54,360 COMPENSATORY VARIANTS MAY MAKE 2803 02:18:54,360 --> 02:18:55,240 THE PHENOTYPE LESS SEVERE. 2804 02:18:55,240 --> 02:18:59,920 IN A SITUATION WHERE YOU HAVE A 2805 02:18:59,920 --> 02:19:02,760 NEW MUTATION THE GENOME HASN'T 2806 02:19:02,760 --> 02:19:05,360 HAD AN OPPORTUNITY TO HAVE OTHER 2807 02:19:05,360 --> 02:19:06,920 VARIANTS TAKE PLACE. 2808 02:19:06,920 --> 02:19:09,840 WHETHER THIS REALLY OCCURS IN A 2809 02:19:09,840 --> 02:19:11,880 SMALL INDIVIDUAL FAMILY LEVEL WE 2810 02:19:11,880 --> 02:19:14,000 DON'T KNOW BUT KNOW IT CAN OCCUR 2811 02:19:14,000 --> 02:19:15,560 IN A POPULATION LEVEL BUT OVER 2812 02:19:15,560 --> 02:19:16,880 MANY GENERATIONS. 2813 02:19:16,880 --> 02:19:19,080 I THINK IT'S AN INTERESTING 2814 02:19:19,080 --> 02:19:20,960 HYPOTHESIS TO CONSIDER IN TERMS 2815 02:19:20,960 --> 02:19:23,880 OF WHETHER MUTATIONAL BURDEN CAN 2816 02:19:23,880 --> 02:19:27,280 ALSO WORK THAT WAY. 2817 02:19:27,280 --> 02:19:29,840 I ALSO WANT TO TALK BRIEFLY 2818 02:19:29,840 --> 02:19:31,320 ABOUT DUAL MOLECULAR DIAGNOSES. 2819 02:19:31,320 --> 02:19:33,800 THESE ARE CONDITIONS IN WHICH AN 2820 02:19:33,800 --> 02:19:36,120 INDIVIDUAL RATHER THAN HAVING 2821 02:19:36,120 --> 02:19:38,880 ONE CONDITION WITH ADDITIONAL 2822 02:19:38,880 --> 02:19:41,360 VARIANTS WITH THE PHENOTYPE MAY 2823 02:19:41,360 --> 02:19:43,120 HAVE TWO CONDITIONS THAT 2824 02:19:43,120 --> 02:19:44,160 SEGREGATE INDEPENDENTLY WHERE 2825 02:19:44,160 --> 02:19:45,800 ONE SIBLING HAS ONE CONDITION 2826 02:19:45,800 --> 02:19:48,920 AND MAYBE THE CHILD HAS THE 2827 02:19:48,920 --> 02:19:50,880 OTHER AND INDEPENDENT 2828 02:19:50,880 --> 02:19:52,600 SEGREGATION OF TWO OR MORE RARE 2829 02:19:52,600 --> 02:19:53,600 DISEASE PHENOTYPES. 2830 02:19:53,600 --> 02:19:54,800 AND IN THE EXAMPLE I'M SHOWING 2831 02:19:54,800 --> 02:19:57,600 YOU HERE ON THE LEFT IS AN 2832 02:19:57,600 --> 02:20:00,880 INDIVIDUAL WHO ACTUALLY HAS TWO 2833 02:20:00,880 --> 02:20:05,760 GENETIC FORMS OF DEVELOPMENT 2834 02:20:05,760 --> 02:20:07,400 ENCEPHALOPATHY WE HAVE IN OUR 2835 02:20:07,400 --> 02:20:08,680 LABORATORY DATABASE AND YOU'D 2836 02:20:08,680 --> 02:20:11,520 EXPECT SOMEBODY LIKE THIS MIGHT 2837 02:20:11,520 --> 02:20:16,720 ACTUALLY PRESENT WITH AN EVEN 2838 02:20:16,720 --> 02:20:19,280 MORE SEVERE PHENOTYPE FOR 2839 02:20:19,280 --> 02:20:21,160 DEVELOPMENT ENCEPHALOPATHY 2840 02:20:21,160 --> 02:20:21,360 ALONE. 2841 02:20:21,360 --> 02:20:23,760 THEY'RE IMPORTANT SCENARIOS TO 2842 02:20:23,760 --> 02:20:24,800 IDENTIFY. 2843 02:20:24,800 --> 02:20:26,080 THEY MAY INFLUENCE TREATMENT BUT 2844 02:20:26,080 --> 02:20:28,280 CAN ALSO EXPLAIN SCENARIOS IN 2845 02:20:28,280 --> 02:20:29,520 WHICH YOU MAY HAVE SOMEONE WHO 2846 02:20:29,520 --> 02:20:31,240 APPEARS TO HAVE A MORE SEVERE 2847 02:20:31,240 --> 02:20:32,520 PHENOTYPE THAN EXPECTED. 2848 02:20:32,520 --> 02:20:33,760 YOU MAY THINK THESE ARE 2849 02:20:33,760 --> 02:20:35,880 INCREDIBLY RARE BUT IT TURNS OUT 2850 02:20:35,880 --> 02:20:40,160 IF YOU TAKE ALL COMERS WHO HAD A 2851 02:20:40,160 --> 02:20:41,800 DIAGNOSTIC WHOLE EXOME 2852 02:20:41,800 --> 02:20:44,760 SEQUENCING STUDY AT LEAST 5 OR 2853 02:20:44,760 --> 02:20:46,160 MORE WILL HAVE TWO OR MORE 2854 02:20:46,160 --> 02:20:46,440 DIAGNOSES. 2855 02:20:46,440 --> 02:20:47,560 IT CAN COME IN TWO FLAVORS. 2856 02:20:47,560 --> 02:20:49,080 THE EXAMPLE I SHOWED YOU A 2857 02:20:49,080 --> 02:20:51,960 MOMENT OKAY NOW HERE ON THE 2858 02:20:51,960 --> 02:20:53,880 RIGHT IS THE OVERLAPPING FLAVOR 2859 02:20:53,880 --> 02:20:55,560 WHERE A PERSON HAS TWO SIMILAR 2860 02:20:55,560 --> 02:20:57,360 CONDITIONS AND YOU EXPECT THEM 2861 02:20:57,360 --> 02:20:58,520 TO HAVE A PHENOTYPE THAT'S EVEN 2862 02:20:58,520 --> 02:21:00,480 MORE SEVERE. 2863 02:21:00,480 --> 02:21:02,160 YOU CAN SEE THE OPPOSITE WHERE 2864 02:21:02,160 --> 02:21:03,640 SOMEONE MAY HAVE A MELDING OF 2865 02:21:03,640 --> 02:21:05,640 TWO CONDITIONS UNRELATED TO EACH 2866 02:21:05,640 --> 02:21:07,360 OTHER BUT CLINICALLY WHEN THEY 2867 02:21:07,360 --> 02:21:09,480 COME IN TO SEE YOU, WHAT YOU'LL 2868 02:21:09,480 --> 02:21:10,760 SEE IS A COMBINATION OF 2869 02:21:10,760 --> 02:21:12,160 PHENOTYPES YOU MAY NEVER HAVE 2870 02:21:12,160 --> 02:21:13,320 SEEN BEFORE AND UNTIL YOU'VE 2871 02:21:13,320 --> 02:21:17,160 DONE THE APPROPRIATE TESTING, 2872 02:21:17,160 --> 02:21:20,720 YOU MAY NOT REALIZE FOR EXAMPLE 2873 02:21:20,720 --> 02:21:28,600 THIS PERSON WITH ABSENT SKIN 2874 02:21:28,600 --> 02:21:29,360 PIGMENTATI 2875 02:21:29,360 --> 02:21:30,720 PIGMENTATION DOES NOT HAVE A 2876 02:21:30,720 --> 02:21:31,360 SINGLE UNIFIED DIAGNOSIS. 2877 02:21:31,360 --> 02:21:33,560 THE LAST THING I WANTED TO 2878 02:21:33,560 --> 02:21:37,200 MENTION IS I WANTED TO BRING UP 2879 02:21:37,200 --> 02:21:40,880 THE IDEA OF MOSAICISM AND HOW 2880 02:21:40,880 --> 02:21:42,040 THAT CAN INFLUENCE DISEASE TRAIT 2881 02:21:42,040 --> 02:21:42,360 EXPRESSION. 2882 02:21:42,360 --> 02:21:45,160 MANY OF US THINK OF IT IN TERMS 2883 02:21:45,160 --> 02:21:47,560 OF WHAT POINT IN AN INDIVIDUAL'S 2884 02:21:47,560 --> 02:21:49,800 DEVELOPMENT A NEW MUTATION 2885 02:21:49,800 --> 02:21:50,160 OCCURS. 2886 02:21:50,160 --> 02:21:53,880 SO IF IT OCCURS SORT OF AT THE 2887 02:21:53,880 --> 02:21:56,960 FIRST MITOSIS OR IF IT OCCURS 2888 02:21:56,960 --> 02:21:59,120 LATER ON AFTER LEFT-RIGHT 2889 02:21:59,120 --> 02:22:01,640 PATTERNING HAS OCCURRED OR A 2890 02:22:01,640 --> 02:22:02,440 MUTATION THAT OCCURS ONLY IN THE 2891 02:22:02,440 --> 02:22:04,080 GERM LINE BUT COULD BE PASSED ON 2892 02:22:04,080 --> 02:22:05,160 TO THE NEXT GENERATION. 2893 02:22:05,160 --> 02:22:06,920 AND AS YOU CAN KIND OF ENVISION 2894 02:22:06,920 --> 02:22:09,800 FROM WHAT YOU CAN SEE HERE, THAT 2895 02:22:09,800 --> 02:22:10,760 CAN GREATLY INFLUENCE THE 2896 02:22:10,760 --> 02:22:11,760 PHENOTYPE THAT MAY BE EXPRESSED 2897 02:22:11,760 --> 02:22:16,080 FROM THE IMPACTED CELLS. 2898 02:22:16,080 --> 02:22:17,480 ONE OF THE REASONS I BRING THIS 2899 02:22:17,480 --> 02:22:20,720 UP IS BECAUSE IN THINKING ABOUT 2900 02:22:20,720 --> 02:22:22,720 THE QUESTION OF DE NOVO 2901 02:22:22,720 --> 02:22:24,560 MUTATIONS AND SPAST, I RAN 2902 02:22:24,560 --> 02:22:25,840 ACROSS A VERY INTERESTING 2903 02:22:25,840 --> 02:22:28,760 PARADOX AND WHAT I CALL THE 2904 02:22:28,760 --> 02:22:32,560 PARADOX OF DISEASE, SEVERITY AND 2905 02:22:32,560 --> 02:22:35,040 CRANIOFRONTAL NASAL SYNDROME. 2906 02:22:35,040 --> 02:22:37,200 THIS PARTICULAR CONDITION IS X 2907 02:22:37,200 --> 02:22:38,400 LINKED WHICH MAKES IT A LITTLE 2908 02:22:38,400 --> 02:22:39,360 BIT DIFFERENT. 2909 02:22:39,360 --> 02:22:43,320 AND IT'S COVERED BY DAMAGING OR 2910 02:22:43,320 --> 02:22:45,800 PATHOGENIC VARIANTS IN EFNV1. 2911 02:22:45,800 --> 02:22:53,800 WHAT'S CURIOUS ABOUT IT IS HETER 2912 02:22:53,800 --> 02:22:54,240 HETE 2913 02:22:54,240 --> 02:22:56,160 HETEROZYGOUS FEMALES ARE MORE 2914 02:22:56,160 --> 02:22:59,160 AFFECTED AND IT MAY SEEM 2915 02:22:59,160 --> 02:23:00,640 COUNTERINTUITIVE AND HERE'S A 2916 02:23:00,640 --> 02:23:01,880 DAUGHTER AND HER FATHER AFFECTED 2917 02:23:01,880 --> 02:23:03,840 AND YOU CAN APPRECIATE FROM THE 2918 02:23:03,840 --> 02:23:06,720 IMAGE SHE AS A MORE SEVERE 2919 02:23:06,720 --> 02:23:08,240 PHENOTYPE THAN HER FATHER THOUGH 2920 02:23:08,240 --> 02:23:11,920 SHE HAS ONE EXTRA CHROMOSOME OF 2921 02:23:11,920 --> 02:23:15,760 THE VARIANT AND ONE THAT IS WILD 2922 02:23:15,760 --> 02:23:16,000 TYPE. 2923 02:23:16,000 --> 02:23:18,360 HER FATHER ONLY HAS ONE AND IT'S 2924 02:23:18,360 --> 02:23:18,600 VARIANT. 2925 02:23:18,600 --> 02:23:20,040 ONE OF THE IMPORTANT THINGS TO 2926 02:23:20,040 --> 02:23:21,760 THINK ABOUT IN THIS PARTICULAR 2927 02:23:21,760 --> 02:23:24,880 CONDITION IS THAT WE KNOW THAT 2928 02:23:24,880 --> 02:23:27,360 FOR SEASONS YOU CAN HAVE 2929 02:23:27,360 --> 02:23:29,160 MOSAICISM FOR GENE EXPRESSION 2930 02:23:29,160 --> 02:23:32,040 FOR THE RELEVANT GENE. 2931 02:23:32,040 --> 02:23:36,600 WE KNOW IN CFNS THAT WOMEN ARE 2932 02:23:36,600 --> 02:23:39,080 MOSAIC FOR EFNB1 EXPRESSION IN 2933 02:23:39,080 --> 02:23:41,280 FEMALES BECAUSE OF THEIR 2934 02:23:41,280 --> 02:23:41,840 CHROMOSOMIC ACTIVATION. 2935 02:23:41,840 --> 02:23:44,240 THEY'LL HAVE A POPULATION OF 2936 02:23:44,240 --> 02:23:48,240 CELLS WHERE A SUBSET ARE 2937 02:23:48,240 --> 02:23:49,720 EXPRESSING THE WILD TYPE GENE. 2938 02:23:49,720 --> 02:23:52,240 THIS IS IMPORTANT IN THIS 2939 02:23:52,240 --> 02:23:53,200 PARTICULAR CONDITION BECAUSE OF 2940 02:23:53,200 --> 02:23:56,440 THE FACT THAT IT RELATES TO 2941 02:23:56,440 --> 02:23:58,040 RECEPTORS AND THEIR ROLE. 2942 02:23:58,040 --> 02:24:02,560 SO EFNB1 IS ONE OF THE EPHRONS 2943 02:24:02,560 --> 02:24:07,320 AND THIS CLASS OF RECEPTORS IS 2944 02:24:07,320 --> 02:24:10,160 IMPORTANT FOR EMBRYONIC TISSUE 2945 02:24:10,160 --> 02:24:11,920 AND THERE'S SUBCLASSES A AND B 2946 02:24:11,920 --> 02:24:17,800 AND THEY'RE DEFINED WHETHER 2947 02:24:17,800 --> 02:24:31,920 THEY'RE THEY BIND TO EPHRIN 2948 02:24:31,920 --> 02:24:35,280 RECEPTORS AND YOU CAN HAVE CELL 2949 02:24:35,280 --> 02:24:36,480 ADHESION ON ONE AND CELL 2950 02:24:36,480 --> 02:24:37,600 REPULSION IN THE OTHER. 2951 02:24:37,600 --> 02:24:40,360 IN THIS PARTICULAR CASE, THIS 2952 02:24:40,360 --> 02:24:45,840 WAS OF NOTE BECAUSE SCIENTISTS 2953 02:24:45,840 --> 02:24:49,080 HYPOTHESIZED THE REASON WHY THE 2954 02:24:49,080 --> 02:24:55,520 MOSAIC FEMALES WITH CFNS WERE 2955 02:24:55,520 --> 02:24:56,080 MORE SEVERELY AFFECTED WAS 2956 02:24:56,080 --> 02:24:58,800 BECAUSE OF TWO POPULATIONS OF 2957 02:24:58,800 --> 02:24:59,160 CELLS. 2958 02:24:59,160 --> 02:25:00,640 ONE EXPRESSING THE WILD TYPE 2959 02:25:00,640 --> 02:25:02,000 COPY AND ONE PRESUMABLY NOT 2960 02:25:02,000 --> 02:25:05,280 EXPRESSING IT WELL. 2961 02:25:05,280 --> 02:25:07,800 WHEREAS THE MALES ONLY HAD ONE 2962 02:25:07,800 --> 02:25:08,200 CELL LINE. 2963 02:25:08,200 --> 02:25:10,800 THEY WERE NOT MOSAIC AND THEY 2964 02:25:10,800 --> 02:25:13,880 WERE PRESUMABLY EXPRESSING A 2965 02:25:13,880 --> 02:25:21,120 KNEW -- MUTANT COPY OR NOT 2966 02:25:21,120 --> 02:25:22,960 EXPRESSING WELL AT ALL. 2967 02:25:22,960 --> 02:25:25,880 THE GROUP FOUND IF YOU MIX CELLS 2968 02:25:25,880 --> 02:25:29,880 THAT SHOWED THE STAIN EPHRIN 2969 02:25:29,880 --> 02:25:30,880 EXPRESSION LEVELS EITHER WILD 2970 02:25:30,880 --> 02:25:32,680 TYPE 2 POPULATIONS WITH WILD 2971 02:25:32,680 --> 02:25:33,840 TYPE OR WILD TYPE POPULATIONS 2972 02:25:33,840 --> 02:25:35,920 WITH MUTANTS, THE CELLS WOULD 2973 02:25:35,920 --> 02:25:37,840 CONTINUE TO INTERACT THROUGH 2974 02:25:37,840 --> 02:25:40,160 THEIR EPHRIN LIGANDS AND MIX AND 2975 02:25:40,160 --> 02:25:48,960 DO THE SIGNALLING NEEDED. 2976 02:25:48,960 --> 02:25:50,920 BUT WHEN YOU MIX A CELL LINE 2977 02:25:50,920 --> 02:25:55,760 WITH A MUTANT EXPRESSING CELL 2978 02:25:55,760 --> 02:25:57,360 LINE SIMILAR TO WOMEN WITH 2979 02:25:57,360 --> 02:26:03,480 ACTIVATION OF GENE, YOU WOULD 2980 02:26:03,480 --> 02:26:04,360 SEE CELL SEGREGATION AND THE 2981 02:26:04,360 --> 02:26:06,200 GREEN AND PURPLE ARE NO LONGER 2982 02:26:06,200 --> 02:26:14,880 MIXING APPROPRIATELY. 2983 02:26:14,880 --> 02:26:17,160 ONE OF THE HYPOTHESES THEN YOU 2984 02:26:17,160 --> 02:26:21,800 WOULD PREDICT MALES WHO ARE GERM 2985 02:26:21,800 --> 02:26:25,800 LINE MOSAIC FOR AN EPHRIN B1 2986 02:26:25,800 --> 02:26:27,560 VARIANT WOULD BE JUST AS 2987 02:26:27,560 --> 02:26:28,320 SEVERELY AFFECTED AS FEMALES. 2988 02:26:28,320 --> 02:26:30,720 I DON'T HAVE ENOUGH TIME TO SHOW 2989 02:26:30,720 --> 02:26:34,760 THIS BUT NOW MULTIPLE MOSAIC 2990 02:26:34,760 --> 02:26:37,560 MALES HAVE SHOWN THEY'RE EQUALLY 2991 02:26:37,560 --> 02:26:40,280 AS AFFECTED AS FEMALES MORE THAN 2992 02:26:40,280 --> 02:26:41,760 THOSE WITH THE MUTATION. 2993 02:26:41,760 --> 02:26:48,760 THIS IS A GREAT EXAMPLE OF HOW 2994 02:26:48,760 --> 02:26:49,760 MOSAICISM CAN INFLUENCE 2995 02:26:49,760 --> 02:26:51,960 PHENOTYPES SOMETIMES IN 2996 02:26:51,960 --> 02:26:52,560 PARADOXICAL WAYS. 2997 02:26:52,560 --> 02:26:55,960 I HOPE I'VE CONVINCED YOU AT A 2998 02:26:55,960 --> 02:26:57,720 POPULATION LEVEL WE 2999 02:26:57,720 --> 02:26:59,160 CONCEPTUALIZE THEM TO HAVE A 3000 02:26:59,160 --> 02:27:00,320 LARGER PHENOTYPIC IMPACT. 3001 02:27:00,320 --> 02:27:03,560 WE KNOW MUTATIONAL BURDEN AND 3002 02:27:03,560 --> 02:27:05,480 COMPOUND BURDEN CAN INFLUENCE 3003 02:27:05,480 --> 02:27:07,480 THE SEVERITY OF DISEASE 3004 02:27:07,480 --> 02:27:08,200 EXPRESSION AND POTENTIALLY 3005 02:27:08,200 --> 02:27:09,840 INFLUENCE PENETRANTS AS WELL AND 3006 02:27:09,840 --> 02:27:11,640 KIND OF RAISES THE QUESTION 3007 02:27:11,640 --> 02:27:13,840 WHETHER THERE COULD BE 3008 02:27:13,840 --> 02:27:16,160 MECHANISMS INVOLVING 3009 02:27:16,160 --> 02:27:17,360 COMPENSATORY MUTATIONS ALSO 3010 02:27:17,360 --> 02:27:17,560 HERE. 3011 02:27:17,560 --> 02:27:21,840 I HOPE I'VE CONVINCED YOU DUAL 3012 02:27:21,840 --> 02:27:23,280 MOLECULAR DIAGNOSES CAN BE 3013 02:27:23,280 --> 02:27:24,840 DIFFICULT TO CLINICALLY 3014 02:27:24,840 --> 02:27:29,840 RECOGNIZE AND WHEN THEY MIGHT 3015 02:27:29,840 --> 02:27:34,280 SHARE A RELATIONSHIP THEY CAN 3016 02:27:34,280 --> 02:27:35,200 INFLUENCE PHENOTYPE AND 3017 02:27:35,200 --> 02:27:37,440 PARADOXICALLY IN SOME CASES MAY 3018 02:27:37,440 --> 02:27:41,160 LEAD TO A MORE SEVERE PHENOTYPIC 3019 02:27:41,160 --> 02:27:41,640 PRESENTATION. 3020 02:27:41,640 --> 02:27:46,240 WITH THAT I'LL WRAP UP. 3021 02:27:46,240 --> 02:27:48,360 OUR RARE DISEASE RESEARCH GROUP 3022 02:27:48,360 --> 02:27:50,200 IS LARGER THAN WHAT I SHOW HERE 3023 02:27:50,200 --> 02:27:51,840 BUT THESE ARE THE MOVERS AND 3024 02:27:51,840 --> 02:27:52,640 SHAKERS THAT CONTRIBUTED TO THE 3025 02:27:52,640 --> 02:27:53,960 WORK I'VE PRESENTED HERE AND MY 3026 02:27:53,960 --> 02:28:23,280 FUNDERS AS WELL. 3027 02:28:23,280 --> 02:28:28,560 >> I'M HEATHER McALAU LAUGLAUGHLIN ONE 3028 02:28:28,560 --> 02:28:29,760 OF THE MEDICAL AFFAIRS DIRECTORS 3029 02:28:29,760 --> 02:28:31,760 AND I'LL TALK ABOUT THE DATA WE 3030 02:28:31,760 --> 02:28:35,520 HAVE ON SPAST RELATED HSP IN 3031 02:28:35,520 --> 02:28:38,000 CHILDREN WITH CP SPECTRUM 3032 02:28:38,000 --> 02:28:43,600 DISORDERS. 3033 02:28:43,600 --> 02:28:44,960 SO A LITTLE BIT ABOUT CEREBRAL 3034 02:28:44,960 --> 02:28:46,760 PALSY FIRST, WHAT WE KNOW ABOUT 3035 02:28:46,760 --> 02:28:49,800 THE DISORDER OR GROUP OF 3036 02:28:49,800 --> 02:28:51,360 DISORDERS IT'S THE MOST COMMON 3037 02:28:51,360 --> 02:28:53,000 CAUSE OF MOTOR DISABILITY IN 3038 02:28:53,000 --> 02:28:56,560 CHILDREN AND INCIDENTS OF 23 PER 3039 02:28:56,560 --> 02:28:58,400 1,000 LIVE BIRTHS IN THE UNITED 3040 02:28:58,400 --> 02:28:58,800 STATES. 3041 02:28:58,800 --> 02:29:01,440 THE TERM REPRESENTS A 3042 02:29:01,440 --> 02:29:02,560 HETEROGENEOUS GROUP OF 3043 02:29:02,560 --> 02:29:06,680 CONDITIONS CHARACTERIZED BY 3044 02:29:06,680 --> 02:29:09,200 IMPAIRMENT OF MOVEMENT POSTURE 3045 02:29:09,200 --> 02:29:11,640 AND OR MOTOR FUNCTION AND ONSET 3046 02:29:11,640 --> 02:29:13,000 OCCURS TYPICALLY BETWEEN TWO TO 3047 02:29:13,000 --> 02:29:16,120 THREE YEARS OF AGE AND IN 3048 02:29:16,120 --> 02:29:18,880 UNDERLYING GENETIC ETIOLOGY CAN 3049 02:29:18,880 --> 02:29:21,840 BE DETERMINED FOR 20% TO 60% OF 3050 02:29:21,840 --> 02:29:44,400 PATIENTS DEPENDING ON THE COHORT 3051 02:29:44,400 --> 02:29:45,840 I WANT TO SHARE ABOUT THE 3052 02:29:45,840 --> 02:29:48,040 MOLECULAR DIAGNOSTICS TODAY. 3053 02:29:48,040 --> 02:29:51,200 FORTUNATELY IT TAKES AN AVERAGE 3054 02:29:51,200 --> 02:29:54,680 OF 4.8 TO 5 YEARS FOR AN 3055 02:29:54,680 --> 02:29:56,760 INDIVIDUAL TO RECEIVE AN 3056 02:29:56,760 --> 02:29:59,400 ACCURATE DIAGNOSIS. 3057 02:29:59,400 --> 02:30:02,440 THE REASONS ARE MULTIFOLD AND WE 3058 02:30:02,440 --> 02:30:03,600 HAVE INDIVIDUALS TRYING TO 3059 02:30:03,600 --> 02:30:05,160 ACCESS AND RECEIVE GENETIC 3060 02:30:05,160 --> 02:30:05,640 TESTING. 3061 02:30:05,640 --> 02:30:07,160 IF PATIENTS ARE HAVING TO PAY 3062 02:30:07,160 --> 02:30:08,880 OUT OF POCKET OR HAVE POOR 3063 02:30:08,880 --> 02:30:10,320 INSURANCE COVERAGE THIS CAN BE A 3064 02:30:10,320 --> 02:30:13,520 VERY LARGE BARRIER FOR MANY MANY 3065 02:30:13,520 --> 02:30:13,880 FAMILIES. 3066 02:30:13,880 --> 02:30:16,200 AND THERE ARE REIMBURSEMENT 3067 02:30:16,200 --> 02:30:17,720 CHALLENGES SO EVEN FOR THOSE 3068 02:30:17,720 --> 02:30:19,360 THAT HAVE INSURANCE THAT MAY PAY 3069 02:30:19,360 --> 02:30:21,840 FOR THIS TYPE OF TESTING OFTEN 3070 02:30:21,840 --> 02:30:24,120 THE OUT OF POCKET COSTS ARE SO 3071 02:30:24,120 --> 02:30:25,280 HIGH IT'S UNREASONABLE FOR THE 3072 02:30:25,280 --> 02:30:30,960 FAMILY TO BE ABLE TO AFFORD THAT 3073 02:30:30,960 --> 02:30:37,560 AND FINALLY WE HAVE AN ISSUE OF 3074 02:30:37,560 --> 02:30:41,120 LACK OF COMFORT WITH GENETIC 3075 02:30:41,120 --> 02:30:42,280 DISORDER AND MANY ARE BEING SEEN 3076 02:30:42,280 --> 02:30:45,800 BY THEIR PEDIATRICIAN AND A LACK 3077 02:30:45,800 --> 02:30:47,440 OF COMFORT WHERE THEY'D LIKE TO 3078 02:30:47,440 --> 02:30:48,960 ORDER THE TEST AND FEEL 3079 02:30:48,960 --> 02:30:49,960 COMFORTABLE EXPLAINING THE TEST 3080 02:30:49,960 --> 02:30:53,880 TO A PATIENT. 3081 02:30:53,880 --> 02:30:58,680 THE COHORT IS FROM OUR CP 3082 02:30:58,680 --> 02:31:00,680 SPECTRUM PANEL AND I'LL TALK 3083 02:31:00,680 --> 02:31:03,080 ABOUT THE GENETIC TESTING 3084 02:31:03,080 --> 02:31:04,760 PROGRAM AND WANTED TO PROVIDE 3085 02:31:04,760 --> 02:31:05,880 BACKGROUND ON WHAT THE TESTING 3086 02:31:05,880 --> 02:31:11,920 PROGRAM IS SO THE GROUP CAN 3087 02:31:11,920 --> 02:31:13,160 BETTER UNDERSTAND THE COHORT AND 3088 02:31:13,160 --> 02:31:19,160 THE WAY THE TESTS ARE DESIGNED. 3089 02:31:19,160 --> 02:31:24,600 PHYSICIANS ARE MADE AWARE OF 3090 02:31:24,600 --> 02:31:25,880 THESE AND WE HAVE PATIENT WE 3091 02:31:25,880 --> 02:31:27,720 SUSPECT HAVE BEEN DIAGNOSED WITH 3092 02:31:27,720 --> 02:31:29,760 A SPECIFIC GENETIC DISORDER AND 3093 02:31:29,760 --> 02:31:31,280 IF THEY MEET CRITERIA THE TEST 3094 02:31:31,280 --> 02:31:33,000 IS ORDERED THROUGH THE PROGRAM 3095 02:31:33,000 --> 02:31:34,720 VIA THEIR CLINICIAN. 3096 02:31:34,720 --> 02:31:36,560 THE CLINICIAN IS THE ONE THAT 3097 02:31:36,560 --> 02:31:37,320 DECIDES WHETHER THIS IS AN 3098 02:31:37,320 --> 02:31:39,120 APPROPRIATE TEST AND THE PATIENT 3099 02:31:39,120 --> 02:31:44,120 CAN DECIDE WHETHER THEY WISH TO 3100 02:31:44,120 --> 02:31:45,000 PARTICIPATE IN THE PROGRAM 3101 02:31:45,000 --> 02:31:46,160 DEPENDING ON WHETHER THEY'D LIKE 3102 02:31:46,160 --> 02:31:47,760 TO SHARE SPECIFIC DATA WITH 3103 02:31:47,760 --> 02:31:50,600 OTHER PROGRAM SPONSORS. 3104 02:31:50,600 --> 02:31:58,040 THE SAMPLES THAT ARE SUBMITTED 3105 02:31:58,040 --> 02:32:03,560 TO INVITAE ARE TEST RESULTS 3106 02:32:03,560 --> 02:32:08,000 DELIVERED TO THE ORDERING 3107 02:32:08,000 --> 02:32:09,880 CLINICIAN AND CLINICIAN AND 3108 02:32:09,880 --> 02:32:13,880 THEY'RE COLLECTED ON OUR QUEST 3109 02:32:13,880 --> 02:32:20,840 REQUISITION FORM. 3110 02:32:20,840 --> 02:32:22,080 THEY'RE SEND REPORTS AND A 3111 02:32:22,080 --> 02:32:23,400 REGULAR CADENCE AND CHARGED 3112 02:32:23,400 --> 02:32:24,760 DIRECTLY FOR THE TEST SO THERE'S 3113 02:32:24,760 --> 02:32:28,880 NO COST INCURRED BY THE PATIENT 3114 02:32:28,880 --> 02:32:30,360 OR FAMILY AND THE SPONSOR HAS 3115 02:32:30,360 --> 02:32:37,760 THE OPTION TO FOLLOW-UP WITH THE 3116 02:32:37,760 --> 02:32:38,560 CLINICIAN NOT THE PATIENT FOR 3117 02:32:38,560 --> 02:32:40,160 THE PROGRAM AND IT'S A WAY WE 3118 02:32:40,160 --> 02:32:42,440 TRY TO GET AROUND THE FACT THAT 3119 02:32:42,440 --> 02:32:44,040 ACCESS TO GENETIC TESTING TODAY 3120 02:32:44,040 --> 02:32:45,760 IS SO DIFFICULT FOR MANY 3121 02:32:45,760 --> 02:32:46,000 FAMILIES. 3122 02:32:46,000 --> 02:32:49,360 SO WE'VE BEEN TRYING TO PROVIDE 3123 02:32:49,360 --> 02:32:51,560 PATIENT TO MEET CERTAIN CRITERIA 3124 02:32:51,560 --> 02:32:54,800 WITH NO CHARGE TESTING IN ORDER 3125 02:32:54,800 --> 02:32:58,360 FOR THEM TO RECEIVE A MOLECULAR 3126 02:32:58,360 --> 02:32:58,600 DIAGNOSIS. 3127 02:32:58,600 --> 02:33:00,360 I WANTED TO BRIEFLY TOUCH BEFORE 3128 02:33:00,360 --> 02:33:05,680 WE START TALKING ABOUT SPAST A 3129 02:33:05,680 --> 02:33:08,160 LITTLE BIT MORE ABOUT WHAT DO I 3130 02:33:08,160 --> 02:33:13,160 MEAN WHEN I SAY DE-IDENTIFIED 3131 02:33:13,160 --> 02:33:14,840 INFORMATION AND THE FIRST IS 3132 02:33:14,840 --> 02:33:16,320 CLINICIAN INFORMATION AND THE 3133 02:33:16,320 --> 02:33:17,520 CLINICIAN'S NAME AND E-MAIL 3134 02:33:17,520 --> 02:33:19,080 ADDRESS OR PHONE NUMBER AND MPI 3135 02:33:19,080 --> 02:33:19,720 NUMBER AND INSTITUTION NAME AND 3136 02:33:19,720 --> 02:33:23,640 ADDRESS. 3137 02:33:23,640 --> 02:33:26,160 NO PATIENT NAME IS EVER SHARED 3138 02:33:26,160 --> 02:33:27,440 IT'S JUST THE CLINICIAN 3139 02:33:27,440 --> 02:33:28,360 IDENTIFYING INFORMATION THAT MAY 3140 02:33:28,360 --> 02:33:29,880 BE SHARED AND CLINICIANS ARE 3141 02:33:29,880 --> 02:33:32,400 AWARE OF THIS AND ATTEST TO IT 3142 02:33:32,400 --> 02:33:33,800 WHEN THEY SEND THEIR PATIENTS 3143 02:33:33,800 --> 02:33:35,360 FOR TESTING THROUGH THE PROGRAM. 3144 02:33:35,360 --> 02:33:36,000 VARYING INFORMATION WE MIGHT 3145 02:33:36,000 --> 02:33:40,200 SHARE WOULD BE THE GENE, THE 3146 02:33:40,200 --> 02:33:43,760 NOMENCLATURE AND VARIANT, THE 3147 02:33:43,760 --> 02:33:50,320 ZYGOCITY AND ARE THEY PATHOGENIC 3148 02:33:50,320 --> 02:33:53,240 OR INSIGNIFICANT VARIANTS AND 3149 02:33:53,240 --> 02:33:53,760 CLINICAL INFORMATION. 3150 02:33:53,760 --> 02:33:57,840 WE'RE NOT PROVIDING SPONSORS A 3151 02:33:57,840 --> 02:34:00,160 WHOLE CLINIC NOTE IT'S JUST THE 3152 02:34:00,160 --> 02:34:03,000 CLINICAL INFORMATION PROVIDED 3153 02:34:03,000 --> 02:34:05,320 THROUGH THE SPONSOR TESTING 3154 02:34:05,320 --> 02:34:07,360 PROGRAM REQUISITION PROGRAM LIKE 3155 02:34:07,360 --> 02:34:09,360 AGE IN YEARS, CLINICAL SYMPTOMS 3156 02:34:09,360 --> 02:34:13,440 AND WE ASK WHAT TYPE OF CARDIO 3157 02:34:13,440 --> 02:34:15,640 MYOPATHY THEY HAVE IS IT 3158 02:34:15,640 --> 02:34:16,440 HYPERTROPHIC, FOR EXAMPLE, 3159 02:34:16,440 --> 02:34:17,880 SPECIFIC LAB AND TEST RESULTS 3160 02:34:17,880 --> 02:34:20,760 THAT MIGHT BE PERTINENT TO THE 3161 02:34:20,760 --> 02:34:22,560 PROGRAM SPONSORS, TREATMENT 3162 02:34:22,560 --> 02:34:28,520 HISTORY SO WE HAVE AN EPILEPSY 3163 02:34:28,520 --> 02:34:29,880 DRUG AND WE'LL ASK HOW MANY 3164 02:34:29,880 --> 02:34:31,840 EPILEPSY DRUGS HAS THE PATIENT 3165 02:34:31,840 --> 02:34:34,760 TRIED SO FAR AND TESTING ARE 3166 02:34:34,760 --> 02:34:37,840 THERE SIMILARLY AFFECTED FAMILY 3167 02:34:37,840 --> 02:34:41,840 MEMBERS AND ANY SUSPECTED 3168 02:34:41,840 --> 02:34:44,520 CLINICAL DIAGNOSES FROM THE 3169 02:34:44,520 --> 02:34:44,920 PHYSICIAN. 3170 02:34:44,920 --> 02:34:47,160 NOW I'LL TALK ABOUT DATA FROM 3171 02:34:47,160 --> 02:34:48,800 THE PINPOINT GENETIC TEST 3172 02:34:48,800 --> 02:34:49,480 PROGRAM. 3173 02:34:49,480 --> 02:34:51,880 THIS SAY PROGRAM THAT IS A 3174 02:34:51,880 --> 02:34:53,160 SPONSORED TESTING PROGRAM THAT 3175 02:34:53,160 --> 02:34:56,800 IS PERFORMED BY INVITAE. 3176 02:34:56,800 --> 02:34:59,280 SO PDC SPONSORS THE PROGRAM BUT 3177 02:34:59,280 --> 02:35:01,760 WE'RE PERFORMING ALL THE TESTING 3178 02:35:01,760 --> 02:35:03,360 IN OUR CLINICAL LABORATORY MUCH 3179 02:35:03,360 --> 02:35:05,160 LIKE ALL THE OTHER GENETIC 3180 02:35:05,160 --> 02:35:07,680 TESTING WE PERFORM. 3181 02:35:07,680 --> 02:35:09,880 FOR INDIVIDUALS TO BE ELIGIBLE 3182 02:35:09,880 --> 02:35:11,280 THEY MUST RESIDE WITHIN THE 3183 02:35:11,280 --> 02:35:17,440 U.S. OR CANADA AND MUST HAVE 3184 02:35:17,440 --> 02:35:20,160 SYMPTOMS SUGGESTIVE CEREBRAL 3185 02:35:20,160 --> 02:35:20,560 PALSY. 3186 02:35:20,560 --> 02:35:21,840 THE FIRST THING YOU'LL NOTICE IS 3187 02:35:21,840 --> 02:35:23,280 FOR MANY SPONSORED TESTING 3188 02:35:23,280 --> 02:35:25,720 PROGRAM WE PURPOSELY MADE THE 3189 02:35:25,720 --> 02:35:27,880 INCLUSION OR THE ELIGIBILITY 3190 02:35:27,880 --> 02:35:29,160 CRITERIA QUITE BROAD SO WE CAN 3191 02:35:29,160 --> 02:35:29,880 IMPACT THE LARGEST NUMBER OF 3192 02:35:29,880 --> 02:35:34,560 PATIENTS. 3193 02:35:34,560 --> 02:35:36,280 NEXT I WANTED TO SHARE A LITTLE 3194 02:35:36,280 --> 02:35:38,320 BIT MORE ABOUT THE PANEL ITSELF. 3195 02:35:38,320 --> 02:35:40,760 THIS IS A VERY LARGE PANEL. 3196 02:35:40,760 --> 02:35:42,840 IT HAS 425 GENES AND SO 3197 02:35:42,840 --> 02:35:44,000 UNFORTUNATELY I'M NOT ABLE TO 3198 02:35:44,000 --> 02:35:45,840 SHOW ALL THE GENES THAT ARE 3199 02:35:45,840 --> 02:35:47,920 INCLUDED IN THE PANEL IN A 3200 02:35:47,920 --> 02:35:49,560 SINGLE SLIDE BUT I DID PROVIDE A 3201 02:35:49,560 --> 02:35:51,680 WEBSITE AT THE BOTTOM OF THIS 3202 02:35:51,680 --> 02:35:55,200 PAGE SHOULD ANYONE WANT TO GO 3203 02:35:55,200 --> 02:35:56,560 REVIEW THE GENES FURTHER THE 3204 02:35:56,560 --> 02:36:01,800 TURN AROUND TIME FOR THIS TEST 3205 02:36:01,800 --> 02:36:05,920 IS 10 AND 21 DAYS AND WE HAD TO 3206 02:36:05,920 --> 02:36:09,600 ACCEPT MULTIPLE TYPES OF 3207 02:36:09,600 --> 02:36:11,360 SPECIMENS INCLUDING BLOOD, 3208 02:36:11,360 --> 02:36:13,800 SALIVA OR GENOMIC DNA IF THAT'S 3209 02:36:13,800 --> 02:36:14,600 AVAILABLE AS WELL. 3210 02:36:14,600 --> 02:36:15,880 AND REALLY WHAT WE'RE TRYING TO 3211 02:36:15,880 --> 02:36:17,800 ACHIEVE WITH THIS PANEL IS 3212 02:36:17,800 --> 02:36:19,240 OFFERING A BROAD PANEL OF GENES 3213 02:36:19,240 --> 02:36:20,760 THAT MIGHT BE ABLE TO DETERMINE 3214 02:36:20,760 --> 02:36:24,400 THE ETIOLOGY OF CEREBRAL PALSY. 3215 02:36:24,400 --> 02:36:27,320 BECAUSE IT'S SUCH A 3216 02:36:27,320 --> 02:36:28,720 HETEROGENEOUS GROUP OF DISORDERS 3217 02:36:28,720 --> 02:36:33,840 WE ALSO INCLUDED GENES 3218 02:36:33,840 --> 02:36:37,320 ASSOCIATED WITH HEREDITARY 3219 02:36:37,320 --> 02:36:39,080 SPASTIC PARAPLEGIAS AND ATAXIAS 3220 02:36:39,080 --> 02:36:41,760 AND OTHER DISORDERS THAT CAN 3221 02:36:41,760 --> 02:36:50,160 MIMIC CEREBRAL PALSY. 3222 02:36:50,160 --> 02:36:52,680 AND WE'RE PERFORMING NEXT 3223 02:36:52,680 --> 02:36:53,840 GENERATION SEQUENCING AND WE 3224 02:36:53,840 --> 02:36:56,200 HAVE WHOLE GENE SEQUENCING AND 3225 02:36:56,200 --> 02:36:57,320 DUPLICATION ANALYSIS OF ALMOST 3226 02:36:57,320 --> 02:37:00,560 EVERY AXON IN EVERY GENE OFFERED 3227 02:37:00,560 --> 02:37:02,280 ON THE PANEL. 3228 02:37:02,280 --> 02:37:09,080 WE HAVE HIGH AVERAGE COVERAGE IN 3229 02:37:09,080 --> 02:37:11,880 THE ANALYSIS ALSO INCLUDES AND 3230 02:37:11,880 --> 02:37:14,760 WE'RE ABLE TO IDENTIFY SEQUENCE 3231 02:37:14,760 --> 02:37:17,800 VARIANCE AND COPY NUMBER 3232 02:37:17,800 --> 02:37:20,480 VARIANTS IN THE ASSAY. 3233 02:37:20,480 --> 02:37:23,120 THE COHORT I WOULD LIKE TO SHARE 3234 02:37:23,120 --> 02:37:25,200 MORE INFORMATION ABOUT TODAY IS 3235 02:37:25,200 --> 02:37:26,920 THE COHORT OF CHILDREN OR 3236 02:37:26,920 --> 02:37:27,680 INDIVIDUALS THAT HAVE BEEN 3237 02:37:27,680 --> 02:37:29,680 TESTED -- SORRY, NOT JUST 3238 02:37:29,680 --> 02:37:33,000 CHILDREN, TESTED THROUGH THE PTC 3239 02:37:33,000 --> 02:37:35,840 PINPOINT CP SPECTRUM PANEL AND 3240 02:37:35,840 --> 02:37:48,360 THE DATE RANGE IS 9/15/2020 TO 3241 02:37:48,360 --> 02:37:49,800 12/15/21 AND THE AVERAGE RANGE 3242 02:37:49,800 --> 02:37:53,840 OF TESTING WAS 8 YEARS OLD BUT 3243 02:37:53,840 --> 02:37:56,280 THERE WAS QUITE A RANGE OF AGES 3244 02:37:56,280 --> 02:38:01,040 AT THE TIME RANGING FROM ZERO TO 3245 02:38:01,040 --> 02:38:01,840 74 YEARS. 3246 02:38:01,840 --> 02:38:04,760 WE HAD PROVIDERS WHO ORDERED 3247 02:38:04,760 --> 02:38:08,520 THROUGH THE PROGRAM COMING FROM 3248 02:38:08,520 --> 02:38:09,800 18 UNIQUE SPECIALTIES. 3249 02:38:09,800 --> 02:38:11,920 I'M PROVIDING MORE INFORMATION 3250 02:38:11,920 --> 02:38:14,200 ABOUT THE EXPERIMENTS HERE. 3251 02:38:14,200 --> 02:38:15,960 A LOT OF THESE MAKE SENSE. 3252 02:38:15,960 --> 02:38:19,120 WE'RE LOOKING AT SOME PEDIATRIC 3253 02:38:19,120 --> 02:38:21,720 SPECIALISTS AND NEUROMUSCULAR 3254 02:38:21,720 --> 02:38:23,040 MEDICINE SPECIALISTS AND HAVE 3255 02:38:23,040 --> 02:38:25,120 MORE MOLECULAR GENETIC AND 3256 02:38:25,120 --> 02:38:26,880 CLINICAL GENETIC FOCUSSED 3257 02:38:26,880 --> 02:38:27,360 SPECIALISTS AS WELL. 3258 02:38:27,360 --> 02:38:33,800 THIS IS TYPICAL OF WHAT WE SEE 3259 02:38:33,800 --> 02:38:39,880 FROM AND MANY ARE BEING SEEN BY 3260 02:38:39,880 --> 02:38:41,520 PROVIDERS AND THERE'S MANY TYPES 3261 02:38:41,520 --> 02:38:42,120 OF PROVIDERS PARTICIPATING IN 3262 02:38:42,120 --> 02:38:45,560 THE PROGRAM. 3263 02:38:45,560 --> 02:38:47,840 IN TERMS OF THE DIAGNOSTIC 3264 02:38:47,840 --> 02:38:50,240 YIELD, THIS IS A PROGRAM WHERE 3265 02:38:50,240 --> 02:38:52,760 THERE ARE OBVIOUSLY MANY 3266 02:38:52,760 --> 02:38:54,280 DIFFERENT CAUSES OF CEREBRAL 3267 02:38:54,280 --> 02:38:54,680 PALSY. 3268 02:38:54,680 --> 02:38:56,800 SOME ARE GENETIC AND SOME 3269 02:38:56,800 --> 02:38:57,440 ENVIRONMENTAL AND SOME MAY BE A 3270 02:38:57,440 --> 02:39:05,240 MIX OF BOTH. 3271 02:39:05,240 --> 02:39:07,720 WHAT WE SEE THIS PERCENTAGE AND 3272 02:39:07,720 --> 02:39:09,280 THERE'S A LARGE NUMBER OF 3273 02:39:09,280 --> 02:39:11,240 INDIVIDUALS THAT MAY NOT ACHIEVE 3274 02:39:11,240 --> 02:39:12,120 A MOLECULAR DIAGNOSIS THAT MAY 3275 02:39:12,120 --> 02:39:17,840 BE FOUND TO BE A CARRIER FOR 3276 02:39:17,840 --> 02:39:19,840 AUTOSOMAL RECESSSIVE DISORDER OR 3277 02:39:19,840 --> 02:39:21,840 HARBOR A VARIANT OF 3278 02:39:21,840 --> 02:39:25,800 SIGNIFICANCE. 3279 02:39:25,800 --> 02:39:30,880 THERE ARE FEW PATIENTS AND 3280 02:39:30,880 --> 02:39:33,560 THERE'S OVER 425 GENES SO THE 3281 02:39:33,560 --> 02:39:35,880 PROBABLE THAT AN INDIVIDUAL DOES 3282 02:39:35,880 --> 02:39:38,560 NOT HARBOR A SINGLE VARIANT 3283 02:39:38,560 --> 02:39:40,240 REPORTABLE IN ANY ONE OF THOSE 3284 02:39:40,240 --> 02:39:41,320 GENES ARE QUITE LOW. 3285 02:39:41,320 --> 02:39:42,160 YOU'RE SEEING THIS SPREAD FOR 3286 02:39:42,160 --> 02:39:51,360 THIS PARTICULAR PROGRAM. 3287 02:39:51,360 --> 02:39:53,400 NEXT I WANT TO TALK ABOUT THE 3288 02:39:53,400 --> 02:39:54,640 MOST COMMON MOLECULAR DIAGNOSES 3289 02:39:54,640 --> 02:39:55,480 THROUGH THE PROGRAM. 3290 02:39:55,480 --> 02:39:58,560 YOU CAN SEE PART OF THE REASON 3291 02:39:58,560 --> 02:40:00,080 WE'RE HERE TODAY IS THE SPAST 3292 02:40:00,080 --> 02:40:01,880 GENE DOESN'T COUNT FOR THE 3293 02:40:01,880 --> 02:40:03,760 MAJORITY OF THE DIAGNOSES WE SEE 3294 02:40:03,760 --> 02:40:04,760 IN THE PROGRAM AND WE'VE 3295 02:40:04,760 --> 02:40:06,920 IDENTIFIED AT THE TIME OF THIS 3296 02:40:06,920 --> 02:40:09,160 DATA CUT 19 INDIVIDUALS. 3297 02:40:09,160 --> 02:40:11,920 I THINK WE'RE ALMOST NEARING 25 3298 02:40:11,920 --> 02:40:13,200 NOW AT THIS POINT. 3299 02:40:13,200 --> 02:40:17,000 SO WHAT THIS MEANS IS 1.1% OF 3300 02:40:17,000 --> 02:40:20,120 ALL MOLECULAR DIAGNOSES ARE 3301 02:40:20,120 --> 02:40:22,200 ATTRIBUTED TO SPAST IN THIS 3302 02:40:22,200 --> 02:40:24,760 COHORT AND SPAST MAKES UP 11% OF 3303 02:40:24,760 --> 02:40:35,520 POSITIVE OF ALL MOLECULAR 3304 02:40:35,520 --> 02:40:37,920 DIAGNOSES RECEIVED IN THE COHORT 3305 02:40:37,920 --> 02:40:39,640 AND IT'S QUITE INTERESTING. 3306 02:40:39,640 --> 02:40:41,680 NEXT I WANTED TO PROVIDE MORE 3307 02:40:41,680 --> 02:40:41,960 INFORMATION. 3308 02:40:41,960 --> 02:40:49,360 I KNOW IN A FEW TALKS TODAY I 3309 02:40:49,360 --> 02:40:51,480 WANTED TO SHARE WHICH PATHOGENIC 3310 02:40:51,480 --> 02:40:52,800 VARIANTS WE'VE IDENTIFIED SO FAR 3311 02:40:52,800 --> 02:40:57,680 IN THE COHORT AND POINT YOUR 3312 02:40:57,680 --> 02:40:59,120 ATTENTION TOWARDS THIS WHICH 3313 02:40:59,120 --> 02:41:01,880 APPEARS TO BE A RECURRING 3314 02:41:01,880 --> 02:41:05,840 PATHOGENIC VARIANT IN THE 3315 02:41:05,840 --> 02:41:06,360 COHORT. 3316 02:41:06,360 --> 02:41:08,760 YOU'LL NOTICE WE TALKED ABOUT 3317 02:41:08,760 --> 02:41:11,560 LOSS OF FUNCTION VARIANTS AND 3318 02:41:11,560 --> 02:41:12,160 THERE'S QUITE A NUMBER ON THIS 3319 02:41:12,160 --> 02:41:32,240 LIST. 3320 02:41:32,240 --> 02:41:41,560 THIS IS A FEMALE CHILD WITH 3321 02:41:41,560 --> 02:41:43,320 SPASTIC DYSPLASIA AND THE 3322 02:41:43,320 --> 02:41:46,360 VARIANT IS AT A HIGHLY CONSERVED 3323 02:41:46,360 --> 02:41:48,160 RESIDUE AND NOT DATABASE AND 3324 02:41:48,160 --> 02:41:49,240 IT'S BEEN REPORTED IN THE 3325 02:41:49,240 --> 02:41:50,640 LITERATURE IN MULTIPLE 3326 02:41:50,640 --> 02:41:53,560 INDIVIDUALS AND FAMILIES 3327 02:41:53,560 --> 02:41:56,120 AFFECTED WITH SPASTIC PARAPLEGIA 3328 02:41:56,120 --> 02:41:58,200 AND WE HAVE IDENTIFIED IT AS 3329 02:41:58,200 --> 02:42:00,120 BEING DE NOVO IN THIS PATIENT 3330 02:42:00,120 --> 02:42:15,920 AND OTHERS AS WELL. 3331 02:42:15,920 --> 02:42:17,960 AND THERE'S A STRONG PATHOGENIC 3332 02:42:17,960 --> 02:42:22,160 VARIANT AND ONE RECURRENT IN OUR 3333 02:42:22,160 --> 02:42:27,520 POPULATION. 3334 02:42:27,520 --> 02:42:29,760 I WANT TO MAKE SURE WE HAVE TIME 3335 02:42:29,760 --> 02:42:30,680 FOR THE OVERALL DISCUSSION OF 3336 02:42:30,680 --> 02:42:32,440 THE GROUP. 3337 02:42:32,440 --> 02:42:35,320 I WANTED TO SHARE THE SPECTRUM 3338 02:42:35,320 --> 02:42:38,600 PANEL CAN BE A MOLECULAR TOOL 3339 02:42:38,600 --> 02:42:40,360 UTILIZED BY A VARIETY OF 3340 02:42:40,360 --> 02:42:40,800 PROVIDERS. 3341 02:42:40,800 --> 02:42:44,200 IT MAY HELP IDENTIFY THE 3342 02:42:44,200 --> 02:42:53,160 UNDERLYING GENETIC CAUSE WITH 3343 02:42:53,160 --> 02:42:54,560 ETIOLOGY AND MAY NEED TO CAUTION 3344 02:42:54,560 --> 02:42:57,600 THEY MAY GET MORE THAN ONE 3345 02:42:57,600 --> 02:42:59,760 SIGNIFICANCE GIVEN THE PANEL 3346 02:42:59,760 --> 02:42:59,960 SIZE. 3347 02:42:59,960 --> 02:43:02,520 THE DIAGNOSTIC YIELD IS EXPECTED 3348 02:43:02,520 --> 02:43:05,120 TO IMPROVE WITH FAMILY STUDIES 3349 02:43:05,120 --> 02:43:05,960 WE ARE ABLE TO PERFORM BY 3350 02:43:05,960 --> 02:43:10,960 TESTING AAFFECTED AND UNAFFECTED 3351 02:43:10,960 --> 02:43:11,960 RELATIVES AND DATA PUBLISHED IN 3352 02:43:11,960 --> 02:43:13,600 THE LITERATURE AND THIS 3353 02:43:13,600 --> 02:43:15,160 NO-CHARGE SPONSORED TESTING 3354 02:43:15,160 --> 02:43:17,440 PROGRAM CAN BE A PART OF A 3355 02:43:17,440 --> 02:43:21,320 TIERED DIAGNOSTIC APPROACH FOR 3356 02:43:21,320 --> 02:43:23,960 PATIENTS WITH CEREBRAL PALSY AND 3357 02:43:23,960 --> 02:43:30,800 I'LL END THERE. 3358 02:43:30,800 --> 02:43:34,000 >> THANK YOU SO MUCH, HEATHER 3359 02:43:34,000 --> 02:43:35,360 FOR A WONDERFUL PRESENTATION. 3360 02:43:35,360 --> 02:43:38,760 THIS COULD BE A GOOD TIME FOR US 3361 02:43:38,760 --> 02:43:41,360 TO OPEN THE ENTIRE PANEL FOR 3362 02:43:41,360 --> 02:43:42,080 DISCUSSION INCLUDING DISCUSSIONS 3363 02:43:42,080 --> 02:43:45,960 ABOUT THE TOPICS THAT WERE 3364 02:43:45,960 --> 02:44:06,480 COVERED IN THE MORNING. 3365 02:44:06,480 --> 02:44:09,520 >> IF PEOPLE CAN INTRODUCE 3366 02:44:09,520 --> 02:44:10,640 THEMSELVES AND I SEE SOME PART 3367 02:44:10,640 --> 02:44:13,280 INITIATIVE THAT HEATHER WAS 3368 02:44:13,280 --> 02:44:14,400 TALKING ABOUT AND I THINK JEFF 3369 02:44:14,400 --> 02:44:16,200 MENTIONED HE HAD A QUESTION SO 3370 02:44:16,200 --> 02:44:18,200 MAYBE WE CAN OPEN WITH THAT IF 3371 02:44:18,200 --> 02:44:25,520 AVAILABLE. 3372 02:44:25,520 --> 02:44:27,080 >> A LOT OF MY QUESTION WAS NOT 3373 02:44:27,080 --> 02:44:28,320 ABOUT THAT TOPIC THOUGH HEATHER 3374 02:44:28,320 --> 02:44:33,760 DID A FABULOUS JOB REVIEWING 3375 02:44:33,760 --> 02:44:33,960 THAT. 3376 02:44:33,960 --> 02:44:37,160 MY QUESTION WAS ABOUT THE 3377 02:44:37,160 --> 02:44:41,040 HYPOMORPHIC VARIANT REVIEWED AND 3378 02:44:41,040 --> 02:44:43,160 WONDERING IF THE PRESENTER CAN 3379 02:44:43,160 --> 02:44:45,320 SPEAK TO HOW THAT HYPOMORPHIC 3380 02:44:45,320 --> 02:44:47,600 VARIANT WAS PROVEN AS SUCH. 3381 02:44:47,600 --> 02:44:53,920 WE'RE INTERESTED IN A 3382 02:44:53,920 --> 02:45:01,080 HYPOMORPHIC IN THE DDC GENE SO 3383 02:45:01,080 --> 02:45:02,920 WE'RE TRYING TO UNDERSTAND THE 3384 02:45:02,920 --> 02:45:05,160 THEORY OF A HYPOMORPHIC VARIANT 3385 02:45:05,160 --> 02:45:06,800 SIMILAR TO WHAT YOU PRESENTED, 3386 02:45:06,800 --> 02:45:09,880 DR. POSEY. 3387 02:45:09,880 --> 02:45:12,640 >> ABSOLUTELY. 3388 02:45:12,640 --> 02:45:15,080 SO BRIEFLY THE TEAM THAT MADE 3389 02:45:15,080 --> 02:45:19,360 THAT DISCOVERY, THEY DID TWO 3390 02:45:19,360 --> 02:45:20,080 THINGS. 3391 02:45:20,080 --> 02:45:24,520 THE FIRST WAS SET UP CELLULAR 3392 02:45:24,520 --> 02:45:27,920 ASSAYS TO TEST LOCALIZATION AND 3393 02:45:27,920 --> 02:45:30,720 FOUND THE HYPOMORPHIC VARIANT 3394 02:45:30,720 --> 02:45:39,720 DID NOT LOCALIZE OR EXPRESS TO 3395 02:45:39,720 --> 02:45:41,640 THE SAME LEVEL AND HAD EVIDENCE 3396 02:45:41,640 --> 02:45:43,440 IT WAS UP FRONT AND THE 3397 02:45:43,440 --> 02:45:44,800 IMPORTANT NEXT THING THEY DID 3398 02:45:44,800 --> 02:45:47,400 WAS BUILT THAT PARTICULAR ALLELE 3399 02:45:47,400 --> 02:45:49,520 IN MICE. 3400 02:45:49,520 --> 02:45:51,000 AND I TAKE THE SLIDE OUT OF MY 3401 02:45:51,000 --> 02:45:53,720 PRESENTATION SO I DON'T HAVE IT 3402 02:45:53,720 --> 02:45:55,040 HANDY QUICKLY BUT ESSENTIALLY 3403 02:45:55,040 --> 02:45:56,640 THEY DID THE SAME EXPERIMENT IN 3404 02:45:56,640 --> 02:45:58,320 MICE THEY'VE BEEN OBSERVING IN 3405 02:45:58,320 --> 02:45:58,760 HUMANS. 3406 02:45:58,760 --> 02:46:02,680 FOR BOTH MOUSE AND HUMANS IF YOU 3407 02:46:02,680 --> 02:46:07,400 HAVE A DOUBLE KNOCKOUT OF TBX6 3408 02:46:07,400 --> 02:46:08,840 WAS LETHAL SO THAT WAS NOT 3409 02:46:08,840 --> 02:46:10,360 AVAILABLE AND COMPARED IT TO THE 3410 02:46:10,360 --> 02:46:13,120 SINGLE HYPOMORPH TO THE COMPOUND 3411 02:46:13,120 --> 02:46:15,640 LOSS TO FUNCTION PLUS HYPOMORPH 3412 02:46:15,640 --> 02:46:18,720 AND THEN ALSO A HOMOZYGOUS 3413 02:46:18,720 --> 02:46:20,040 HYPOMORPH AND IT WAS ONLY THE 3414 02:46:20,040 --> 02:46:23,080 MICE THAT HAD THE LOSS OF 3415 02:46:23,080 --> 02:46:25,280 FUNCTION WITH THE HYPOMORPH WITH 3416 02:46:25,280 --> 02:46:26,880 A SKELETAL PHENOTYPE AND WHAT 3417 02:46:26,880 --> 02:46:28,280 WAS CURIOUS WAS THE MICE AND 3418 02:46:28,280 --> 02:46:31,960 HUMANS HAVE A SIMILAR SKELETAL 3419 02:46:31,960 --> 02:46:32,240 PHENOTYPE. 3420 02:46:32,240 --> 02:46:34,360 THE SCOLIOSIS INVOLVES THE LOWER 3421 02:46:34,360 --> 02:46:36,680 SPINE WHICH WAS IMPORTANT TO 3422 02:46:36,680 --> 02:46:40,560 THEM BECAUSE THEY WERE ABLE TO 3423 02:46:40,560 --> 02:46:41,760 OPERATE ON THE PATIENTS MORE 3424 02:46:41,760 --> 02:46:45,400 READILY AND MORE ACCESSIBLE THAN 3425 02:46:45,400 --> 02:46:46,720 THE THORACIC SPINE WHERE YOU 3426 02:46:46,720 --> 02:46:48,960 HAVE TO WORRY ABOUT THE RIBS AND 3427 02:46:48,960 --> 02:46:51,400 THINGS BECOME MORE CHALLENGING. 3428 02:46:51,400 --> 02:46:52,960 THEY SIMPLY DID CELLULAR ASSAYS 3429 02:46:52,960 --> 02:46:55,560 AND FOLLOWED IT UP WITH MOUSE 3430 02:46:55,560 --> 02:46:57,760 GENOMICS AS WELL. 3431 02:46:57,760 --> 02:46:58,600 >> THANK YOU. 3432 02:46:58,600 --> 02:46:59,200 VERY HELPFUL. 3433 02:46:59,200 --> 02:47:01,400 WE HAVE A GROUP IN ITALY DOING 3434 02:47:01,400 --> 02:47:02,680 THE CELLULAR FUNCTIONAL STUDIES 3435 02:47:02,680 --> 02:47:04,880 BUT I DON'T KNOW IF ANYONE'S 3436 02:47:04,880 --> 02:47:05,920 LOOKED AT ANIMAL MODELS. 3437 02:47:05,920 --> 02:47:25,560 THANK YOU FOR EXPLAINING. 3438 02:47:25,560 --> 02:47:29,720 >> AND LOOKING HOW THE MUTATIONS 3439 02:47:29,720 --> 02:47:30,880 CAN LEAD TO THE PHENOTYPE AND 3440 02:47:30,880 --> 02:47:32,840 HAVE TROUBLE UNDERSTANDING WHERE 3441 02:47:32,840 --> 02:47:33,960 THE INHERITANCE MECHANISM SHOULD 3442 02:47:33,960 --> 02:47:36,400 CAUSE A DIFFERENT PHENOTYPE. 3443 02:47:36,400 --> 02:47:37,920 AT FIRST I THOUGHT IT'S THE VERY 3444 02:47:37,920 --> 02:47:39,760 NATURE OF THE SPECIFIC MUTATIONS 3445 02:47:39,760 --> 02:47:42,880 THAT LEAD TO A SEVERE PHENOTYPE 3446 02:47:42,880 --> 02:47:44,960 AND THE SEVERITY OF THE 3447 02:47:44,960 --> 02:47:49,480 PHENOTYPE IN TURN LEADS TO A 3448 02:47:49,480 --> 02:48:01,840 MORE COMMONLY OBSERVED DE NOVO 3449 02:48:01,840 --> 02:48:04,760 INHERITANCE AND FIND THE SAME 3450 02:48:04,760 --> 02:48:06,720 MUTATIONS IN DE NOVO IN OUR 3451 02:48:06,720 --> 02:48:08,680 ADULT POPULATIONS WITH A MILDER 3452 02:48:08,680 --> 02:48:08,960 PHENOTYPE. 3453 02:48:08,960 --> 02:48:11,680 THIS IS SOMETHING I REALLY DON'T 3454 02:48:11,680 --> 02:48:11,960 UNDERSTAND. 3455 02:48:11,960 --> 02:48:13,840 I'M WONDERING WHETHER ANYBODY 3456 02:48:13,840 --> 02:48:17,960 HAS IDEAS THERE. 3457 02:48:17,960 --> 02:48:20,360 >> I GUESS I CAN GO FIRST. 3458 02:48:20,360 --> 02:48:22,200 I DEFINITELY DON'T HAVE A 3459 02:48:22,200 --> 02:48:22,960 DEFINITIVE ANSWER FOR YOU BUT 3460 02:48:22,960 --> 02:48:25,800 THERE'S A COUPLE THINGS I WONDER 3461 02:48:25,800 --> 02:48:27,320 ABOUT WHEN I LOOK AT SOME OF THE 3462 02:48:27,320 --> 02:48:29,560 DATA THAT HAVE BEEN PRESENTED ON 3463 02:48:29,560 --> 02:48:32,040 INDIVIDUALS WITH A MORE SEVERE 3464 02:48:32,040 --> 02:48:32,320 PHENOTYPE. 3465 02:48:32,320 --> 02:48:35,920 ONE OF THE FIRST THINGS THAT I 3466 02:48:35,920 --> 02:48:39,880 WONDER IS HAS ANYBODY LOOKED AT 3467 02:48:39,880 --> 02:48:41,160 ADDITIONAL VARIANTS IN THEIR 3468 02:48:41,160 --> 02:48:43,800 EXOMES OR EVEN GENOMES THAT MAY 3469 02:48:43,800 --> 02:48:45,720 BE MODIFYING THE PHENOTYPE? 3470 02:48:45,720 --> 02:48:47,600 AND ONE OF THE REASONS IT'S SO 3471 02:48:47,600 --> 02:48:49,360 COMPELLING TO ME IS FOR THIS 3472 02:48:49,360 --> 02:48:52,600 TYPE OF PHENOTYPE AND FOR 3473 02:48:52,600 --> 02:48:53,960 SIMILAR RELATED NEUROLOGICAL 3474 02:48:53,960 --> 02:48:54,960 PHENOTYPES WE HAVE SUCH A LONG 3475 02:48:54,960 --> 02:48:56,760 LIST OF GENES. 3476 02:48:56,760 --> 02:49:00,120 MANY OF WHICH HAVE EITHER EPI 3477 02:49:00,120 --> 02:49:07,600 EPISTAFFIC -- EPISTATIC 3478 02:49:07,600 --> 02:49:08,600 INTERACTIONS AND THE COMBINATION 3479 02:49:08,600 --> 02:49:09,760 OF THEIR MUTATION PLUS THE 3480 02:49:09,760 --> 02:49:11,960 SECOND HIT COULD BE LEADING TO 3481 02:49:11,960 --> 02:49:12,880 MORE SEVERE DISEASE. 3482 02:49:12,880 --> 02:49:14,960 YOU COULD KIND OF COUNTER THAT 3483 02:49:14,960 --> 02:49:17,840 AND SAY WHY IS IT ONLY THE DE 3484 02:49:17,840 --> 02:49:18,040 NOVOS. 3485 02:49:18,040 --> 02:49:21,840 IT'S POSSIBLE WE HAVEN'T LOOKED 3486 02:49:21,840 --> 02:49:23,480 EXTENSIVELY ENOUGH. 3487 02:49:23,480 --> 02:49:24,840 THAT'S ONE THING TO CONSIDER. 3488 02:49:24,840 --> 02:49:41,800 I DON'T HAVE A GOOD SENSE AND 3489 02:49:41,800 --> 02:49:45,800 KNOW FROM A CLINICAL GENETIC 3490 02:49:45,800 --> 02:49:47,160 PERSPECTIVE IT'S EASY TO GET 3491 02:49:47,160 --> 02:49:49,040 SAMPLES FROM THEM AND THEY HAVE 3492 02:49:49,040 --> 02:49:50,240 SEVERE DISEASE AT LEAST IN THE 3493 02:49:50,240 --> 02:49:56,640 U.S. AND ARE MORE LIKELY TO GET 3494 02:49:56,640 --> 02:49:57,760 EXOME SEQUENCING CLINICALLY 3495 02:49:57,760 --> 02:49:59,760 COVERED SO THE TEST AVAILABILITY 3496 02:49:59,760 --> 02:50:01,440 IS LESS LIMITING BUT EVEN HERE 3497 02:50:01,440 --> 02:50:04,000 WE'RE LEFT WITH THE QUESTION OF 3498 02:50:04,000 --> 02:50:05,600 NON-CODING VARIANTS AND WE'RE 3499 02:50:05,600 --> 02:50:07,360 NOT FREQUENTLY LOOKING FOR THOSE 3500 02:50:07,360 --> 02:50:09,160 AND IT'S TOUGH TO GET TRIOS. 3501 02:50:09,160 --> 02:50:12,200 THE QUESTION OF COULD THERE BE A 3502 02:50:12,200 --> 02:50:17,600 MUTATIONAL BURDEN AND I HAVE TO 3503 02:50:17,600 --> 02:50:19,240 SAY I WAS SURPRISED TO COME 3504 02:50:19,240 --> 02:50:21,800 ACROSS THE STORY OF THE 3505 02:50:21,800 --> 02:50:22,720 CRANIONASAL SYNDROME AND IF YOU 3506 02:50:22,720 --> 02:50:24,560 HAVE DE NOVO MUTATIONS AND IF 3507 02:50:24,560 --> 02:50:25,880 SOME OF OUR PATIENTS WITH DE 3508 02:50:25,880 --> 02:50:30,240 NOVO MUTATIONS HAPPEN TO BE 3509 02:50:30,240 --> 02:50:32,520 MOSAIC, WHETHER IT'S FOR THAT 3510 02:50:32,520 --> 02:50:35,960 VARIANT OR MOSAICISM FOR OTHER 3511 02:50:35,960 --> 02:50:39,360 VARIANTS AND IT'S SUPER TOUGH TO 3512 02:50:39,360 --> 02:50:41,400 , COULD WE BE SETTING UP 3513 02:50:41,400 --> 02:50:42,920 SCENARIOS WHERE THERE'S SOME 3514 02:50:42,920 --> 02:50:44,360 ASPECT CAUSING A MORE SEVERE 3515 02:50:44,360 --> 02:50:44,600 PHENOTYPE? 3516 02:50:44,600 --> 02:50:45,800 THAT'S A BIG HYPOTHESIS. 3517 02:50:45,800 --> 02:50:47,560 WE'D HAVE TO STUDY A LOT BUT I 3518 02:50:47,560 --> 02:50:48,560 THINK IT WOULD BE REALLY 3519 02:50:48,560 --> 02:50:50,480 INTERESTING TO LOOK AT THE NEW 3520 02:50:50,480 --> 02:50:52,400 MUTATIONS IN INDIVIDUALS THAT WE 3521 02:50:52,400 --> 02:50:54,760 HAVE AND TRY TO TRY TO 3522 02:50:54,760 --> 02:50:57,400 UNDERSTAND WHERE THOSE INHERITED 3523 02:50:57,400 --> 02:50:59,280 FROM A PARENTAL GERM LINE OR AT 3524 02:50:59,280 --> 02:51:03,920 THE TIME OF CONCEPTION OR 3525 02:51:03,920 --> 02:51:06,760 ACTUALLY POST-ZYGOTIC AND ARE WE 3526 02:51:06,760 --> 02:51:07,840 SEQUENCING DEEPLY ENOUGH TO 3527 02:51:07,840 --> 02:51:10,760 DETECT IT AND LOOKING AT THE 3528 02:51:10,760 --> 02:51:11,960 RIGHT TISSUES TO DETECT THAT. 3529 02:51:11,960 --> 02:51:14,400 IT'S NOT GOING TO BE EASY BUT TO 3530 02:51:14,400 --> 02:51:17,840 ME IT MAY BE VERY COMPELLING TO 3531 02:51:17,840 --> 02:51:23,240 LOOK AT. 3532 02:51:23,240 --> 02:51:25,560 >> I'LL ADD TO THAT THAT YOU CAN 3533 02:51:25,560 --> 02:51:28,120 THINK OF IT AS AN OPPORTUNITY. 3534 02:51:28,120 --> 02:51:29,640 AND THERE'S A SIZABLE NUMBER OF 3535 02:51:29,640 --> 02:51:32,640 PATIENTS WITH MUTATIONS ON THE 3536 02:51:32,640 --> 02:51:36,000 SAME LOCUS. 3537 02:51:36,000 --> 02:51:39,520 SOME DE NOVO, SOME INHERITED OR 3538 02:51:39,520 --> 02:51:40,760 PROVEN INHERITED THAT COULD BE A 3539 02:51:40,760 --> 02:51:44,600 POPULATION WHERE ONE CAN BEGIN 3540 02:51:44,600 --> 02:51:45,640 STUDYING THAT PARTICULAR 3541 02:51:45,640 --> 02:51:45,920 QUESTION. 3542 02:51:45,920 --> 02:51:49,280 I DON'T KNOW WHICH ONE WOULD BE 3543 02:51:49,280 --> 02:51:52,000 THE 409 OR THE ONES THAT ARE 3544 02:51:52,000 --> 02:51:53,240 FREQUENTLY FOUND IN BOTH 3545 02:51:53,240 --> 02:51:55,280 SETTINGS THAT MAYBE THAT 3546 02:51:55,280 --> 02:51:57,280 POPULATION IS HOMOGENOUS ENOUGH 3547 02:51:57,280 --> 02:51:58,760 IN TERMS OF THE MOLECULAR 3548 02:51:58,760 --> 02:52:01,960 FINDINGS TO BE ABLE TO ASK THIS 3549 02:52:01,960 --> 02:52:21,840 PRECISE QUESTIONS. 3550 02:52:21,840 --> 02:52:21,960 3551 02:52:21,960 --> 02:52:23,440 >> I THINK GETTING TO THE 3552 02:52:23,440 --> 02:52:25,840 QUESTION OF GENETIC MODIFIERS IS 3553 02:52:25,840 --> 02:52:29,880 NOT JUST TO DETERMINE THAT FROM 3554 02:52:29,880 --> 02:52:31,880 AN ETIOLOGY STANDPOINT AND THIS 3555 02:52:31,880 --> 02:52:33,520 WILL BE A QUESTION FOR TOMORROW. 3556 02:52:33,520 --> 02:52:35,120 I THINK THE WHOLE QUESTION OF 3557 02:52:35,120 --> 02:52:38,840 GAIN OF FUNCTION VERSUS LOSS OF 3558 02:52:38,840 --> 02:52:40,160 IS I THINK HOVERING OVER ALL 3559 02:52:40,160 --> 02:52:41,960 THIS BECAUSE THE REAL 3560 02:52:41,960 --> 02:52:43,960 IMPLICATION HERE IS WHAT'S THE 3561 02:52:43,960 --> 02:52:45,800 MECHANISM AND HOW IT WILL BE 3562 02:52:45,800 --> 02:52:46,360 TARGET FROM A THERAPEUTIC 3563 02:52:46,360 --> 02:52:49,120 STANDPOINT. 3564 02:52:49,120 --> 02:52:52,760 AND IF THERE'S A GENETIC 3565 02:52:52,760 --> 02:52:54,520 MODIFYING GREAT IT MAY GIVE AN 3566 02:52:54,520 --> 02:52:55,480 ADDITIONAL TARGET. 3567 02:52:55,480 --> 02:52:58,560 IT'S VERY IMPORTANT TO THINK OF 3568 02:52:58,560 --> 02:53:03,400 STUDYING THAT AND GOING GENOME 3569 02:53:03,400 --> 02:53:04,520 SEQUENCING. 3570 02:53:04,520 --> 02:53:05,880 WE HAVE DIFFERENT APPROACHES. 3571 02:53:05,880 --> 02:53:11,160 I WANTED TO SAY THAT AND ALSO 3572 02:53:11,160 --> 02:53:12,640 ASK A SIMPLE QUESTION OF THE 3573 02:53:12,640 --> 02:53:13,880 PROGRAM FOR HEATHER, DO YOU EVER 3574 02:53:13,880 --> 02:53:16,640 GO BACK AND TEST THE PARENTS AND 3575 02:53:16,640 --> 02:53:20,080 DO YOU KNOW IF THESE ARE DE NOVO 3576 02:53:20,080 --> 02:53:25,840 OR INHERITED AND IS THERE A 3577 02:53:25,840 --> 02:53:28,520 MECHANISM WHERE THEY MAKE 3578 02:53:28,520 --> 02:53:30,600 FAMILIES AWARE OF ONGOING 3579 02:53:30,600 --> 02:53:31,320 RESEARCH? 3580 02:53:31,320 --> 02:53:33,360 IS THIS A WAY A COMMUNITY CAN BE 3581 02:53:33,360 --> 02:53:37,600 INFORMED OF ONGOING PROJECTS? 3582 02:53:37,600 --> 02:53:39,680 >> ANY TIME A PATIENT IS 3583 02:53:39,680 --> 02:53:42,560 IDENTIFIED TO HAVE A POSITIVE 3584 02:53:42,560 --> 02:53:45,640 MOLECULAR FINDING OR DIAGNOSIS, 3585 02:53:45,640 --> 02:53:47,560 WE OFFER NO CHARGE TESTING UP TO 3586 02:53:47,560 --> 02:53:50,120 TWO FAMILY MEMBERS AND THE SAME 3587 02:53:50,120 --> 02:53:51,280 COULD BE SAID FOR CERTAIN 3588 02:53:51,280 --> 02:53:53,520 VARIANTS OF UNCERTAIN 3589 02:53:53,520 --> 02:53:53,920 SIGNIFICANCE. 3590 02:53:53,920 --> 02:53:57,280 LET'S SAY WE SEE A SINGLE 3591 02:53:57,280 --> 02:53:59,240 VARIANT IN A CHILD AND IT VERY 3592 02:53:59,240 --> 02:54:01,880 MUCH FITS THEIR PHENOTYPE WE CAN 3593 02:54:01,880 --> 02:54:03,560 ACCEPT UP TO TWO BIOLOGICAL 3594 02:54:03,560 --> 02:54:03,840 RELATIVES. 3595 02:54:03,840 --> 02:54:05,720 THE BEST THING WOULD BE THE 3596 02:54:05,720 --> 02:54:07,160 PARENTS BUT SOMETIMES THOSE 3597 02:54:07,160 --> 02:54:07,760 AREN'T AVAILABLE. 3598 02:54:07,760 --> 02:54:09,160 AND WE ARE ABLE USING OUR DATA 3599 02:54:09,160 --> 02:54:14,080 TO BE ABLE TO CONFIRM MATERNITY 3600 02:54:14,080 --> 02:54:21,640 AND PATERNITY SO WE'RE ABLE TO 3601 02:54:21,640 --> 02:54:23,160 TELL THE SAMPLES ARE COMING FROM 3602 02:54:23,160 --> 02:54:24,760 THE BIOLOGICAL PARENTS. 3603 02:54:24,760 --> 02:54:26,160 IN TERMS OF RESEARCH 3604 02:54:26,160 --> 02:54:27,080 OPPORTUNITIES AND THAT WITH 3605 02:54:27,080 --> 02:54:28,960 PATIENTS WE HAVE A LOT OF 3606 02:54:28,960 --> 02:54:30,880 RESEARCHERS WHO WILL CONTACT US 3607 02:54:30,880 --> 02:54:31,760 AND THEY'RE INTERESTED IN 3608 02:54:31,760 --> 02:54:34,960 SPECIFIC GENES OR COHORTS OF 3609 02:54:34,960 --> 02:54:36,760 PATIENTS THAT WANT TO MAYBE 3610 02:54:36,760 --> 02:54:40,880 REACH OUT TO THEIR ORDERING 3611 02:54:40,880 --> 02:54:41,840 PROVIDERS TO PERFORM ADDITIONAL 3612 02:54:41,840 --> 02:54:43,640 STUDIES OR INVITE THEM FOR 3613 02:54:43,640 --> 02:54:45,840 SEARCH RESEARCH OPPORTUNITIES. 3614 02:54:45,840 --> 02:54:47,960 THAT'S SOMETHING THAT OUR 3615 02:54:47,960 --> 02:54:49,720 LABORATORY IS INTERESTED IN 3616 02:54:49,720 --> 02:54:53,920 FACILITATING AND WOULD BE HAPPY 3617 02:54:53,920 --> 02:55:00,240 TO DISCUSS FURTHER. 3618 02:55:00,240 --> 02:55:00,920 >> THANK YOU. 3619 02:55:00,920 --> 02:55:03,040 >> NEXT TO MICHELLE. 3620 02:55:03,040 --> 02:55:04,760 >> THESE ARE GENETICALLY IT'S 3621 02:55:04,760 --> 02:55:06,560 ALL REALLY IMPORTANT QUESTIONS 3622 02:55:06,560 --> 02:55:09,800 WE'RE ASKING AND I'M WONDERING 3623 02:55:09,800 --> 02:55:12,920 IF WE CAN TAKE LIKE STEP 1, STEP 3624 02:55:12,920 --> 02:55:18,960 2, STEP 3 APOACH -- APPROACH 3625 02:55:18,960 --> 02:55:20,720 WHAT I HEARD FROM OUR WONDERFUL 3626 02:55:20,720 --> 02:55:27,560 FAMILIES THEY GET THE DIAGNOSE 3627 02:55:27,560 --> 02:55:29,600 AND DON'T GET THE OUTLOOK AND IT 3628 02:55:29,600 --> 02:55:31,920 SOUNDS LIKE THEY'RE ALMOST 3629 02:55:31,920 --> 02:55:33,400 WORRIED THEIR CHILD WOULD PASS 3630 02:55:33,400 --> 02:55:40,880 AWAY ON THEM IS WHAT I TOOK FROM 3631 02:55:40,880 --> 02:55:41,160 IT. 3632 02:55:41,160 --> 02:55:42,080 DO YOU THINK WE HAVE ENOUGH 3633 02:55:42,080 --> 02:55:44,120 PATIENTS TOGETHER TO GET THAT 3634 02:55:44,120 --> 02:55:46,000 ANSWERED BECAUSE THAT'S POWERFUL 3635 02:55:46,000 --> 02:55:48,920 IN ITSELF. 3636 02:55:48,920 --> 02:55:51,120 ARE WE SEEING SLIGHT CHANGES FOR 3637 02:55:51,120 --> 02:55:55,000 THESE PATIENTS IN THEIR FUNCTION 3638 02:55:55,000 --> 02:55:56,680 DURING GROWTH? 3639 02:55:56,680 --> 02:55:58,960 ARE WE SEEING TRUE DECLINE LATER 3640 02:55:58,960 --> 02:56:00,400 IN LIFE AND THAT HAS A LOT OF 3641 02:56:00,400 --> 02:56:03,720 POWER TO IT AND AT THE SAME TIME 3642 02:56:03,720 --> 02:56:04,400 DEFINITELY WE NEED TO BE PULLING 3643 02:56:04,400 --> 02:56:07,400 OUR GENETICS TOGETHER AND 3644 02:56:07,400 --> 02:56:08,760 WORKING ON AND IT'S COMPLEX 3645 02:56:08,760 --> 02:56:11,920 GENETICALLY WHEN YOU START 3646 02:56:11,920 --> 02:56:14,880 THINKING OF IT WHICH ACTUALLY 3647 02:56:14,880 --> 02:56:17,400 JENNIFER YOU BROUGHT UP 3648 02:56:17,400 --> 02:56:20,360 WONDERFULLY AND WHY DO PATIENTS 3649 02:56:20,360 --> 02:56:22,600 WITH THE SAME MUTATION AND LOOK 3650 02:56:22,600 --> 02:56:24,360 DIFFERENTLY AND WHY DID MOM 3651 02:56:24,360 --> 02:56:25,440 PRESENT SO LATE WHEN IT'S 3652 02:56:25,440 --> 02:56:27,080 EXACTLY THE SAME MUTATION. 3653 02:56:27,080 --> 02:56:28,360 THOSE ARE MY THOUGHTS AND MY 3654 02:56:28,360 --> 02:56:33,800 HOPES TOGETHER WE CAN ALL WORK 3655 02:56:33,800 --> 02:56:37,320 DEATH START ASKING WHAT IS THE 3656 02:56:37,320 --> 02:56:37,960 NATURAL HISTORY AND WORK FURTHER 3657 02:56:37,960 --> 02:56:50,880 TOGETHER. 3658 02:56:50,880 --> 02:56:57,720 >> I SEE A QUESTION CAN THE 3659 02:56:57,720 --> 02:56:59,920 PROTEOMICS WITH DE NOVO PATIENTS 3660 02:56:59,920 --> 02:57:01,560 WITH INHERITED BE INSIGHTFUL TO 3661 02:57:01,560 --> 02:57:15,680 LOOK AT THE GENETIC MODIFIERS? 3662 02:57:15,680 --> 02:57:18,160 >> I THINK TRANSCRIPTOMICS AND 3663 02:57:18,160 --> 02:57:22,880 LOOKING AT EXPRESSION AND 3664 02:57:22,880 --> 02:57:34,960 PERHAPS AT THE EXPRESSION OF AND 3665 02:57:34,960 --> 02:57:37,800 IF YOU CAN LINE UP A SET OF 3666 02:57:37,800 --> 02:57:39,160 INDIVIDUALS WITH THE EXACT SAME 3667 02:57:39,160 --> 02:57:41,760 VARIANT AND SEPARATE THEM BY 3668 02:57:41,760 --> 02:57:44,160 DIFFERENCES IN THEIR PROTEOMIC 3669 02:57:44,160 --> 02:57:45,760 AND OMIC PROFILES YOU CAN START 3670 02:57:45,760 --> 02:57:48,600 TO ASK THE QUESTION WHAT'S 3671 02:57:48,600 --> 02:57:50,880 DIFFERENT BETWEEN THE TWO WE'RE 3672 02:57:50,880 --> 02:57:52,160 SEEING A CLEAR MOLECULAR 3673 02:57:52,160 --> 02:57:53,600 SIGNATURE AND NOW LET'S ASK THE 3674 02:57:53,600 --> 02:57:57,840 QUESTION WHAT'S DIFFERENT. 3675 02:57:57,840 --> 02:58:05,560 THAT COULD BE POWERFUL. 3676 02:58:05,560 --> 02:58:10,560 >> YOU SAY LOSS OF FUNCTION. 3677 02:58:10,560 --> 02:58:13,080 AND THERE'S A CATEGORIZATION OF 3678 02:58:13,080 --> 02:58:14,760 LOSS OF FUNCTION AND VARIANTS. 3679 02:58:14,760 --> 02:58:17,600 CAN YOU CLARIFY HOW YOU USE THE 3680 02:58:17,600 --> 02:58:17,800 TERMS? 3681 02:58:17,800 --> 02:58:23,920 MY USE OF THE TERM WOULD BE MOST 3682 02:58:23,920 --> 02:58:40,000 MUTATIONS AS LOSS OF FUNCTION. 3683 02:58:40,000 --> 02:58:42,560 >> WE CAN'T DETERMINE WHETHER 3684 02:58:42,560 --> 02:58:47,720 IT'S LEADING IT GAIN OF FUNCTION 3685 02:58:47,720 --> 02:58:55,920 SO WE HAVE FUNCTIONAL STUDIES IN 3686 02:58:55,920 --> 02:58:58,360 THE LITERATURE AND I CALL THEM 3687 02:58:58,360 --> 02:59:01,840 VARIANTS AND TRY NOT TO INFER. 3688 02:59:01,840 --> 02:59:03,920 THE MOLECULAR MECHANISM OF THE 3689 02:59:03,920 --> 02:59:05,760 GENE IS LESS OF A FUNCTION THAN 3690 02:59:05,760 --> 02:59:07,840 WE EXPECT LOSS OF FUNCTION BUT I 3691 02:59:07,840 --> 02:59:11,800 THINK AS WE SEE WITH OTHER 3692 02:59:11,800 --> 02:59:12,920 GENETIC DISORDERS THE MECHANISM 3693 02:59:12,920 --> 02:59:14,520 OF DISEASE IS LOSS OF FUNCTION 3694 02:59:14,520 --> 02:59:15,320 AND SEE A DIFFERENT PHENOTYPE 3695 02:59:15,320 --> 02:59:16,400 WITH LOSS OF FUNCTION. 3696 02:59:16,400 --> 02:59:19,640 I DON'T KNOW IF WE CAN REALLY 3697 02:59:19,640 --> 02:59:22,040 SAY WHAT'S HAPPENING HERE RIGHT 3698 02:59:22,040 --> 02:59:23,160 NOW. 3699 02:59:23,160 --> 02:59:25,360 >> I WANT TO INTERJECT ONE 3700 02:59:25,360 --> 02:59:26,440 AUDIENCE FROM THE ONLINE 3701 02:59:26,440 --> 02:59:29,840 AUDIENCE AND THEN GO BACK TO THE 3702 02:59:29,840 --> 02:59:32,560 CHAT. 3703 02:59:32,560 --> 02:59:37,160 WE HAVE JOINING US A PEDIATRIC 3704 02:59:37,160 --> 02:59:39,760 NEUROLOGIST AND SPECIALIZES AT 3705 02:59:39,760 --> 02:59:41,920 MOVEMENT DISORDER AND HAS A 3706 02:59:41,920 --> 02:59:45,920 STRONG INTEREST IN DYSTONIA AND 3707 02:59:45,920 --> 02:59:47,880 CEREBRAL PALSY AND AS A PARENT 3708 02:59:47,880 --> 02:59:59,640 OF A CHILD THAT WAS MISDIAGNOSED 3709 02:59:59,640 --> 03:00:04,880 I ASK WE BE CAUTIOUS OF USING 3710 03:00:04,880 --> 03:00:13,840 THE LABEL CEREBRAL PALSY AND A 3711 03:00:13,840 --> 03:00:22,240 MAJOR AND WE FIRST HEARD OF HSP. 3712 03:00:22,240 --> 03:00:24,440 THE IMPACT HAS BEEN PROFOUND. 3713 03:00:24,440 --> 03:00:28,560 IT'S IMPERATIVE WE WORK WITH 3714 03:00:28,560 --> 03:00:30,360 PROFESSIONALS AND FAMILIES AND I 3715 03:00:30,360 --> 03:00:31,320 UNDERSTAND THIS CHANGE IN 3716 03:00:31,320 --> 03:00:33,840 LABELLING IS IMPACTED BY THE 3717 03:00:33,840 --> 03:00:46,480 FACT CEREBRAL PALSY IS LOOKED AT 3718 03:00:46,480 --> 03:00:47,920 THE CAUSE OF CP. 3719 03:00:47,920 --> 03:00:50,200 I WONDER IF YOU HAVE COMMENTS 3720 03:00:50,200 --> 03:00:52,760 FOR THIS MOTHER. 3721 03:00:52,760 --> 03:00:53,960 >> THANK YOU AND THANK YOU FOR 3722 03:00:53,960 --> 03:00:55,960 HAVING ME TODAY. 3723 03:00:55,960 --> 03:01:01,360 THE QUESTION'S AN IMPORTANT ONE 3724 03:01:01,360 --> 03:01:03,560 DIFFERENTIATE IG 3725 03:01:03,560 --> 03:01:04,560 DIFFERENTIATING I THINK 3726 03:01:04,560 --> 03:01:06,480 DIFFERENT PEOPLE HAVE DIFFERENT 3727 03:01:06,480 --> 03:01:06,760 DEFINITIONS. 3728 03:01:06,760 --> 03:01:08,920 WHEN I THINK OF THIS WE THINK OF 3729 03:01:08,920 --> 03:01:11,920 THIS AND THINK OF DISORDERS THAT 3730 03:01:11,920 --> 03:01:20,960 MAY INITIALLY PRESENT WITH A NON 3731 03:01:20,960 --> 03:01:21,760 PROGRESSIVE MOTOR DISABILITY 3732 03:01:21,760 --> 03:01:30,240 THEN LATER MAY DECLARE ITSELF 3733 03:01:30,240 --> 03:01:33,560 FOR A NEURO DEGENERATIVE 3734 03:01:33,560 --> 03:01:35,560 DISORDER AND BY THE TIME YOU'RE 3735 03:01:35,560 --> 03:01:38,160 6 IT'S CLEAR IT'S A PROGRESSIVE 3736 03:01:38,160 --> 03:01:45,000 DISORDER. 3737 03:01:45,000 --> 03:01:49,280 THERE'S A CONCEPT OF HAVING A 3738 03:01:49,280 --> 03:01:53,880 PROVISIONAL CP DIAGNOSIS THAT IS 3739 03:01:53,880 --> 03:02:04,040 THEN CONFIRMED AS YOU AGE 3740 03:02:04,040 --> 03:02:06,600 THEY'LL GIVE A DIAGNOSIS IN AGE 3741 03:02:06,600 --> 03:02:08,560 2 AND GIVE A DIFFERENT DIAGNOSIS 3742 03:02:08,560 --> 03:02:09,880 AT AGE 5. 3743 03:02:09,880 --> 03:02:11,960 THE EARLY DIAGNOSIS IS 3744 03:02:11,960 --> 03:02:12,240 IMPORTANT. 3745 03:02:12,240 --> 03:02:13,480 AND I THINK BEING AWARE OF WHAT 3746 03:02:13,480 --> 03:02:16,440 THE MIMICS COULD BE AND WHICH 3747 03:02:16,440 --> 03:02:19,680 MIM IBS REQUIRE EARLY IS 3748 03:02:19,680 --> 03:02:20,240 CRITICAL. 3749 03:02:20,240 --> 03:02:21,400 FOR THE EARLY DIAGNOSIS IN MANY 3750 03:02:21,400 --> 03:02:23,400 PARTS OF THE WORLD ESPECIALLY IN 3751 03:02:23,400 --> 03:02:29,800 THE U.S. IS ACCESS TO THERAPIES. 3752 03:02:29,800 --> 03:02:31,800 ACCESS TO SERVICES. 3753 03:02:31,800 --> 03:02:33,240 ACCESS PERIOD TO THINGS CHILDREN 3754 03:02:33,240 --> 03:02:36,160 NEED TO SUCCEED BUT THINKING OF 3755 03:02:36,160 --> 03:02:37,160 REVISITING THE DIAGNOSIS EARLY 3756 03:02:37,160 --> 03:02:40,080 IN LIFE TO SEE IF PROGRESSION IS 3757 03:02:40,080 --> 03:02:41,600 OCCURRING IS IMPORTANT. 3758 03:02:41,600 --> 03:02:44,160 I'M NOT SURE WHAT THE SITUATION 3759 03:02:44,160 --> 03:02:49,800 WAS WITH DONOVAN BUT WONDERING 3760 03:02:49,800 --> 03:02:50,560 IF THAT HELPED CLARIFY THE 3761 03:02:50,560 --> 03:03:02,360 DIFFERENCE FOR THE FAMILY. 3762 03:03:02,360 --> 03:03:04,760 AND I THINK IT'S VALUABLE TO 3763 03:03:04,760 --> 03:03:08,560 THINK ABOUT IT IN THE CONTEXT OF 3764 03:03:08,560 --> 03:03:10,720 OTHERS IN A COMPARABLE WAY IN 3765 03:03:10,720 --> 03:03:13,200 THE WAY WE LOOK AT EPILEPSY AND 3766 03:03:13,200 --> 03:03:21,000 AUTISM WHERE WE CAN SAY SOMEONE 3767 03:03:21,000 --> 03:03:23,360 HAS AND CARRY BOTH LABELS 3768 03:03:23,360 --> 03:03:24,520 SIMULTANEOUSLY. 3769 03:03:24,520 --> 03:03:26,120 AND I THINK THAT SHOULD ALSO BE 3770 03:03:26,120 --> 03:03:29,600 TRUE FOR CP AND THEN WE CAN GET 3771 03:03:29,600 --> 03:03:32,120 INTO THE DEBATE ARE THERE SOME 3772 03:03:32,120 --> 03:03:34,080 TYPES THAT ARE SLOW PROGRESSING 3773 03:03:34,080 --> 03:03:37,840 AND NOT AND FIT A PHENOTYPE AND 3774 03:03:37,840 --> 03:03:41,920 HAVE MAYBE AN INFANTILE 3775 03:03:41,920 --> 03:03:43,160 DIAGNOSIS AND CP DIAGNOSIS AT 3776 03:03:43,160 --> 03:03:47,920 THE SAME TIME AND THAT'S NUANCED 3777 03:03:47,920 --> 03:03:52,760 AND OPEN TO DEBATE AND IN THE 3778 03:03:52,760 --> 03:03:57,120 EARLY YEARS IT SHOULDN'T BE A 3779 03:03:57,120 --> 03:03:59,120 ONE AND DONE PHENOMENON AND 3780 03:03:59,120 --> 03:04:03,520 SHOULD BE REASSESSED WITHIN THE 3781 03:04:03,520 --> 03:04:05,880 FIRST YEARS OF LIFE. 3782 03:04:05,880 --> 03:04:07,280 >> TO ADD TO THE BEAUTIFUL 3783 03:04:07,280 --> 03:04:08,720 POINT, IT'S ONE THING WITH 3784 03:04:08,720 --> 03:04:11,560 RESIDENTS I HARP ON ACTUALLY IS 3785 03:04:11,560 --> 03:04:21,040 I SAY CP DUE TO WHAT? 3786 03:04:21,040 --> 03:04:23,760 AND THE DEFINITION SAY MOVEMENT 3787 03:04:23,760 --> 03:04:25,360 DISORDER EARLY ON AT BIRTH BUT 3788 03:04:25,360 --> 03:04:32,720 DOESN'T TELL US THE ETIOLOGY AND 3789 03:04:32,720 --> 03:04:36,640 IT'S SO IMPORTANT. 3790 03:04:36,640 --> 03:04:39,040 I IT'S A HOT TOPIC AND WE NEED 3791 03:04:39,040 --> 03:04:41,360 TO MOVE TOWARDS CP DUE TO WHAT 3792 03:04:41,360 --> 03:04:42,520 AND IF WE DON'T KNOW THE WHAT 3793 03:04:42,520 --> 03:04:51,320 YET WE NEED TO KEEP LOOKING. 3794 03:04:51,320 --> 03:04:55,200 >> THIS IS KIM MOM OF OWEN. 3795 03:04:55,200 --> 03:04:57,760 SHE HAS A QUESTION I'LL SAVE FOR 3796 03:04:57,760 --> 03:04:59,640 TOMORROW AND ALSO SAID SHE LOVED 3797 03:04:59,640 --> 03:05:00,160 SEEING THE VIDEOS OF THE 3798 03:05:00,160 --> 03:05:02,160 CHILDREN YOU SHOWED. 3799 03:05:02,160 --> 03:05:04,480 HER SON HAS A MORE SEVERE 3800 03:05:04,480 --> 03:05:07,760 PHENOTYPE AND SOME OTHER PARENTS 3801 03:05:07,760 --> 03:05:09,280 ALSO MENTIONED THAT WHAT SOME OF 3802 03:05:09,280 --> 03:05:13,000 THE S WHO PRINTED WERE SLOWER 3803 03:05:13,000 --> 03:05:14,840 PROGRESSION THAN SOME CHILDREN 3804 03:05:14,840 --> 03:05:16,440 AND WONDERED WHY IS THAT. 3805 03:05:16,440 --> 03:05:18,280 AND THEN THEY ALSO HOPED YOUR 3806 03:05:18,280 --> 03:05:19,480 DAUGHTER FEELS BETTER SOON. 3807 03:05:19,480 --> 03:05:24,040 >> WELL, THANK YOU, EVERYONE FOR 3808 03:05:24,040 --> 03:05:24,240 THAT. 3809 03:05:24,240 --> 03:05:25,800 I ALSO FOLLOW PATIENTS. 3810 03:05:25,800 --> 03:05:28,520 WE DIDN'T HAVE THE LONG-TERM 3811 03:05:28,520 --> 03:05:33,320 DATA ON THEM WHO PRESENT WITH A 3812 03:05:33,320 --> 03:05:35,160 VERY COMPLEX FORM. 3813 03:05:35,160 --> 03:05:39,000 WHERE YOU KNOW THEY DON'T REACH 3814 03:05:39,000 --> 03:05:40,920 AMBULATION AND THEY DON'T REACH 3815 03:05:40,920 --> 03:05:42,360 TYPICALLY THEY HAVE A LOT OF 3816 03:05:42,360 --> 03:05:42,920 EPILEPSY ALONG WITH THAT AS 3817 03:05:42,920 --> 03:05:44,080 WELL. 3818 03:05:44,080 --> 03:05:47,400 AND I THINK THAT REALLY WAS -- I 3819 03:05:47,400 --> 03:05:50,320 AGREE WITH YOU THE QUESTIONS I 3820 03:05:50,320 --> 03:05:52,680 HAVE FOR OUR AMAZING GENETICISTS 3821 03:05:52,680 --> 03:05:56,160 AND BENCH SIDE RESEARCHERS, WHY 3822 03:05:56,160 --> 03:05:59,920 ARE WE SEEING MUTATIONS EVEN 3823 03:05:59,920 --> 03:06:01,840 WITHIN THE SAME REGION OF THE 3824 03:06:01,840 --> 03:06:05,160 GENE THE MAJORITY ARE WITHIN 3825 03:06:05,160 --> 03:06:07,120 THAT TRIPLE A SET AND WHY WHERE 3826 03:06:07,120 --> 03:06:11,920 HE GETTING SOME BEAUTIFUL 3827 03:06:11,920 --> 03:06:18,320 CHILDREN WHO HAVE AND THE ONES I 3828 03:06:18,320 --> 03:06:19,360 PRESENTED LONG-TERM DATA ON 3829 03:06:19,360 --> 03:06:21,360 WHERE THEY PRESENTED IN INFANCY 3830 03:06:21,360 --> 03:06:23,200 AS WELL AND THEY REACHED 3831 03:06:23,200 --> 03:06:24,960 AMBULATION FOR SHORT DISTANCES 3832 03:06:24,960 --> 03:06:28,160 AND THINGS LIKE THAT. 3833 03:06:28,160 --> 03:06:31,600 HOPEFULLY I'LL HAVE SOME MORE 3834 03:06:31,600 --> 03:06:34,400 WE'LL KEEP GATHERING TOGETHER 3835 03:06:34,400 --> 03:06:38,360 THAT'S THE IMPORTANCE OF THESE 3836 03:06:38,360 --> 03:06:39,360 MEETING TO SEE WHAT'S THE AND A 3837 03:06:39,360 --> 03:06:41,160 HALF HISTORY FOR THE MORE SEVERE 3838 03:06:41,160 --> 03:06:43,000 PHENOTYPES AND I HOPE YOUR 3839 03:06:43,000 --> 03:06:43,760 CHILDREN ARE DOING WELL AS WELL. 3840 03:06:43,760 --> 03:06:46,040 WE ALL WANT TO CARE FOR THEM 3841 03:06:46,040 --> 03:06:59,160 DEEPLY. 3842 03:06:59,160 --> 03:07:05,840 >> WE HAVE NON-MOTOR SYSTEMS 3843 03:07:05,840 --> 03:07:08,760 WITH SPASTIC PARAPLEGIA AND TO 3844 03:07:08,760 --> 03:07:10,600 THE EXTENT THEY'RE CAPTURED IN 3845 03:07:10,600 --> 03:07:13,120 THE SCALES IT SEEMS PARTICULARLY 3846 03:07:13,120 --> 03:07:15,520 IMPORTANT FOR THE PATIENTS DE 3847 03:07:15,520 --> 03:07:17,840 NOVO SINCE THEY SEEM TO HAVE A 3848 03:07:17,840 --> 03:07:21,000 PHENOTYPE THAT ENCOMPASSES OTHER 3849 03:07:21,000 --> 03:07:22,600 DOMAINS BESIDES PLASTICITY. 3850 03:07:22,600 --> 03:07:23,920 IF YOU CAN ANSWER THAT QUESTION. 3851 03:07:23,920 --> 03:07:35,920 THANK YOU. 3852 03:07:35,920 --> 03:07:40,360 >> AND I'LL SAY THE POINT IS 3853 03:07:40,360 --> 03:07:42,760 WELL TAKEN I THINK THE SYMPTOMS 3854 03:07:42,760 --> 03:07:45,160 OF THE SPECTRUM GOES BEYOND 3855 03:07:45,160 --> 03:07:46,560 MOTOR DISABILITY AND SPACTICITY 3856 03:07:46,560 --> 03:07:48,520 AND IT'S IMPORTANT TO RECOGNIZE. 3857 03:07:48,520 --> 03:07:50,000 IT DOES MAKE THINGS MORE 3858 03:07:50,000 --> 03:07:53,440 COMPLICATED WHEN WE THINK ABOUT 3859 03:07:53,440 --> 03:07:55,320 OUTCOME MEASURES THAT ARE 3860 03:07:55,320 --> 03:07:57,840 RELIABLE AND CHANGING IN A TIME 3861 03:07:57,840 --> 03:08:01,320 FRAME THAT WOULD BE AMENABLE FOR 3862 03:08:01,320 --> 03:08:03,520 USING THIS OUTCOME MEASURE IN 3863 03:08:03,520 --> 03:08:04,640 THE CLINICAL AND INTERVENTIONAL 3864 03:08:04,640 --> 03:08:05,840 TRIAL. 3865 03:08:05,840 --> 03:08:10,760 IT'S DEFINITELY A CHALLENGE. 3866 03:08:10,760 --> 03:08:15,400 THE WAY WE APPROACHED THIS IN 3867 03:08:15,400 --> 03:08:17,560 OUR NATURAL HISTORY STUDY WAS 3868 03:08:17,560 --> 03:08:20,520 ENROLLMENT AND IN DESIGNING THE 3869 03:08:20,520 --> 03:08:21,240 FOLLOW-UP QUESTIONNAIRES AND THE 3870 03:08:21,240 --> 03:08:23,160 FOLLOW-UP STUDY VISITS, WE 3871 03:08:23,160 --> 03:08:26,360 INITIALLY TOOK THE APPROACH THAT 3872 03:08:26,360 --> 03:08:30,680 WOULD BE ADAPTED TO MANY OF THE 3873 03:08:30,680 --> 03:08:31,680 NON-MOTOR FEATURES. 3874 03:08:31,680 --> 03:08:33,240 AND THAT PROVED TO BE 3875 03:08:33,240 --> 03:08:35,680 COMPLICATED FOR PRACTICAL 3876 03:08:35,680 --> 03:08:35,920 REASONS. 3877 03:08:35,920 --> 03:08:38,560 SO WE HAVE NOW A ONE SIZE FITS 3878 03:08:38,560 --> 03:08:41,800 ALL APPROACH FOR THE FOLLOW-UP 3879 03:08:41,800 --> 03:08:43,120 QUESTIONNAIRE BUT WE DO PAY 3880 03:08:43,120 --> 03:08:45,640 CLOSE ATTENTION TO NON-MOTOR 3881 03:08:45,640 --> 03:08:45,920 FEATURES. 3882 03:08:45,920 --> 03:08:48,400 IT'S A GENERAL PROBLEM AND MAY 3883 03:08:48,400 --> 03:08:51,200 BE A SEGUE TO WHAT REBECCA CAN 3884 03:08:51,200 --> 03:08:53,160 SPEAK ABOUT FOR THE SPASTIC 3885 03:08:53,160 --> 03:08:58,520 PARAPLEGIA RATING SCALE. 3886 03:08:58,520 --> 03:09:01,840 IT'S A CHALLENGE FOR US BECAUSE 3887 03:09:01,840 --> 03:09:03,520 MANY ASSESSMENTS WE USE DEPEND 3888 03:09:03,520 --> 03:09:05,840 ON THE LEVEL OF COGNITIVE 3889 03:09:05,840 --> 03:09:11,840 ABILITIY IEY IES AND DEPEND ON THE 3890 03:09:11,840 --> 03:09:14,840 ABILITY TO PARTICIPATE AND IN 3891 03:09:14,840 --> 03:09:15,760 CHILDREN WITH DEVELOPMENT 3892 03:09:15,760 --> 03:09:15,960 DELAYS. 3893 03:09:15,960 --> 03:09:17,840 WE NEED TO ADAPT SOME OF THE 3894 03:09:17,840 --> 03:09:18,320 TOOLS. 3895 03:09:18,320 --> 03:09:21,840 I THINK WE NEED TO ADAPT THEM 3896 03:09:21,840 --> 03:09:23,400 FURTHER FOR A SPECIFIC SCENARIO. 3897 03:09:23,400 --> 03:09:27,720 I DO WANT TO SAY I THINK THE 3898 03:09:27,720 --> 03:09:31,720 MOTOR OUTCOMES AS CLINICIANS AND 3899 03:09:31,720 --> 03:09:33,640 RESEARCHERS ARE IMPORTANT 3900 03:09:33,640 --> 03:09:35,920 BECAUSE WE CAN QUANTITATE THEM 3901 03:09:35,920 --> 03:09:37,920 AND ASSESS THEM ON A CLINICAL 3902 03:09:37,920 --> 03:09:39,520 BASIS EVERY DAY. 3903 03:09:39,520 --> 03:09:41,800 I DO WANT TO EMPHASIZE THAT'S 3904 03:09:41,800 --> 03:09:44,160 THE REASON WHY WE'RE CHOOSING 3905 03:09:44,160 --> 03:09:47,760 THOSE AND PUTTING THOSE UP FRONT 3906 03:09:47,760 --> 03:09:52,920 BUT WE RECOGNIZE THAT MANY 3907 03:09:52,920 --> 03:10:01,840 CHILDREN WITH HEREDITARY SPASTIC 3908 03:10:01,840 --> 03:10:02,760 DISPLAGIA MAY HAVE THIS. 3909 03:10:02,760 --> 03:10:04,960 >> AND WHILE TALK ABOUT THE 3910 03:10:04,960 --> 03:10:06,560 SITUATION IS CURRENTLY WHAT WE 3911 03:10:06,560 --> 03:10:09,560 KNOW NOW AND WHAT SHOULD BE 3912 03:10:09,560 --> 03:10:10,200 DONE. 3913 03:10:10,200 --> 03:10:11,560 SO CURRENTLY I THINK WE'RE NOT 3914 03:10:11,560 --> 03:10:16,160 CAPTURING THE SYMPTOMS ENOUGH. 3915 03:10:16,160 --> 03:10:21,840 WHAT WE KNOW ABOUT THIS TYPE IS 3916 03:10:21,840 --> 03:10:26,480 ERECTILE DYSFUNCTION AND BLADDER 3917 03:10:26,480 --> 03:10:28,000 DISTURBANCES ARE QUITE COMMON. 3918 03:10:28,000 --> 03:10:29,760 I HAVE LOOKED AT THE FIRST 3919 03:10:29,760 --> 03:10:32,080 ANALYSIS OF A NEUROPSYCHOLOGY 3920 03:10:32,080 --> 03:10:35,320 STUDY WHICH WAS COMPLETED WITH 3921 03:10:35,320 --> 03:10:38,280 AN EXTENSIVE NEUROPSYCHOLOGY 3922 03:10:38,280 --> 03:10:39,200 BATTERY IN SPG4 PATIENTS 3923 03:10:39,200 --> 03:10:40,960 COMPARED TO CONTROLS WHERE WE 3924 03:10:40,960 --> 03:10:45,040 SEE ACROSS THE BOARD ADULT 3925 03:10:45,040 --> 03:10:47,920 PATIENT WITH SP4 ARE COGNITIVE 3926 03:10:47,920 --> 03:10:49,720 DEFICITS IN MEMORY AND EXECUTIVE 3927 03:10:49,720 --> 03:10:49,960 FUNCTION. 3928 03:10:49,960 --> 03:10:57,880 IN THE WAY THEY CAN STILL 3929 03:10:57,880 --> 03:10:59,520 FUNCTION BUT IT INTERFERES WITH 3930 03:10:59,520 --> 03:11:01,640 FUNCTION AND ACTIVITIES AND 3931 03:11:01,640 --> 03:11:01,920 FUNCTION. 3932 03:11:01,920 --> 03:11:02,760 THAT'S WHAT WE KNOW NOW. 3933 03:11:02,760 --> 03:11:04,840 WHAT WE HAVE TO FIND OUT I THINK 3934 03:11:04,840 --> 03:11:07,800 IS WHAT THE RELEVANCE FOR 3935 03:11:07,800 --> 03:11:08,840 DISEASE BURDEN IS OF THESE 3936 03:11:08,840 --> 03:11:09,360 ADDITIONAL SYMPTOMS. 3937 03:11:09,360 --> 03:11:11,680 SO WE HAVE TO FIND OUT THE 3938 03:11:11,680 --> 03:11:17,000 SPECTRUM AND WHAT THE MEANINGFUL 3939 03:11:17,000 --> 03:11:19,760 IS BECAUSE IF WE'RE TALKING 3940 03:11:19,760 --> 03:11:22,600 ABOUT CLINICAL TRIALS DO WEE 3941 03:11:22,600 --> 03:11:25,520 HAVE TO MAKE A GOOD DECISION 3942 03:11:25,520 --> 03:11:26,920 WHAT THE SYMPTOMS ARE THAT 3943 03:11:26,920 --> 03:11:29,600 AFFECT PATIENTS MOST. 3944 03:11:29,600 --> 03:11:31,640 AND THIS IS WHY WE ARE CURRENTLY 3945 03:11:31,640 --> 03:11:33,600 PUTTING SO MUCH EFFORT IN 3946 03:11:33,600 --> 03:11:34,360 DEVELOPING THESE 3947 03:11:34,360 --> 03:11:36,920 PATIENT-REPORTED PARAMETERS AND 3948 03:11:36,920 --> 03:11:37,520 STARTING FROM SCRATCH FROM A 3949 03:11:37,520 --> 03:11:41,800 CONCEPT OF DISABILITY AND ASK 3950 03:11:41,800 --> 03:11:45,360 PATIENTS TO DO TWO LARGE SURVEYS 3951 03:11:45,360 --> 03:11:49,840 IN SEVERAL LANGUAGES WITH A 3952 03:11:49,840 --> 03:11:51,800 THOUSAND RESPONDENTS TO FIND OUT 3953 03:11:51,800 --> 03:11:53,160 THE MOST RELEVANT SYMPTOMS AND 3954 03:11:53,160 --> 03:11:53,920 SOMETHING WE'RE CURRENTLY 3955 03:11:53,920 --> 03:11:55,640 ANALYZING. 3956 03:11:55,640 --> 03:11:57,120 I THINK WE HAVE TO BE MORE 3957 03:11:57,120 --> 03:12:00,280 CAREFUL TO HAVE A MORE 3958 03:12:00,280 --> 03:12:01,880 COMPREHENSIVE VIEW NOT A MOTOR 3959 03:12:01,880 --> 03:12:03,040 PREDOMINANT VIEW AND THIS IS THE 3960 03:12:03,040 --> 03:12:04,800 MAIN WAY WE HAVE TO START WITH 3961 03:12:04,800 --> 03:12:06,520 THE PATIENT VIEW AND THEN ADAPT 3962 03:12:06,520 --> 03:12:07,800 OUR THINKING. 3963 03:12:07,800 --> 03:12:09,560 BECAUSE WHAT WE THINK MIGHT BE 3964 03:12:09,560 --> 03:12:11,240 THE MOST IMPORTANT FEATURE MAY 3965 03:12:11,240 --> 03:12:13,040 BE ISN'T THE MOST IMPORTANT 3966 03:12:13,040 --> 03:12:16,280 FEATURE AT ALL. 3967 03:12:16,280 --> 03:12:18,600 BECAUSE THERE ARE MANY WAYS TO 3968 03:12:18,600 --> 03:12:20,000 OVERCOME YOUR IMPAIRED MOBILITY. 3969 03:12:20,000 --> 03:12:23,600 IT'S MUCH HARDER IF YOU'RE 3970 03:12:23,600 --> 03:12:26,840 IMPAIRED LANGUAGE WISE AND YOUR 3971 03:12:26,840 --> 03:12:29,360 COGNITION IS IMPAIRED TO FIND 3972 03:12:29,360 --> 03:12:29,960 SOLUTIONS TO STILL PARTICIPATE. 3973 03:12:29,960 --> 03:12:35,280 >> THANK YOU. 3974 03:12:35,280 --> 03:12:39,200 >> I THINK KATHARINE ALTER HAD A 3975 03:12:39,200 --> 03:12:39,480 QUESTION. 3976 03:12:39,480 --> 03:12:40,400 >> HI, EVERYONE. 3977 03:12:40,400 --> 03:12:46,720 I HAD A COMMENT AND A QUESTION. 3978 03:12:46,720 --> 03:12:53,880 ONE IS I'LL GO WITH MY COMMENT 3979 03:12:53,880 --> 03:12:57,760 FIRST. 3980 03:12:57,760 --> 03:13:00,280 IF ALL THE WE'RE DOING IS 3981 03:13:00,280 --> 03:13:02,840 FOCUSSING ON SPACTICITY WE'RE 3982 03:13:02,840 --> 03:13:03,880 MISSING THE BOAT BECAUSE THE 3983 03:13:03,880 --> 03:13:07,000 FUNCTION IS IMPAIRED MORE BY 3984 03:13:07,000 --> 03:13:09,880 HYPERTONIA THAN SPACTICITY. 3985 03:13:09,880 --> 03:13:11,880 ALL THE PATIENTS WHOSE VIDEOS WE 3986 03:13:11,880 --> 03:13:14,200 SAW TODAY AND THE COHORT WE'VE 3987 03:13:14,200 --> 03:13:16,760 SEEN AT NIH THE PREDOMINANT 3988 03:13:16,760 --> 03:13:18,160 SYMPTOM WE SEE IS LOW MUSCLE 3989 03:13:18,160 --> 03:13:23,440 TONE IN THE CORE MUSCLES AND 3990 03:13:23,440 --> 03:13:25,600 AXIAL MUSCLES AND THOSE CHILDREN 3991 03:13:25,600 --> 03:13:28,080 JUST LIKE WHAT YOU WANT TO CALL 3992 03:13:28,080 --> 03:13:31,240 TYPICAL CP, AS THEY AGE THE 3993 03:13:31,240 --> 03:13:33,680 IMPACT OF WEAKNESS HAS A BIGGER 3994 03:13:33,680 --> 03:13:35,320 IMPACT ON FUNCTION OVER TIME 3995 03:13:35,320 --> 03:13:39,240 BECAUSE YOUNG CHILDREN ARE 3996 03:13:39,240 --> 03:13:40,080 ACTUALLY STRONGER THAN WHEN 3997 03:13:40,080 --> 03:13:42,360 CHILDREN GET OLDER AND IT'S 3998 03:13:42,360 --> 03:13:46,480 COUNTER INTUITIVE BUT YOU'RE 3999 03:13:46,480 --> 03:13:49,080 STRONGER THAN 3 AND 4 THAN 13 4000 03:13:49,080 --> 03:13:49,800 AND 14. 4001 03:13:49,800 --> 03:13:52,760 YOU CAN'T JUST MEASURE 4002 03:13:52,760 --> 03:13:53,400 SPACTICITY. 4003 03:13:53,400 --> 03:13:55,800 YOU HAVE TO MEASURE HYPERTONIA 4004 03:13:55,800 --> 03:13:57,880 AND WEAKNESS WHICH WE AREN'T 4005 03:13:57,880 --> 03:13:59,280 REALLY GOING. 4006 03:13:59,280 --> 03:14:01,880 AND THE OTHER THING WITH 4007 03:14:01,880 --> 03:14:05,320 SPACTICITY YOU HAVE TO MEASURE 4008 03:14:05,320 --> 03:14:09,880 IT CORRECTLY AND MOST THE TIME 4009 03:14:09,880 --> 03:14:11,680 WE AREN'T MEASURING IT 4010 03:14:11,680 --> 03:14:12,160 CORRECTLY. 4011 03:14:12,160 --> 03:14:14,360 THE QUESTION WAS FOR HEATHER 4012 03:14:14,360 --> 03:14:20,560 WHICH WAS THE INVITAE AND THE 4013 03:14:20,560 --> 03:14:23,960 GENE TEST. 4014 03:14:23,960 --> 03:14:25,960 YOU'RE TESTING KIDS WHO PRESENT 4015 03:14:25,960 --> 03:14:28,160 WITH A CP PHENOTYPE BUT NO KNOWN 4016 03:14:28,160 --> 03:14:32,040 CAUSE OR RISK FACTORS FOR IT BUT 4017 03:14:32,040 --> 03:14:33,840 ARE WE AGAIN MISSING SOMETHING 4018 03:14:33,840 --> 03:14:38,560 HERE BECAUSE THEY'RE LIKELY 4019 03:14:38,560 --> 03:14:41,840 GOING TO BE KIDS WHO HAVE THEY 4020 03:14:41,840 --> 03:14:44,960 HAD PERINATAL ASPHYXIA OR PRE 4021 03:14:44,960 --> 03:14:47,400 TERM AND HAVE PBL BUT HAVE SOME 4022 03:14:47,400 --> 03:14:49,200 GENETIC CAUSE AS WELL AND THAT 4023 03:14:49,200 --> 03:14:50,880 MAY INFLUENCE THE SEVERITY OF 4024 03:14:50,880 --> 03:14:52,480 THEIR CONDITION OR THE LONG-TERM 4025 03:14:52,480 --> 03:14:52,960 IMPACT. 4026 03:14:52,960 --> 03:14:54,560 SO IF WE JUST KEEP SAYING AND 4027 03:14:54,560 --> 03:14:56,760 I'VE HAD THIS HAPPEN THROUGH MY 4028 03:14:56,760 --> 03:14:58,800 CAREER MULTIPLE TIMES WHERE A 4029 03:14:58,800 --> 03:15:01,480 CHILD WAS DIAGNOSED WITH CP THEY 4030 03:15:01,480 --> 03:15:07,440 WERE PRETERM AND HAD CRANIAL 4031 03:15:07,440 --> 03:15:12,760 HEMORRHAGE WE ATTRIBUTED IT TO 4032 03:15:12,760 --> 03:15:13,880 THIS AND THEN DIAGNOSED WITH 4033 03:15:13,880 --> 03:15:15,960 SOMETHING ELSE AND YOU CAN HAVE 4034 03:15:15,960 --> 03:15:17,880 BAD LUCK TWICE. 4035 03:15:17,880 --> 03:15:21,880 SHOULD WE BE TESTING EVERY CHILD 4036 03:15:21,880 --> 03:15:22,440 WITH CP? 4037 03:15:22,440 --> 03:15:23,600 >> THAT'S A GREAT POINT AND 4038 03:15:23,600 --> 03:15:25,880 MAYBE I DIDN'T DO A GREAT JOB 4039 03:15:25,880 --> 03:15:27,200 EXPLAINING SO CERTAINLY THE 4040 03:15:27,200 --> 03:15:31,920 PROGRAM ELIGIBILITY FOR THE PTC 4041 03:15:31,920 --> 03:15:33,600 SPONSORED PROGRAM I DISCUSSED 4042 03:15:33,600 --> 03:15:35,880 TODAY REQUIRES ABSENT OF RISK 4043 03:15:35,880 --> 03:15:39,080 FACTORS FOR AN ACQUIRED BRAIN 4044 03:15:39,080 --> 03:15:40,600 INJURY AND THERE'S OUTSIDE 4045 03:15:40,600 --> 03:15:42,320 SPONSORED TESTING AS WELL SO 4046 03:15:42,320 --> 03:15:44,920 PATIENTS WHO MAY NOT QUALIFY FOR 4047 03:15:44,920 --> 03:15:47,320 THAT TESTING CAN STILL ORDER THE 4048 03:15:47,320 --> 03:15:48,600 TESTING THROUGH THEIR INSURANCE 4049 03:15:48,600 --> 03:15:50,440 OR PATIENT PAY OR THINGS LIKE 4050 03:15:50,440 --> 03:15:53,240 THAT AS WELL AND I TOTALLY AGREE 4051 03:15:53,240 --> 03:15:54,560 WITH YOUR POINT THAT SOMETHING 4052 03:15:54,560 --> 03:15:57,080 THAT MIGHT SEEM LIKE A RISK 4053 03:15:57,080 --> 03:15:58,600 FACTOR, I THINK THERE'S COMMON, 4054 03:15:58,600 --> 03:16:01,640 LIKE YOU SAID, PREMATURE BIRTH 4055 03:16:01,640 --> 03:16:04,280 AND OTHER FACTORS WE COMMONLY 4056 03:16:04,280 --> 03:16:04,440 SEE. 4057 03:16:04,440 --> 03:16:05,800 THANK YOU SO MUCH FOR YOUR 4058 03:16:05,800 --> 03:16:19,760 COMMENTS. 4059 03:16:19,760 --> 03:16:21,400 >> THIS IS A QUESTION FROM 4060 03:16:21,400 --> 03:16:24,800 SOMEONE WHO HAS A DAUGHTER WITH 4061 03:16:24,800 --> 03:16:28,120 COMPLICATED HSPA AND FOR THE 4062 03:16:28,120 --> 03:16:30,720 REGISTRY, DO YOU HAVE PLANS TO 4063 03:16:30,720 --> 03:16:32,840 RECRUIT MORE PATIENTS FROM OTHER 4064 03:16:32,840 --> 03:16:34,920 POPULOUS COUNTRIES LIKE CHINA, 4065 03:16:34,920 --> 03:16:37,000 INDIA AND INDONESIA, ETCETERA 4066 03:16:37,000 --> 03:16:40,920 AND CAN RESEARCH IN THOSE 4067 03:16:40,920 --> 03:16:44,280 COUNTRIES COLLABORATE FOR EARLY 4068 03:16:44,280 --> 03:16:48,360 ONSET ESP TO GET THE MOST 4069 03:16:48,360 --> 03:16:51,120 PATIENTS FOR THE ENDEAVORS. 4070 03:16:51,120 --> 03:16:53,760 >> WE'D LIKE TO HAVE AS BROAD 4071 03:16:53,760 --> 03:16:56,560 REPRESENTATION AS POSSIBLE AND 4072 03:16:56,560 --> 03:16:57,400 CERTAINLY WOULD LOVE TO 4073 03:16:57,400 --> 03:16:58,600 COLLABORATE WITH RESEARCHERS IN 4074 03:16:58,600 --> 03:16:59,760 THE COUNTRIES. 4075 03:16:59,760 --> 03:17:01,240 I THINK THAT BRINGS UP THE POINT 4076 03:17:01,240 --> 03:17:01,880 OF COLLABORATION HOW IMPORTANT 4077 03:17:01,880 --> 03:17:04,720 IT IS. 4078 03:17:04,720 --> 03:17:07,840 WE AS A COMMUNITY WE HAVE TO GET 4079 03:17:07,840 --> 03:17:09,160 TOGETHER AND BUILD THE BIGGEST 4080 03:17:09,160 --> 03:17:12,360 NETWORK POSSIBLE TO ALLOW ACCESS 4081 03:17:12,360 --> 03:17:12,920 IN DIVERSE REPRESENTATION 4082 03:17:12,920 --> 03:17:16,760 FRANKLY BECAUSE ALL OF US WHO 4083 03:17:16,760 --> 03:17:19,160 PRACTICE IN TERTIARY CARE 4084 03:17:19,160 --> 03:17:20,560 MEDICAL CENTERS AND RESEARCH 4085 03:17:20,560 --> 03:17:22,080 INSTITUTIONS THERE'S A BIAS 4086 03:17:22,080 --> 03:17:22,280 HERE. 4087 03:17:22,280 --> 03:17:25,800 I THINK THE PATIENTS THAT WE'RE 4088 03:17:25,800 --> 03:17:28,680 SEEING ARE NOT NECESSARILY 4089 03:17:28,680 --> 03:17:29,760 REPRESENTATIVE OF THE BROAD 4090 03:17:29,760 --> 03:17:30,080 PROPOSITION. 4091 03:17:30,080 --> 03:17:33,080 SO YES, ABSOLUTELY, WE WOULD 4092 03:17:33,080 --> 03:17:33,800 LOVE TO COLLABORATE. 4093 03:17:33,800 --> 03:17:37,280 WE HAVE CERTAINLY IN THE EARLY 4094 03:17:37,280 --> 03:17:41,080 DAYS WE REACHED OUT AND ON A 4095 03:17:41,080 --> 03:17:42,760 SCIENTIFIC LEVEL HAVE HAD A LOT 4096 03:17:42,760 --> 03:17:43,920 OF COLLABORATIONS BUT I THINK WE 4097 03:17:43,920 --> 03:17:46,160 NEED TO FORMALIZE THAT AND THIS 4098 03:17:46,160 --> 03:17:46,760 IS EXACTLY WHAT WE'RE HOPING TO 4099 03:17:46,760 --> 03:17:52,640 DO. 4100 03:17:52,640 --> 03:17:58,520 >> THERE IS A QUESTION FROM 4101 03:17:58,520 --> 03:17:59,480 DR. CHANG. 4102 03:17:59,480 --> 03:18:01,160 HE HOPE TO HAVE HIM SPEAK AT A 4103 03:18:01,160 --> 03:18:01,760 FUTURE CONFERENCE AND WORKS IN 4104 03:18:01,760 --> 03:18:04,560 THE FIELD AND HAD A QUESTION FOR 4105 03:18:04,560 --> 03:18:06,920 ANYBODY IN THE PANEL. 4106 03:18:06,920 --> 03:18:11,960 CONSIDERING THE VAST HETERO 4107 03:18:11,960 --> 03:18:14,120 HETEROGENEITY WOULD YOU PREDICT 4108 03:18:14,120 --> 03:18:17,800 THERE'S A DOSE DEPENDENT 4109 03:18:17,800 --> 03:18:21,800 MECHANISM BEHIND THE ETIOLOGY OF 4110 03:18:21,800 --> 03:18:40,440 THE DISEASE? 4111 03:18:40,440 --> 03:18:42,440 >> MAYBE I'LL PROVIDE A QUICK 4112 03:18:42,440 --> 03:18:42,920 ANSWER. 4113 03:18:42,920 --> 03:18:46,560 WE DON'T STUDY SPAST IN THE LAB 4114 03:18:46,560 --> 03:18:48,920 SO I HAVE NO TRUE MOLECULAR 4115 03:18:48,920 --> 03:18:50,640 INSIGHTS INTO THIS BUT YOU ARE 4116 03:18:50,640 --> 03:18:51,280 RIGHT. 4117 03:18:51,280 --> 03:18:53,760 YOU BRING UP I THINK THE 4118 03:18:53,760 --> 03:19:00,560 QUESTION -- THE HE WILL -- 4119 03:19:00,560 --> 03:19:01,240 ELEPHANT IF THE ROOM IS THIS 4120 03:19:01,240 --> 03:19:03,920 GAIN OF FUNCTION AND WE CAN 4121 03:19:03,920 --> 03:19:05,760 SPECULATE ABOUT THE MUTATIONS A 4122 03:19:05,760 --> 03:19:07,120 LOT BUT THE ONLY WAY TO REALLY 4123 03:19:07,120 --> 03:19:10,560 GET TO THIS IS TO TEST 4124 03:19:10,560 --> 03:19:10,920 EXPERIMENTALLY. 4125 03:19:10,920 --> 03:19:13,320 AND THE HYPOTHESIS YOU'RE 4126 03:19:13,320 --> 03:19:14,360 PROPOSING IS CERTAINLY POSSIBLE 4127 03:19:14,360 --> 03:19:15,360 BUT TO MY KNOWLEDGE AND AGAIN 4128 03:19:15,360 --> 03:19:17,280 I'M NOT IN THE FIELD AND FROM A 4129 03:19:17,280 --> 03:19:18,560 MOLECULAR STANDPOINT I DON'T 4130 03:19:18,560 --> 03:19:20,520 KNOW IF ANY CONVINCING STUDIES 4131 03:19:20,520 --> 03:19:24,200 HAVE SHOWN A DOSE-DEPENDENT 4132 03:19:24,200 --> 03:19:32,360 EFFECT. 4133 03:19:32,360 --> 03:19:35,920 >> THE ONLY GENE DOSAGE STUDIES 4134 03:19:35,920 --> 03:19:37,800 REALLY RELATE TO THE RECURRENT 4135 03:19:37,800 --> 03:19:41,040 DELETIONS WHERE YOU DO PREDICT 4136 03:19:41,040 --> 03:19:43,240 YOU HAVE FULL LOSS OF FUNCTION 4137 03:19:43,240 --> 03:19:45,800 OF ONE OF THE TWO COPIES THOUGH 4138 03:19:45,800 --> 03:19:49,560 I DON'T KNOW WHETHER SOMEONE 4139 03:19:49,560 --> 03:19:50,720 LOOKED AT GENE EXPRESSION 4140 03:19:50,720 --> 03:19:52,560 DISEASE REDUCED BY HALF BUT I 4141 03:19:52,560 --> 03:19:56,560 AGREE THERE COULD EASILY BE LOSS 4142 03:19:56,560 --> 03:19:58,720 FUNCTION AND GAIN OF FUNCTION OR 4143 03:19:58,720 --> 03:20:00,480 EVEN DOMINANT/NEGATIVE AND SOME 4144 03:20:00,480 --> 03:20:04,400 VARIANTS WE'RE LOOKING AT RIGHT 4145 03:20:04,400 --> 03:20:05,840 NOW MIGHT FALL INTO DIFFERENT 4146 03:20:05,840 --> 03:20:07,160 FUNCTIONAL IMPACTS AND THAT 4147 03:20:07,160 --> 03:20:13,800 MIGHT LEAD TO SOME VERY NUANCED 4148 03:20:13,800 --> 03:20:14,760 PHENOTYPIC DIFFERENCES. 4149 03:20:14,760 --> 03:20:17,840 IT MOST DEFINITELY WARRANTS 4150 03:20:17,840 --> 03:20:20,880 FURTHER STUDY. 4151 03:20:20,880 --> 03:20:22,880 >> I MISSED A QUESTION IN THE 4152 03:20:22,880 --> 03:20:23,080 CHAT. 4153 03:20:23,080 --> 03:20:24,560 PETER, WOULD YOU LIKE TO UNMUTE 4154 03:20:24,560 --> 03:20:31,600 OR WOULD YOU LIKE ME TO READ 4155 03:20:31,600 --> 03:20:32,120 YOU'RE QUESTION. 4156 03:20:32,120 --> 03:20:34,200 >> I CAN READ IT IF I CAN FIND 4157 03:20:34,200 --> 03:20:34,360 IT. 4158 03:20:34,360 --> 03:20:37,800 >> I'LL READ IT FOR YOU. 4159 03:20:37,800 --> 03:20:40,520 FOR DARIUS, DO ALL THE 4160 03:20:40,520 --> 03:20:41,360 PATHOGENIC MUTATIONS IN THE 4161 03:20:41,360 --> 03:20:45,480 TRIPLE A DOMAIN ABOLISH THE 4162 03:20:45,480 --> 03:20:45,840 ENZYME FUNCTION? 4163 03:20:45,840 --> 03:20:49,480 >> THE SHORT ANSWER IS WE DON'T 4164 03:20:49,480 --> 03:20:49,720 KNOW. 4165 03:20:49,720 --> 03:20:51,160 WE HAVEN'T DONE ANY EXPERIMENTAL 4166 03:20:51,160 --> 03:20:53,200 TESTING OF THESE VARIANTS TO 4167 03:20:53,200 --> 03:20:55,720 REALLY KNOW IF IT'S ABOLISHING 4168 03:20:55,720 --> 03:21:00,040 THE TRIPLE A DOMAINS FUNCTION. 4169 03:21:00,040 --> 03:21:02,000 I THINK THAT'S ALL I CAN SAY. 4170 03:21:02,000 --> 03:21:03,120 THAT'S EXACTLY THE QUESTION I 4171 03:21:03,120 --> 03:21:05,120 THINK WE NEED TO ANSWER. 4172 03:21:05,120 --> 03:21:06,760 >> AND THE SECOND QUESTION IS 4173 03:21:06,760 --> 03:21:08,080 FOR REBECCA. 4174 03:21:08,080 --> 03:21:11,560 DO YOU EVER SEE PATIENTS WITH A 4175 03:21:11,560 --> 03:21:13,080 COMPLETE ARE SPAST GENE DELETION 4176 03:21:13,080 --> 03:21:14,480 AND WHAT ARE THEIR SYMPTOMS LIKE 4177 03:21:14,480 --> 03:21:16,760 COMPARED TO TRUNCATING 4178 03:21:16,760 --> 03:21:17,000 MUTATIONS. 4179 03:21:17,000 --> 03:21:17,720 >> WE ALREADY DISCUSSED THIS 4180 03:21:17,720 --> 03:21:19,560 OVER THE CHAT. 4181 03:21:19,560 --> 03:21:20,840 I'LL NEED TO CHECK MY DATABASE 4182 03:21:20,840 --> 03:21:22,360 BUT THIS IS AN EXCELLENT 4183 03:21:22,360 --> 03:21:24,360 QUESTION FROM PETER BECAUSE THIS 4184 03:21:24,360 --> 03:21:26,160 WILL HELP US FIGURE OUT EXACTLY 4185 03:21:26,160 --> 03:21:28,240 THE GAIN OF FUNCTION, LOSS OF 4186 03:21:28,240 --> 03:21:29,120 FUNCTION MECHANISM AND SEE 4187 03:21:29,120 --> 03:21:31,120 WHETHER A COMPLETE LOSS OF 4188 03:21:31,120 --> 03:21:32,280 FUNCTION BY LOSS OF THE WHOLE 4189 03:21:32,280 --> 03:21:34,920 GENE CAUSES A SIMILAR PHENOTYPE 4190 03:21:34,920 --> 03:21:37,800 THAN THE OTHER MORE REGULAR 4191 03:21:37,800 --> 03:21:39,000 SPAST MUTATIONS WE SEE SO I'LL 4192 03:21:39,000 --> 03:21:39,800 FOLLOW-UP ON THAT. 4193 03:21:39,800 --> 03:21:41,160 >> AND THE LAST QUESTION FROM 4194 03:21:41,160 --> 03:21:42,800 PETER, ARE THERE ANY PEOPLE IN 4195 03:21:42,800 --> 03:21:44,160 FAMILIES WITH A GENE MUTATION 4196 03:21:44,160 --> 03:21:46,000 THAT LIVE INTO OLD AGE WITH NO 4197 03:21:46,000 --> 03:21:53,000 SYMPTOMS WHATSOEVER? 4198 03:21:53,000 --> 03:21:54,960 >> DO YOU MEAN REGULAR RUN OF 4199 03:21:54,960 --> 03:21:56,760 THE MILL SPG4 MUTATIONS OR WHOLE 4200 03:21:56,760 --> 03:21:58,200 GENE DELETIONS? 4201 03:21:58,200 --> 03:22:00,040 >> RUN OF THE MILL. 4202 03:22:00,040 --> 03:22:03,040 >> WE SEE THAT. 4203 03:22:03,040 --> 03:22:06,680 SO WE COMMONLY HAVE -- NO, NOT 4204 03:22:06,680 --> 03:22:09,880 COMMONLY BUT WE HAVE A FEW 4205 03:22:09,880 --> 03:22:12,160 PERCENT IN THE SINGLE DIGITS OF 4206 03:22:12,160 --> 03:22:15,520 PARENTS WHERE WE FIND THE 4207 03:22:15,520 --> 03:22:18,040 MUTATION THAT'S VERY SUBTLE OR 4208 03:22:18,040 --> 03:22:19,320 NO CLINICAL SIGNS OF THE 4209 03:22:19,320 --> 03:22:19,560 DISEASE. 4210 03:22:19,560 --> 03:22:21,960 IT'S NOT COMMON. 4211 03:22:21,960 --> 03:22:27,600 IT HAPPENS. 4212 03:22:27,600 --> 03:22:29,880 I CAN'T SEE A PATTERN WHERE IT 4213 03:22:29,880 --> 03:22:31,560 WOULD HAPPEN MORE OFTEN. 4214 03:22:31,560 --> 03:22:34,400 >> I HAD A QUESTION FOR REBECCA. 4215 03:22:34,400 --> 03:22:37,320 I WAS ACTUALLY REALLY INTERESTED 4216 03:22:37,320 --> 03:22:39,560 IN YOUR DATA ON PROGRESSION AND 4217 03:22:39,560 --> 03:22:41,440 HOW THE PEOPLE THAT HAD LATER 4218 03:22:41,440 --> 03:22:43,360 ONSET DISEASE SEEMED TO HAVE A 4219 03:22:43,360 --> 03:22:45,800 FASTER PROGRESSION AND I WONDER 4220 03:22:45,800 --> 03:22:49,800 IF YOU HAVE AN EXPLANATION OR 4221 03:22:49,800 --> 03:22:53,880 HYPOTHESIS TO ACCOUNT FOR IT. 4222 03:22:53,880 --> 03:22:57,000 >> I DON'T HAVE AN ANSWER. 4223 03:22:57,000 --> 03:22:59,520 I CAN JUST SHARE MY BOX ON THIS 4224 03:22:59,520 --> 03:23:03,400 AND I SEE BASICALLY TWO POSSIBLE 4225 03:23:03,400 --> 03:23:03,760 EXPLANATIONS. 4226 03:23:03,760 --> 03:23:06,280 ONE WOULD BE AN EXPLANATION THAT 4227 03:23:06,280 --> 03:23:08,000 HAS NOTHING TO DO WITH THE 4228 03:23:08,000 --> 03:23:09,920 DISEASE ITSELF AND MORE A 4229 03:23:09,920 --> 03:23:11,680 FUNCTIONAL EXPLANATION. 4230 03:23:11,680 --> 03:23:13,880 AND IT MIGHT CONTRIBUTE. 4231 03:23:13,880 --> 03:23:20,080 IF YOU HAVE EARLIER ONSET MOTOR 4232 03:23:20,080 --> 03:23:22,720 DYSFUNCTION THE COMPENSATORY 4233 03:23:22,720 --> 03:23:23,320 MECHANISMS ARE MORE ABLE TO 4234 03:23:23,320 --> 03:23:24,280 COMPENSATE THAT. 4235 03:23:24,280 --> 03:23:27,040 WE SEE THAT IN CEREBRAL PALSY 4236 03:23:27,040 --> 03:23:28,160 CHILDREN FOR EXAMPLE. 4237 03:23:28,160 --> 03:23:32,520 WE HAVE A STATIC NEUROLOGICAL 4238 03:23:32,520 --> 03:23:37,720 INJURY AND WHEN THE PATIENTS AGE 4239 03:23:37,720 --> 03:23:39,200 WE SEE THAT MULTI-DETERIORATION 4240 03:23:39,200 --> 03:23:41,840 AND THE COMPENSATION STRATEGIES 4241 03:23:41,840 --> 03:23:48,760 OF SOMEONE OLDER AND MOTOR 4242 03:23:48,760 --> 03:23:49,880 DYSFUNCTION WOULD BE A MORE 4243 03:23:49,880 --> 03:23:53,560 GENERAL EXPLANATION. 4244 03:23:53,560 --> 03:23:56,920 WHAT SPEAKS AGAINST THAT IS IN 4245 03:23:56,920 --> 03:23:57,920 OTHER NEUROLOGICAL DISEASES IT'S 4246 03:23:57,920 --> 03:24:01,880 THE OTHER WAY AROUND, EARLY 4247 03:24:01,880 --> 03:24:05,880 ONSET IS SEVERE AND LATE ONSET 4248 03:24:05,880 --> 03:24:06,920 IS MILDER DISEASE. 4249 03:24:06,920 --> 03:24:08,520 SO IT ARGUES AGAINST IT. 4250 03:24:08,520 --> 03:24:10,360 THE OTHER EXPLANATION IS IT HAS 4251 03:24:10,360 --> 03:24:12,760 SOMETHING TO DO WITH DISEASE 4252 03:24:12,760 --> 03:24:12,960 ITSELF. 4253 03:24:12,960 --> 03:24:15,560 BUT WHAT IT IS I'M AFRAID I 4254 03:24:15,560 --> 03:24:16,200 DON'T KNOW. 4255 03:24:16,200 --> 03:24:17,920 IT WOULD BE REALLY INTERESTING 4256 03:24:17,920 --> 03:24:19,560 TO FIND OUT. 4257 03:24:19,560 --> 03:24:21,120 IF ANYBODY ELSE HAS BETTER IDEAS 4258 03:24:21,120 --> 03:24:24,040 THAN I HAVE FOR THE QUESTION I'D 4259 03:24:24,040 --> 03:24:30,240 BE INTERESTED TO HEAR. 4260 03:24:30,240 --> 03:24:32,440 >> THE LAST QUESTION IN THE CHAT 4261 03:24:32,440 --> 03:24:36,040 FROM MIGUEL, ACCORDING TO G TEX 4262 03:24:36,040 --> 03:24:41,840 IT APPEARS X ON 4 IS SPLICED 4263 03:24:41,840 --> 03:24:51,600 BETWEEN THE GENOFORM HAS ANYONE 4264 03:24:51,600 --> 03:24:53,920 LOOK AT ISO FORM EXPRESSION 4265 03:24:53,920 --> 03:24:54,160 LEVELS? 4266 03:24:54,160 --> 03:24:57,360 >> I HAVE A PARTIAL COMMENT. 4267 03:24:57,360 --> 03:24:59,280 WE HAVE CHECKED THE EXPRESSION 4268 03:24:59,280 --> 03:25:00,080 LEVELS. 4269 03:25:00,080 --> 03:25:01,840 I CAN COMMENT HOWEVER THAT THERE 4270 03:25:01,840 --> 03:25:10,160 ARE NO DISEASE CAUSING MUTATIONS 4271 03:25:10,160 --> 03:25:15,160 KNOWN LOCATED IN EXOME 4 AND THE 4272 03:25:15,160 --> 03:25:18,960 OTHER THING WE HAVE DONE IS WE 4273 03:25:18,960 --> 03:25:22,520 TRIED TO DONE ISOFORM SPECIFIC 4274 03:25:22,520 --> 03:25:22,880 ANALYSIS. 4275 03:25:22,880 --> 03:25:25,880 WE TRIED TO FIND OUT WHETHER 4276 03:25:25,880 --> 03:25:28,600 THERE'S INTERACTIONS WHERE IT'S 4277 03:25:28,600 --> 03:25:33,880 MEDIATED SOMEHOW BY THE PIECE OF 4278 03:25:33,880 --> 03:25:37,240 SEQUENCE ENCODED BY EXON 4 BUT 4279 03:25:37,240 --> 03:25:38,520 IT DOESN'T SEEM TO BE THE CASE. 4280 03:25:38,520 --> 03:25:43,640 THESE ARE THE TWO PIECES OF 4281 03:25:43,640 --> 03:25:45,560 INFORMATION I CAN OFFER BUT IT 4282 03:25:45,560 --> 03:25:49,800 DOESN'T EXACTLY ANSWER THE 4283 03:25:49,800 --> 03:25:50,080 QUESTION. 4284 03:25:50,080 --> 03:25:52,160 >> IS THERE DIFFERENTIAL ALLELIC 4285 03:25:52,160 --> 03:25:52,560 USE? 4286 03:25:52,560 --> 03:25:56,360 >> NOT THAT I KNOW OF. 4287 03:25:56,360 --> 03:25:58,920 JENNIFER, MAYBE YOU KNOW MORE. 4288 03:25:58,920 --> 03:26:01,360 >> FOR THIS LOCUS NOT THAT I'M 4289 03:26:01,360 --> 03:26:04,880 AWARE OF BUT I THINK IT'S 4290 03:26:04,880 --> 03:26:06,040 DEFINITELY WORTH DIGGING BACK 4291 03:26:06,040 --> 03:26:08,200 INTO AND INVESTIGATE. 4292 03:26:08,200 --> 03:26:10,200 I KNOW IN OUR RARE DISEASE 4293 03:26:10,200 --> 03:26:12,120 COHORT WE HAVE PREVIOUSLY 4294 03:26:12,120 --> 03:26:13,200 STUDIED CASES MOST WITH 4295 03:26:13,200 --> 03:26:14,360 DELETIONS IN THE REGION BECAUSE 4296 03:26:14,360 --> 03:26:17,760 THEY WERE ASCERTAINED BY 4297 03:26:17,760 --> 03:26:18,760 CLINICAL ARRAY BUT IT WOULD BE 4298 03:26:18,760 --> 03:26:19,840 INTERESTING TO GO BACK AND LOOK 4299 03:26:19,840 --> 03:26:21,160 AT SOME OF THOSE INDIVIDUALS AND 4300 03:26:21,160 --> 03:26:24,040 TRY TO GET A SENSE FOR WHETHER 4301 03:26:24,040 --> 03:26:30,560 THAT COULD BE THE CASE. 4302 03:26:30,560 --> 03:26:32,160 >> THANK YOU EVERYBODY. 4303 03:26:32,160 --> 03:26:34,560 WE'RE AT THE 2:00 HOUR. 4304 03:26:34,560 --> 03:26:37,680 THANKS SO MUCH FOR A WONDERFUL 4305 03:26:37,680 --> 03:26:38,600 DISCUSSION AND Q&A SESSION AND 4306 03:26:38,600 --> 03:26:39,760 WE THANK EVERYBODY FOR 4307 03:26:39,760 --> 03:26:41,600 PARTICIPATING AND WE LOOK 4308 03:26:41,600 --> 03:26:43,880 FORWARD TO SEEING YOU TOMORROW 4309 03:26:43,880 --> 03:26:45,760 SO WE'LL MEET AGAIN TOMORROW AT 4310 03:26:45,760 --> 03:26:47,960 THE SAME TIME, 10:00 A.M. 4311 03:26:47,960 --> 03:26:49,560 EASTERN STANDARD TIME TO 2:00 4312 03:26:49,560 --> 03:26:52,520 P.M. AND TOMORROW WE HAVE TWO 4313 03:26:52,520 --> 03:26:52,920 SYMPOSIUMS. 4314 03:26:52,920 --> 03:26:54,560 THE FIRST ON TRANSLATION YAL 4315 03:26:54,560 --> 03:26:56,360 RESEARCH AND THE SECOND WILL BE 4316 03:26:56,360 --> 03:26:56,960 ON THERAPEUTICS. 4317 03:26:56,960 --> 03:26:58,640 WE HOPE TO BUILD UPON WHAT WAS 4318 03:26:58,640 --> 03:26:59,760 DISCUSSED TODAY AND WE THANK 4319 03:26:59,760 --> 03:27:01,920 EVERYBODY SO MUCH FOR THEIR TIME 4320 03:27:01,920 --> 03:27:03,000 AN EXPERTISE. 4321 03:27:03,000 --> 03:27:03,560 WE'LL SEE YOU ALL TOMORROW. 4322 03:27:03,560 --> 03:27:05,840 THANK YOU SO MUCH. 4323 03:27:05,840 --> 03:27:05,920