>> WE'LL START THE INAUGURAL SYMPOSIUM AND WE HAVE SOME WELCOMING WORDS AND HOUSEKEEPING ITEMS. THE CONFERENCE IS SPONSORED BY THE NIH INTERMURAL PROGRAM AND THE NATIONAL GENOME INSTITUTE OFFICE OF THE CLINICAL DIRECTOR AND UNDIAGNOSED DISEASES PROGRAM. WE WANTED TO CENTER AROUND PATIENTS AND FAMILIES WE'VE BEEN PRIVILEGED TO CARE FOR AND BRING TOGETHER CLINICIANS, SCIENTISTS, GENETIC TESTING COMPANIES AND ADVOCACY GROUPS TO DISCUSS WHAT IS KNOWN ABOUT THIS DISEASE AND WHAT WE CURRENTLY UNDERSTAND IS MUTATIONS WHEN THEY OCCUR DE NOVO SEEM TO OCCUR TO A KNEW PHENOTYPE OF CHILDHOOD ONSET CEREBRAL PALSY DIFFERENT FROM THE ADULT PHENOTYPE OF THE CLASSIC SPG4 DISEASE. THE GOALS ARE TO REVIEW WHAT IS KNOWN ABOUT DE NOVO SPG4 AND INFORM TRANSLATIONAL RESEARCH WITH THE GOAL OF THERAPEUTICS DEVELOPMENT AND ESTABLISH A RESEARCH NETWORK. WE HOPE TO HAVE FUTURE IN PERSON MEETINGS AND IF YOU WORK IN THE FIELD AND WOULD LIKE TO PRESENT IN FUTURE MEETINGS WE WELCOME YOUR PARTICIPATION. AND WE HAVE THE ACTING DIRECTOR. BEFORE COMING TO NIH SHE WAS AT THE UNIVERSITY OF PITTSBURGH BECOMING THE PROFESSOR OF PEDIATRIC RESEARCH IN THE DEPARTMENT OF PEDIATRICS AND ASSOCIATE DEAN FOR AT THE MEDICAL SCHOOL. IN 2006 SHE BECAME THE CHAIR OF THE DEPARTMENT OF PEDIATRICS AND PEDIATRICIAN OF CHIEF AT THE UNIVERSITY OF RODCHESTER. AND THAT POST SHE HELD UNTIL JANUARY 2018 WHEN WE WERE LUCKY ENOUGH FOR HER TO COME AS DEPUTY DIRECTOR OF NINDS. FOR 27 YEARS HER RESEARCH HAS CENTERED ON NEURAL DEVELOPMENT AND HAS BEEN FUNDED BY THE NIH. SHE CURRENTLY LEADS THE DIVISION OF INTRAMURAL RESEARCH AND THE ULTRA RARE GENE THERAPIES AND CAREER DEVELOPMENT PROGRAMS AT NINDS AND SERVED AS THE NEUROLOGY DIRECTOR FOR THE AMERICAN BOARD OF PSYCHIATRY AND NEUROLOGY. THE SECOND WELCOMING SPEAKER WILL BE CYNTHIA TIFFT AND SPEAK ON BEHALF OF NHGRI AND WILL TALK ABOUT THE UNDIAGNOSED DISEASES NETWORK AND ABOUT HER GROUNDBREAKING TRIAL ON GM1 THERAPY AND IT'S A UNIQUE RESOURCE FOR RARE DISEASES AND TREATMENT TRIALS. SHE RECEIVED HER Ph.D. IN GENETICS FROM THE UNIVERSITY OF TEXAS AT MD ANDERSON CANCER CENTER AND HER MD FROM THE CANCER CENTER IN HOUSTON AND COMPLETED HER RESIDENCY AT JOHNS HOPKINS AND JOINED THE FACULTY OF THE GEORGE WASHINGTON SCHOOL OF MEDICINE AT NATIONAL MEDICAL CENTER IN 1991 AND BECAME CHAIR OF GENETICS IN 2006. SHE WAS RECRUITED TO THE NATIONAL GENOME INSTITUTE AS THE DEPUTY CLINICAL DIRECTOR WHERE SHE DIRECTS THE UNDIAGNOSED DISEASES PROGRAM. HER RESEARCH HAS BEEN AROUND DISEASES AFFECTING THE CENTRAL NERVOUS SYSTEM AND THE PRINCIPLE INVESTIGATOR OF CHILDREN WITH CYTOSIS. THANK YOU AND WE'LL START WITH DR. SCHOR. >> I WANT TO TELL YOU ABOUT AN INITIATIVE INTERESTED TO ALL OF YOU IN RESEARCH AND DEVELOPMENT OF THERAPIES FOR ULTRA RARE GENE-BASED DISORDERS. THAT'S THE NINDS URGENT NETWORK. SO THIS AUDIENCE IS NO STRANGER TO ALL THE CHALLENGES THAT ARE PRESENTED BY DEVELOPING THERAPEUTICS FOR INDIVIDUALS FOR RARE DISORDER. THERE'S A COMPLEX REGULATORY PATH YOU HAVE TO RAISE FUNDS TO TWO NF IS TRIALS AND GETTING INTEREST FROM ACADEMIC RESEARCHERS FOR DISORDERS FOR BASIC DISEASE MECHANISMS MAY NOT BE KNOWN OR WHERE THIS THE TRIAL DESIGN IS CHALLENGING AND ACCESS TO THERAPY DEVELOPMENT EXPERIENCE OR TO TOXICOLOGY AND MANUFACTURING AND SCALE-UP KIND OF RESOURCES. THERE'S LITTLE IN THE WAY OF MARKET FOR MANY THERAPIES FOR THESE DISORDER SO IT'S DIFFICULT TO ENGAGE INDUSTRY AND THERE'S UNIQUE CONCERNS WHEN YOU'RE DOING THIS WITH SMALL ENDS AND THERE'S MANY CHALLENGES. FOR MANY OF THESE DISORDERS WE DON'T KNOW YET WHAT THE NATURAL HISTORY IS AND RECRUITING PATIENTS FROM A VERY VERY DIVERSE ARRAY OF VENUES BECOMES CHALLENGING AS WELL. SMALL NUMBERS OF PATIENTS IN PERHAPS HUNDREDS OF VENUES EACH OF WHICH PRESENT DIFFERENT CHALLENGES. THE OLE OF THE URGENT NETWORK THAT NINDS HAS CREATED IS TO FACILITATE RESEARCH ON THERAPIES FOR THESE DISORDERS. TO ACCELERATE ADVANCEMENT OF THE THERAPIES INTO THE CLINIC, TO DEMOCRATIZE THE AVAILABILITY OF GENE THERAPY TO PEOPLE WHO WANT TO DO THIS RESEARCH AND TO PATIENTS AND FAMILIES SUFFERING FROM THESE DISORDER TO DEVELOP THERAPEUTICS TO PATIENTS WITH ULTRA RARE NEUROLOGIC DISEASE REGARDLESS OF WHERE THEY LIVE AND WHAT RESOURCES ARE AROUND THEM AND STANDARDIZE BEST PRACTICES AND PROTOCOLS AN DATA COLLECTION TO MAKE DATA AVAILABLE TO PEOPLE ALL OVER THE GLOBE. AND THE RESEARCH THE NETWORK PROVIDES RUNS THE GAMUT FROM GMP MANUFACTURING OF CLINICAL LOTS OF VIRUS AND THERAPEUTICS AND TO THE NOTION OF PERFORMING FOR THE SCIENTIFIC AND THE PHARMACO KINETICS THAT MAKE OBTAINING AN IND AND HAVE AVAILABLE SUBJECT MATTER EXPERTS AS CONSULTANTS ON SUCH THINGS AS MANUFACTURING PK TOXICOLOGY AND TO REALLY DO THE DISCUSSION WITH THE FDA AND OTHER REGULATORY AGENCIES TO OBTAINING AN IND AND CLINICAL TRIAL DESIGN AND AT THE CLINICAL CENTER AT NIH CONDUCT OF THE CLINICAL TRIAL AND TO REALLY CENTRALIZE DATA COLLECTION AND COORDINATION. THERE'S CURRENTLY FUNDING AVAILABLE. WE'RE AT THE BEGINNING OF WHAT I HOPE WILL BE A LONG STORY FOR URGENT NETWORK. BUT THERE ARE TWO RFA'S OUT FOR FUNDING OF THE INITIAL ONE OF PAR22030 IS AIMED AT THE AIMED AT THE TRIAL READINESS RESOURCES. THE KINDS OF THINGS YOU WOULD DO TO GET AN IND OR TO DECIDE IF IT'S REASONABLE BASED ON THE YOU CURRENTLY HAVE. AND THE SECOND IS PAR22028 AND THAT'S BEFORE YOU DO THE STUDIES TO DO THE BASIC SCIENCE MECHANISTIC DATA TO DESIGN WHAT YOU USE IN THE CLINICAL TRIAL A AND TALKING ABOUT URGENT NETWORK AND OUTABILITY FOR WHAT IT IS THEY ACCOMPLISH. CHRIS BOSHOFF IS THE LEAD AND HIS COLLEAGUES YOU CAN SEND INQUIRIES TO. IF YOU HAVE INQUIRIES OR JUST WANT TO SET UP A TIME TO TALK WITH THE PRINCIPLE PROGRAM DIRECTORS INVOLVED IN URGENT NETWORK I HOPE YOU GET A ROBUST RESPONSE TO THE RFAs BECAUSE LIKE YOU I'M HOPING WE DEVELOP KNOWLEDGE AND CLINICAL TRIALS FOR RARE DISORDER INVOLVING THE NERVOUS SYSTEM. AND WE HAVE A GROUP OF SUBJECT MATTER EXPERTS WE ASSEMBLED AND ENGAGED IN ORDER TO GET YOU THE INFORMATION YOU NEED TO GET NOT WHOLE THERAPIES OUT THERE AND AVAILABLE TO PATIENTS AND MAKING IT AVAILABLE TO EVERYONE IN THE SCIENTIFIC COMMUNITY. SO I'LL CLOSE BY THANKING ALL OF YOU FOR BEING OUR PARTNERS IN THIS. THANKS TO OUR FUNDERS FOR THIS WONDERFUL CONFERENCE AND THANKS TO ALL OF YOU FOR BEING WITH US TODAY. >> THANK YOU SO MUCH FOR THOSE WONDERFUL COMMENTS AND THOSE WONDERFUL INITIATIVES. NOW I'LL PASS IT OVER TO DR. TIFFT. >> THANK YOU FOR THE KIND INTRODUCTION ARRINE. ARE YOU SEEING THIS IN THE APPROPRIATE WAY? >> YES. >> OKAY, PERFECT. SO MY ROLE AS I UNDERSTAND IT IS TO TALK ABOUT THE UNDIAGNOSED DISEASE PROGRAM AND A PATHWAY OR AS A PATHWAY MAYBE EVEN TO RARE DISEASE RESEARCH AND SHARE MY EXPERIENCE IN THAT VENUE THE NIN CLINICAL CENTER IS A 200 BED HOSPITAL DEDICATED SOLELY TO CLINICAL RESEARCH AND IMPROVING THE NATION'S HEALTH. AND PATIENTS WHO COME TO THE NIH INCUR NO COST TO BEING INVOLVED AND THERE'S ROUGHLY 1600 ACTIVE RESEARCH PROTOCOLS AND HALF OF THESE STUDIES ARE NATURAL HISTORY STUDIES ESPECIALLY FOR RARE AND ULTRA RARE DISEASES AND THE OTHER HALF WILL CLINICAL TRIALS AND OFTEN THEY'RE FIRST IN HUMAN STUDIES TO TEST SAFETY AND EFFICACY OF NEW THERAPEUTICS. THE VAST MAJORITY OF THE PROTOCOLS ARE DISEASE BASED. AS A RESULT OF THAT IN 2008, THE NIH UNDIAGNOSED DISEASES PROGRAM WAS LAUNCHED TO BASICALLY ALLOW ACCESS TO THE NIH CLINICAL CENTER FOR FOLKS WHO DIDN'T HAVE A DIAGNOSIS AND WERE NOT ELIGIBLE FOR THE PROTOCOLS OR RESOURCES OF THE NIH. THERE'S TWO OBJECTIVES TO REFLECT THE MISSION OF THE NIH BOTH FOR PUBLIC SERVICE AND FOR ADVANCING BIOMEDICAL RESEARCH. SO THE NIH UNDIAGNOSED DISEASE PROGRAM OVER THE LAST 12 YEARS WE ESSENTIALLY LOOKED AT ABOUT 4,000 MEDICAL RECORDS AND WE DID THIS ON PAPER IN VAST STACKS AND NOW DOING MOST ELECTRONICALLY. WE HAVE ACCEPTED ROUGHLY 1200 PATIENTS OF WHICH 40% ARE KIDS. CONSIDERABLY MORE THAN 50% OF PARTICIPANTS HAVE NEUROLOGIC CONDITIONS RELEVANT TO THE CONFERENCE TODAY. THERE'S BEEN AT LEAST TWO SPG4 DIAGNOSES THUS FAR AND WE FOUND THE DIAGNOSIS IN A THIRD OF THE PATIENTS THAT APPLY AND GENERATED PUBLICATIONS MANY ON ULTRA RARE OR UNIQUE DISEASES. AND IN 2013 WE BECAME PART OF THE NIH UNDIAGNOSED DISEASES NETWORK WHICH EVENTUALLY MORPHED TO 12 CLINICAL SITES THROUGHOUT THE COUNTRY AND A COORDINATING CENTER AT HARVARD, A DNA COORDINATING CENTER AT THE BAYLOR COLLEGE OF MEDICINE AND A LOCATION AT VANDERBILT UNIVERSITY AND A MODEL SCREENING UNIVERSITY AND A METABOLOMICS WARD AT MAYO CLINICAL WORKING TOGETHER TRYING TO SOLVE THESE WHILE LINKED THROUGH A COMMON DATABASE. SO FAR THE UDN EXPERIENCE AS OF THIS MORNING HAD RECEIVED 5700 APPLICATIONS. PATIENTS APPLY ONLINE AND IT IS A PATIENT-INITIATED AN EXPERIENCE AND THEY UPLOAD A LETTER FROM A PRACTITIONER THAT SUMMARIZES THE WORK THEY'VE ALREADY HAD AND ASKING TO BE CONSIDERED FOR ADMISSION TO THE UDN. WE HAVE APPLICATIONS UNDER REVIEW OF ABOUT 2200 HAVE BEEN ACCEPTED ACROSS THE NETWORK AND WE EVALUATED A LITTLE OVER 1300 PATIENTS AND SEQUENCED 1700 BY GENOME SEQUENCING AND MADE MODEL ORGANISMS AND HAVE CELL LINES IN THE REPOSITORY AND HAVE DONE METABOLOMICS AND TOGETHER SINCE 2013, NOT COUNTING THE DIAGNOSES BETWEEN 2008 AND 2013 BUT WORKING TOGETHER AS PART OF THE UDN MADE ROUGHLY 550 DIAGNOSES. ONE OF THE FIRST WE EVER SOLVED AND LINKED TO MY SECOND INTEREST IS A PATIENT NAMED JESSIE AND SHE WAS 17 YEARS OLD AND HAD BEEN SEARCHING FOR A DIAGNOSIS ALMOST 12 YEARS. HER PARENTS HAD BEEN TO MULTIPLE ACADEMIC INSTITUTIONS AND ON EXOME SEQUENCE WE FOUND SHE HAD MUTATIONS IN GLB1. AND HAD THE TYPE 2 JUVENILE ONSET FORM BEGINNING AT ABOUT AGE 4 OR 5. SHE ACTUALLY HAD HAD A LYSOMAL SCREEN AND WAS A JUVENILE ONSET CASE AND HER CONDITION WAS RARE AND THERE WAS NO APPROVED THERAPY. JESSIE WAS ONE OF THE FIRST PATIENTS WE ENROLLED FOR GM1 AND GM2 AND 12 YEARS LATER WE'VE SEEN ROUGHLY 50 PATIENTS TO CHARACTERIZE THE DISEASE PROGRESSION IN THAT DISEASE. AFTER 12 YEARS OF CHARACTERIZING THE DISEASE PROGRESSION, WORKING WITH OUR COLLEAGUES AT THE UNIVERSITY OF MASSACHUSETTS AT AUBURN UNIVERSITY WHO DEVELOPED THE VIRAL AAV9 VECTOR AND TESTED IT IN AN ANIMAL MODEL WE LAUNCHED OUR THERAPY TRIAL IN MAY OF 2019. YOU CAN SEE HERE OUR FIRST PARTICIPANTS AND A WHOLE GROUP OF FOLKS AND U-MASS AND BECAME CYTOGENE THERAPIES HELPING SUPPORT US IN THE TRIAL AND IF YOU WANT THE FULL GOOD STORY, THAT'S THE LINK. BUT OVER THE NEXT TWO AND A HALF YEARS AND ONE PANDEMIC, WE HAVE ENROLLED AN ADDITIONAL 10 PATIENTS INTO OUR CLINICAL TRIAL AND TREATED THEM WITH GENE THERAPY INCLUDING TWO INFANTS THAT DR. SCHOR IS WELL AWARE OF BECAUSE SHE WAS INSTRUMENTAL IN HELPING US WORK THROUGH THE ISSUES WITH THE CLINICAL CENTER. THESE WERE THE FIRST TWO INFANTS TO BE TREATED AT THE CENTER IN DECADES. IT WAS GRATIFYING TO BE ABLE TO DO THAT. AND WE'VE HAD NO SERIOUS DRUG-RELATED ADVERSE EVENTS AS A RESULT OF THE TRIAL THAT IS ONGOING AND WE NEED THE RESOURCES OF THE NIH CLINICAL CENTER NOW MORE THAN EVER BECAUSE LESS THAN 48 HOURS AGO OUR PARTNER IN THIS WHO WAS FUNDING THE TRIAL ANNOUNCED IT WAS TERMINATING BOTH OUR TRIAL, THE GM1 TRIAL AT THE NIH AND A COMPANION GM2 TRIAL AT THE UNIVERSITY OF MASSACHUSETTS. SO FOR THE LAST 36, 48 HOURS WE'VE BEEN SCRAMBLING. FORTUNATELY, CARE AT THE NIH IS PROVIDED TO NO COST TO PATIENTS AND BASED ON THAT WE'RE IN HOPES OF BEING ABLE TO CONTINUE TO TREAT OUR PATIENTS BOTH FOR THE PATIENTS WE CURRENTLY ENROLLED AND FOR THE ENTIRE GM1 COMMUNITY WHO WORKED SO HARD TO BRING THIS STUDY TO FRUITION. SO WITH THAT, I WON'T TAKE QUESTIONS BECAUSE WE'LL SAVE THEM FOR THE END. THANK YOU. >> THANK YOU VERY MUCH FOR THOSE IMPORTANT REMARKS AND HOPE YOU'RE TRIAL WILL BE ABLE TO CONTINUE AS IT'S SO IMPORTANT. I'LL INTRODUCE THE MODERATOR OF OUR FIRST SYMPOSIUM. DO PEOPLE SEE MY SLIDES? GREAT. THE FIRST SYMPOSIUM IS GOING TO REVIEW THE CLINIC PHENOTYPE OF DE NOVO SPG4 MODERATED BY DR. KATHARINE ALTER. SHE IS BOARD-CERTIFIED IN PEDIATRICS, PHYSICAL MEDICINE AND ELECTRODIAGNOSTIC MEDICINE AND MEDICAL DIRECTOR OF THE NIH REHABILITATION FUNCTIONAL AND APPLIED BIOMECHANICS SECTION WITH MEASUREMENTS AND QUANTIFICATION OF GAIT IN MANY CLINICAL TRIALS AT THE NIH AND HAS EXPERTISE IN CEREBRAL PALSY AND GAIT ANALYSIS IN RARE NEUROLOGICAL DISEASES AND HAS SEEN MANY OF THE NIH PATIENTS WITH DE NOVO SPG4. TO BRIEFLY GO OVER OUR SCHEDULE FOR THE FIRST SYMPOSIUM. WE'LL HAVE SPEAKERS TO 11:05 AND THEN A TEN MINUTE BREAK AND SPEAKERS TO 12:05 AND THEN A 30-MINUTE LUNCH BREAK. I'LL PASS IT OVER TO DR. ALTER. >> THANK YOU. THE FIRST PORTION OF OUR PROGRAM THIS MORNING WILL BE TWO SETS OF, WELL, FOUR PARENTS OF FOUR CHILDREN WHO ARE AFFECTED BY SPG4 DE NOVO VARIANTS AND THEY'LL BRING THEIR EXPERTISE TO THE CHALLENGES OF NAVIGATING THE MEDICAL AND REHABILITATION SYSTEM AND ALL THE OTHER CHALLENGES THAT ARE ASSOCIATED WITH RAISING A CHILD WITH A DISABILITY ESPECIALLY A RARE GENETIC DISEASE. AND WE'LL HAVE MORE ABOUT AN OVERVIEW OF THE CURE SPG4 NETWORK WHICH SOME ARE BEEN INSTRUMENTAL IN THE DEVELOPMENT AND DR. SCHULE FROM TUBINGEN, GERMANY WILL TALK ABOUT THE SPASTIC PARAPLEGIC PHENOTYPE AND CONDUCTS RESEARCH IN GERMANY AND WORKED ON THERAPY IN THE RATING SCALE WHICH HAS BEEN INSTRUMENTAL FOR US IN MEASURING QUANTITATIVELY ACROSS MULTIPLE CENTERS FORM AND FUNCTION AND IMPAIRMENT. AND IS COORDINATING THE NETWORK. WE WANT TO WELCOME ALL THE SPEAKERS AND START OFF WITH THE FIRST SET OF PARENTS, CHRIS AND KATIE GREGG. >> THANK YOU FOR THE INTRODUCTION. I'LL JUST SHARE MY SCREEN. HOPEFULLY YOU CAN ALL SEE IT? CAN YOU CONFIRM? >> YES. >> GREAT. AGAIN, THANK YOU DR. ALTER AND NIH FOR ARRANGING THIS MEETING AND FOR THE INVITATION TO SPEAK. I COULD NEVER HAVE IMAGINED I WOULD HELP OPEN A MEDICAL SYMPOSIUM WITH DOCTORS ALL OVER THE WORLD AND HAVING A CHILD DIAGNOSED WITH AN INCURRABLE DEBILITATING DISEASE FINDS YOU IN PLACES YOU WOULD NEVER IMAGINE. SCIENTIFICALLY SPEAKING WE ALL KNOW WHY WE'RE HERE. AS THE PROGRAM STATES WE'RE HERE TO SHARE INFORMATION ABOUT DE NOVO SPG4 TO INFORM FUTURE RESEARCH AND THE REASON I'M HERE TODAY IS TO SEE IF I HAVE HOPE FOR MY DAUGHTER. DEVELOPING A TREATMENT FOR CURE OR DE NOVO CASES OF SPG WOULD HAVE RECOGNITION ON THE CONTRIBUTORS IT'S MORE THAN THAT. IT WILL FUNDAMENTALLY ALTER THE COURSE OF THE LIVES OF PEOPLE THAT LIVE WITH THIS DISEASE AND EVERYONE WHO CARES DEEPLY ABOUT THEM. THE IMPACTS OF THE DISEASE MAY BE UNDERSTAND BUT FELT BY THE PATIENTS AND EVERYONE WHO HELPS CARE FOR THEM. I WILL NEVER BE ABLE TO FULLY UNDERSTAND OR APPRECIATE ALL THE CHALLENGES THAT MY 4-YEAR-OLD DAUGHTER BLAIR DIAGNOSED WITH THE DE NOVO SPG4 WILL FACE. I CAN OBSERVE SOME CHALLENGES INCLUDING THE FACT SHE'S MISSED NUMEROUS DEVELOPMENTAL MILESTONES. EVEN AT 4 YEARS OF AGE SHE'S NOT ABLE TO STAND OR WALK. I CAN WATCH HER AT THE PLAYGROUND WITH A LONGING LOOK ON HER FACE WHILE OTHERS RUN AROUND AND SEE FRUSTRATION IN HER EYES WHEN SHE WANTS A TOY ON THE OTHER SIDE OF THE ROOM BUT WAITING FOR US TO GET IT FOR HER AND SEE THE FEAR ON HER FACE TO SIT IN A RESTAURANT AND NEEDS TO CLUTCH ON US TO MY WIFE AND I FOR THE ENTIRE MEAL TO HAVE A SENSE OF STABILITY. I CANNOT UNDERSTAND WHAT SHE THINKS OR FEELS INSIDE ESPECIALLY WHEN OTHER CHILDREN ASK WHY CAN'T YOU WALK OR DROOL SO MUCH OR WHAT'S WRONG WITH YOU? ALL I CAN COMMENT ON IS HER LIFE THROUGH THE PERSPECTIVE AND THROUGH MY PERSPECTIVE IT'S A CHALLENGING LIFE SHE DOESN'T DESERVE. LIKE WE CAN'T UNDERSTAND WHAT IT FEELS LIKE WITHOUT BEING IN THAT POSITION IT'S HARD TO UNDERSTAND WHAT IT'S LIKE TO BE PARENTS. IT'S NOT UNCKOCON COMMON TO HAVE THE UNEASE OF KNOWING OUR CHILD HAS A PROGRESS DISEASE AND WE HAVE GUILT WE DON'T DO ENOUGH FOR BLAIR. THE VAST MAJORITY OF OUR TIME GOES TO HER INCLUDING PHYSICALLY MOVING HER AROUND THE HOUSE AND HELPING WITH HER STRETCHING ROUTINE OR JUST HELPING HER EAT THOUGH WE DON'T HAVE TIME FOR ALL THE ASSIGNMENTS FROM OTHER THERAPISTS. THERE'S EMOTIONAL AND PHYSICAL DEMANDS. AN OFTEN OVERLOOKED CHALLENGE IS THE ADMINISTRATIVE BURDEN. CONSTANTLY SCHEDULING AND RESCHEDULING DOCTOR AND THERAPIST APPOINTMENTS AND COMPLETING MEDICAID APPLICATIONS OR DEALING WITH INSURANCE COMPANIES TO NAME A FEW. IT'S HARD TO DESCRIBE THE EMOTION I FELT WHEN MY WIFE CAME UP TO ME WITH TEARS BECAUSE ASSIST AFTER HAVING BEEN ON THE PHONE TWO HOURS ARGUING WITH THE INSURANCE COMPANY WE WERE DENIED A MEDICAL DEVICE PRESCRIBED. IT WAS A CULMINATION OF THOUSANDS OF HOURS BATTLING INSURANCE COMPANIES TO GET WHAT WAS PRESCRIBED AND OWED. IT'S NORMAL TO WOND HER WHAT KIND OF LIFE YOU'RE CHILD WILL HAVE AND WILL THEY ARE BE SUCCESSFUL OR FIND A LOVING PARTNERS. WE FIND OURSELVES FOCUSSED ON OTHER QUESTIONS, WILL OUR DAUGHTER BE ABLE TO WALK OR BE SPEAK OR RELYING ON US THE REST OF HER LIFE AND WHO WILL TAKE CARE OF HER IF WE CANNOT? DESPITE HER CHALLENGES, BLAIR IS ONE OF THE HAPPIEST CHALLENGES YOU'LL EVER MEET AND HAS A SMILE THAT LIGHTS UP EVERY ROOM SHE ENTERS AND SOMEHOW CONTINUES TO BE PATIENT THROUGH HER SESSIONS AND PROCEDURES. WE CONTINUE WITH HER REGIMENT IN HOPE WE CAN HER HER MEET HER POTENTIAL AND IN HER YEARS SHE TAUGHT EVERYONE A VALUABLE LESSON ON PERSEVERANCE. I'M PROVIDING INSIGHT TO OUR LIVES NOT BECAUSE I WANT YOU TO FEEL BAD OR HAVE SYMPATHY FOR US BUT TO PROVIDE INSIGHT TO THE UNSEEN IMPACT OF THE DISEASE AND STRESS THE IMPORTANCE OF WHAT WE'RE HERE TO DO TODAY AND TOMORROW. I BELIEVE HNIH HAS BEEN ABLE TO COLLECT THE BEST MINDS TO SOLVE THE PROBLEM. I HAVE SPOKEN WITH A NUMBER OF YOU AND KNOW YOUR TALENTED PROFESSIONALS AND SUPPORTIVE OF THE PATIENTS. THIS SYMPOSIUM IS AN IMPORTANT STEP TO BRING FOCUS TO DE NOVO SPG4 BECAUSE I FEEL FINDING A CURE TO STOP THIS DISEASE IS NOT IF BUT WHEN BUT TIME THE ESSENCE. EACH DAY THAT PASSES RESULTS IN A WORSENING STATE FOR BLAIR AND ALL OTHER IMPACTED PATIENTS. IT'S THE ONLY GROUP THAT CAN HELP LEAD PROGRESS AND CURRENTLY THERE ARE NO OTHER OPTIONS. PLEASE, HELP ME TO HAVE HOPE. HAVE BLAIR TO HAVE HOPE. HELP ALL FAMILIES IMPACTED BY THE DISEASE TO HAVE HOPE. LET'S STOP THE DISEASE AND RELIEVE ALL FUTURE GENERATIONS FROM AN UNJUST LIFE. I SINCERELY THANK YOU FOR ALL THE CONTRIBUTIONS YOU'VE MADE AS DOCTORS, CLINICIANS, RESEARCHERS, THERAPISTS, GENETICISTS AND SUPPORTERS AND THANK YOU FOR JOINING US TODAY. I'LL DO ANYTHING NECESSARY AS A PATIENT ADVOCATE TO PARTNER WITH YOU TO SOLVE THE CHALLENGE AND LOOK FORWARD TO THE PROGRESS WE'LL MAKE TOGETHER. THANK YOU. >> THANK YOU SO MUCH FOR THE BEAUTIFUL WORDS AND THANKS FOR SHARING YOUR EXPERIENCE AND WE'LL PASS IT ON TO KATIE. >> GOOD MORNING. LET ME GO TO MY SCREEN SHARE AND LET ME NO IF THERE'S ANY ISSUES WITH SEEING IT. >> ARE WE GOOD? >> JUST MAKE IT PRESENTER MODE, IF YOU DON'T MIND. >> IT SAYS IT IS. >> THAT'S GREAT. >> PERFECT. GOOD MORNING, EVERYONE. DOWNTOWN, I'M KATIE GREG. I'M SO GLAD WE'RE ALL HERE TOGETHER AND SOMEHOW ALMOST MAY. TIME FLIES AND I BELIEVE NO MORE SO THAN FOR A LOT OF HERE TODAY. MY DAUGHTER LILY HAS EARLY ONSET SPG4. A LITTLE BACKGROUND SHE MISSED MILESTONES EARLY IN LIFE. AT 15 AND 18 MONTHS THE PEDIATRICIAN ADVISED US TO WAIT ON INTERVENTION. AT 20 MONTHS WE CHOSE TO MOVE AHEAD ON OUR OWN AND WE RECEIVED A VERY CONFIDENT CP DIAGNOSIS EVEN IN THE ABSENCE OF MRI. WE PURSUED GENETIC TESTING ON OUR OWN AND TWO MONTHS LATER WE HAD RESULTS DELIVERED TO US BY A GENETICISTS WHO CRIED WHEN SHE GAVE US THE NEWS. SHE GAVE US HER SYMPATHIES BUT NO REALS TO OUR QUESTIONS AND WE STILL HAVE A LOT OF QUESTIONS. I DON'T SAY THAT FOR SYMPATHY OR TO DISCOUNT THE WORK THAT'S BEING DONE. I SAY THAT BECAUSE ONE DAY IT WON'T BE ME ASKING THE QUESTION IT WILL BE LILLY. AND MY JOB IS TO PROTECT HER. I DON'T WANT MY DAUGHTER GROWING UP IN A WORLD WHERE HER QUESTIONS OR CONCERNS AREN'T BE ADDRESSED AND HER ACCESS ARE WITH LIMITATIONS. TODAY LILLY IS 3 1/2 AND BRIGHT AND CURIOUS AND FUNNY AND THE MOST MOTIVATED AND DETERMINED LITTLE GIRL I KNOW. SHE CAN'T STAND OR WALK INDEPENDENTLY AND USE AS A WALKER TO NAVIGATE AT SCHOOL AND WHEEL CLAIR FOR LONGER DISTANCES. SHE DOES AQUATIC THERAPIES, GOES TO PRESCHOOL AND INTENSIVES THAT REQUIRED US MOVING TO VIRGINIA THREE TO FOUR WEEKS AT A TIME THREE OR FOUR TIMES A YEAR. MEANWHILE THE OBLIGATIONS OF MY HUSBAND AND I GO BEYOND THERAPY, SCHOOL AND SOCIAL SCHEDULE, WE STRETCH HER MULTIPLE TIMES A DAY FOR 20 MINUTES AT A TIME AND WORK ON HER ADLs SHE CAN'T DO WITHOUT ASSISTANCE AND PUT HER ON HER STANDER AND SHE USES CRUSHES AND ROLLING WALKER THAT OFFER HER OPTIONS BUT TAKE TIME TO SET HER UP IN AND SHE HAS ROTATION STRAPS THAT HAVE TO BE UNDONE EVERY TIME HER PANTS NEED TO BE REMOVED. WE ALSO CARRY AND LIFT HER INTO CHAIRS, BEDS, CARS AND IN THE BACK YARD. OUTSIDE THE EQUIPMENT, RESEARCH, READING, CALLS TO DOCTOR'S OFFICES, INSURANCE PROVIDERS AND HOME MODIFICATION PROVIDERS ARE ENDLESS AND THERE'S NOT ENOUGH HOURS IN THE DAY AND THERE'S NO CLEAR DIRECTION FOR A PATH FORWARD. WE FIND OURSELVES DOING EVERYTHING AND YET AT THE END OF THE DAY FEELING LIKE IT'S NEVER ENOUGH. BUT IT'S NOT MY TIME I'M WORRIED ABOUT IT'S HERS. SHE SPENDS HER HOURS IN THE TRAPPINGS OF ROUTINE AND EQUIPMENT AND WE'RE HARD PRESSED ALBEIT DETERMINED TO HAVE HER EXPLORE HER ENVIRONMENT AND MEET NEW PEOPLE ALL HINDERED IF WE CAN'T FIGURE OUT THE BEST WAY TO MANAGE HER CONDITION AND EQUIP HER FOR THE DAY AND FRANKLY HER LIFE AND WE DON'T KNOW HOW MUCH TIME SHE HAS TO DO THIS OR WHAT WILL GIVE THE BEST OUTCOME AND I'M NOT FAULTING HER CARE TEAM. THERE'S A LACK OF INFORMATION, INFORMATION, OPTIONS, FAMILIARITY AND PRESENTATION. I CHALLENGE US TODAY TO CONSIDER HOW WE GET A COMMON UNDERSTANDING. A COMMON CONSENSUS AND GET HOPE. I WOULD ARGUE THAT LILLY HAS MORE HOPE IN HER LITTLE HEART THAN ANYONE I KNOW BUT I ALSO KNOW IT WILL START TO CHANGE. SHE'LL GET OLDER AND ASK QUESTIONS ABOUT HER CONDITIONS AS SHE'S STARTED TO. GOING FROM YESTERDAY'S QUESTION OF HEY, MOMMY, THAT PERSON IS STANDING ON THEIR OWN, CAN I DO THAT WHEN I'M A GROWN UP TO THE MORE LIKELY REALITY OF WHAT'S BEING DONE? HOW CAN I MANAGE THIS? HOW CAN I HAVE HOPE? IT'S MY HOPE WHEN SHE'S OLDER AND STARTS TO ASK THOSE QUESTIONS THERE ARE SOME ANSWERS. SHE'S WORTHY OF THE ACCOMMODATION AND ACCESS AND FRANKLY THE CONSIDERATION THAT WE ARE ALL AFFORDED EACH AND EVERY DAY. AND THAT ALL STARTS HERE AND HAS TO START NOW. THE VERY PEOPLE AT THIS SYMPOSIUM ARE THE PEOPLE I KNOW CAPABLE OF MAKING AN IMMEASURABLE IMPACT OF THE LIVES OF THOSE AFFLICTED WITH THIS DISEASE. I'M NOT A SCIENTIST, RESEARCHER OR DOCTOR BUT I AM A FORMER NON-PROFIT EXECUTIVE, A MOM, A CARETAKER AND ADVOCATE. AND I'M HONORED TO BE HERE WITH SUCH BRIGHT AND DEDICATED PROFESSIONALS AND SUCH DEVOTED AND PASSIONATE FAMILIES. LIKE I SAID, THOSE OF US NAVIGATING THIS EXPERIENCE KNOW ALL TOO WELL TIME FLIES. BUT THIS SYMPOSIUM IS GIVING US A CHANCE TO BE THE PILOT AND TO STEER US TOWARDS SOME INFORMATION, SOME ANSWERS AND SOME HOPE. THANK YOU ALL SO SO FOR YOUR TIME AND FOR YOUR DEDICATION AND A LOOK FORWARD TO WORKING WITH YOU. >> THANKS SO MUCH, KATIE. NEXT WE'LL WELCOME REBECCA SCHULE. >> CAN YOU HEAR ME? >> YES. >> WONDERFUL. I'LL SHARE MY SCREEN. >> GREAT. SO HI, THANK YOU SO MUCH FOR HAVING US HERE. I'M ANDREA McCONNELL AND ERIN DEAR AND I WILL TAKE TIME TO TALK ABOUT OUR FAMILIES AND CHILDREN AND MOVE ON TO TALK ABOUT OUR CURE SPG4 FOUNDATION YOU CAN SEE HERE. SO HOUR NOW 6-YEAR-OLD SON CONNOR WAS DIAGNOSED WITH SPG4 WHEN HE WAS ABOUT 3 YEARS OLD. FOR THE FIRST YEAR OF CONNOR'S LIFE HE HIT ALL MILESTONES HOWEVER, LOOKING BACK THERE WERE SOME SUBTLE NUANCES, FOR EXAMPLE, HE ARMY CRAWLED FOR A LITTLE LONGER BEFORE MOVING ON TO BEAR CRAWLING. HIS BEAR CRAWLING WASN'T MAYBE AS FLUID AS WE NOW SEE WITH OUR YOUNGER CHILDREN. OR HE DIDN'T SIT UP MAYBE AS STRAIGHT BUT VERY VERY SUBTLE NUANCES AND REALLY NO RED FLAGS. IT WASN'T UNTIL ABOUT 14 OR SO MONTHS AROUND THE TIME HE WAS SUPPOSED TO BE WALKING THAT WE DID START TO DO PT AND HAD INITIAL CONCERNS WHEN WE WENT TO OUR PEDIATRICIAN IT WAS KIND OF BRUSHED OFF AS HE'S JUST A DELAYED WALKER. HE'LL CATCH UP. NO BIG RED FLAGS. THEN WHEN CONNOR WAS ABOUT 16, 17 MONTHS HE WAS TAKING INDEPENDENT STEPS BUT STILL HAD AN AWKWARD GAIT AND WAS GIVEN A DIAGNOSIS OF CP, SPASTIC DYSPLASIA AND A DIAGNOSIS SIMILAR TO WHAT I'M HEARING FROM KATIE'S STORY. THIS NEVER REALLY FELT RIGHT TO US. VERY NORMAL PREGNANCY AND LABOR. WE DID CONTINUE TO PUSH FOR ADDITIONAL TESTING AND WE DID GET THE RESULTS WHICH CONFIRMED THE SPAST MUTATION IN THE FOUND IN MY HUSBAND OR MYSELF. WE'RE NOW GRATEFUL TO HAVE THE DIAGNOSIS TO PUT A PLAN IN PLACE TODAY TO SUPPORT CORNER IN THE BEST WAY WE CAN AND ALSO PUSH FOR ADVANCEMENTS FOR HIS FUTURE AND FOR RESEARCH. SO WE DO FEEL GRATEFUL TO HAVE FINALLY LANDED ON THE DIAGNOSIS. AND JUST A LITTLE BIT ABOUT CONNOR TODAY, HERE'S HIS CUTE LITTLE SMILE. HE WAS TAKE INDEPENDENT STEPS UNTIL ABOUT 4 YEARS OLD WHEN HE DID START TO USE A WALKER MORE CONSISTENTLY. HE TRULY IS THE HAPPIEST MOST CONFIDENT LITTLE BOY WITH THE BRIGHTEST SMILE. IF HE FALLS, HE GETS RIGHT BACK UP AND IT DOESN'T GET HIM DOWN. WE'RE TRULY BLESSED WITH HIS POSITIVE ATTITUDE AND OUR JOB AS PARENTS IS TO HOPEFULLY ENSURE THE POSITIVE ATTITUDE CONTINUES BECAUSE WE DO SEE IT DOES HELP. I'LL PASS IT ON TO ERIN TO TALK A LITTLE BIT ABOUT ALICE. >> HI, MY NAME IS ERIN DEAR. CAN YOU SEE ME? >> YES, THANKS. >> GREAT. I HAVE A 4-YEAR-OLD DAUGHTER DIAGNOSED WITH DE NOVO SPG4 WHEN SHE WAS 4 YEARS OLD. SHE'S ACTUALLY A TWIN AND WE WERE ABLE TO SEE HER GROSS MORT DELAYS ALONGSIDE HER TWIN BROTHER AND SHE -- WE STARTED SEEKING ANSWERS SHORTLY AFTER SHE BEGAN WALKING. WE NOTICED SHE WAS FALLING A LOT AND HAD AN AWKWARD GAIT. WE SPENT A LITTLE OVER A YEAR RULING OUT CP AND THE OTHER POSSIBLE THINGS IT COULD BE. WE HAD HEARD ABOUT HSP HALFWAY THROUGH OUR DIAGNOSIS JOURNEY AND EVERYTHING WE READ INDICATED A HEREDITARY DISEASE AND KNEW OUR FAMILY TREE PRETTY WELL AND DIDN'T THINK THAT WAS POSSIBLE FOR HER TO HAVE HSP. SO OF COURSE IT WAS A BIG SHOCK FOR US WHEN WE GOT THE DIAGNOSIS AND LEARNED ABOUT DE NOVO SPG4. LIKE ANYONE ELSE WHO RECEIVES THIS KIND OF DIAGNOSIS AND WE FELT HOPELESS AND WEREN'T SURE WHAT TO DO NEXT BUT KNEW WE COULDN'T SIT AND DO NOTHING. WE HAD TO DO SOMETHING AND STARTED REACHING OUT TO DOCTORS AND SCIENTISTS CONNECTED WITH SOME AMAZING FAMILIES WHO ALSO HAVE CHILDREN WITH SPG4. WE JUST NEEDED A WAY TO FEEL LIKE WE CAN MAKE A DIFFERENCE FOR SPG4 SPECIFICALLY EVEN IF IN THE SMALLEST OF WAYS. WE ALSO WANTED A WAY TO DIRECT OUR FAMILY AND FRIENDS WHO WANTED TO KNOW ABOUT THE DISEASE AND WANTED TO HELP IN SOME WAY AND ASKED HOW CAN WE HELP. WE WANTED A WAY THAT'S MEANINGFUL FOR THEM AND WHERE THE SPG4 FOUNDATION COMES TO PLAY. SO JUST LIKE ALL THE OTHER CHILDREN WITH SPG4 I THINK IT'S A COMMON THEME THEY ALL HAVE SUCH POSITIVE ATTITUDES AND WORK SO HARD AND TEACH US SOMETHING DAILY ABOUT PERSEVERANCE. SO I'M GOING TO LET ANDREA TALK ABOUT OUR FOUNDATION AND MISSION. >> THANK YOU. SO OUR FOUNDATION IS CURE SPG4 FOUNDATION AND MORE ABOUT HOW IT CAME ABOUT AND WHAT WE FOCUS ON. SO WE CONNECTED WITH THE DEAR FAMILY SHORTLY AFTER ALICE'S DIAGNOSIS AND NOT TOO LONG AFTER CONNOR'S DIAGNOSIS AND IT WAS HELPFUL TO CONNECT WITH A FAMILY WITH SIMILAR EXPERIENCES AND PARALLEL STORIES IN DIAGNOSIS JOURNEY AND FELT COMPELLED TO TAKE ACTION AND BOTH FELT HOPELESS AND HELPLESS LEAVING THE NEUROLOGIST APPOINTMENT WHERE ALL WE CAN DO WAS TO CONTINUE PT AND THAT WAS IT. SO WE BANDED TOGETHER AND FORMED THE CURE SPG4 FOUNDATION WHERE WE WANTED TO HAVE DIRECT IMPACT ON FUND RAISING AND INITIATING RESEARCH TO HELP FIND A CURE OR TREATMENT. AND SO WHILE WE DO FOCUS ON SPG4 HOLISTICALLY WHETHER DE NOVO OR HEREDITARY WE HAVE KIDS WITH SPG4 AND WE DO WANT TO ENSURE THIS IS AN AREA THAT IS GETTING ATTENTION AS WE HAVE FOUND THAT DE NOVO AND INFANT ONSET CASES ARE NOT AS COMMONLY TALKED ABOUT OR REALLY EVEN FOCUSSED ON. SO WE'RE SO GRATEFUL AND HAPPY THIS SYMPOSIUM IS HAPPENING TODAY. SO AS A PARENT-LED ORGANIZATION, 100% OF OUR DONATIONS ARE FOCUSSED ON RESEARCH. SO WE CAN BE FLEXIBLE AND NIMBLE AND FOCUS ON THE RESEARCH THAT WE FEEL HAS THE MOST LEGS AND IS MOST DIRECTLY CONNECTED TO FINDING A CURE OR A TREATMENT. SO OUR MISSION IS TO INCREASE AWARENESS OF SPG4 HEREDITARY SPASTIC PARAPLEGIA AND FUND RESEARCH TO HELP FIND A CURE FOR SPECIFICALLY SPG4 HEREDITARY SPASTIC PARAPLEGIA. WE'RE FOCUSSED ON TWO BROADER RESEARCH PROJECTS AND THE FIRST IS GENE THERAPY WE'RE HONORED TO HAVE DR. MIGUEL ESTEVEZ ON THE LINE WITH DR. BASS AND TEAM AT DREXEL. AND SO THIS IS GENE THERAPY WHICH THEY'LL BE ABLE TO TALK MORE ABOUT IN TERMS OF THE CURRENT STATUS BUT WE DID FEEL ONE OF OUR PRIORITIES WAS TO ENSURE WE COMMUNICATED UPDATES TO PATIENTS AFFECTED WITH SPG4 AND ALSO OUR DONATORS TO GIVE THEM A BETTER UNDERSTANDING OF EXACTLY HERE IS WHERE YOUR DONATIONS AND DOLLARS ARE GOING. SO WE DO TRY TO BE VERY TRANSPARENT WITH UPDATES ON THE PROJECT STATUS. THAT'S ONE THING WE FOUND EVEN DONATING TO OTHER FOUNDATIONS. WE DO APPRECIATE WHEN WE KNOW EXACTLY WHERE OUR DOLLARS ARE GOING. SO THE FIRST IS GENE THERAPY AND THE SECOND IS NU9 FOR SPG4 SPECIFICALLY PARTNERING A DOCTOR FROM NORTHWESTERN AND PIGGY BACKING ON HER SUCCESS ON NU-9 FOR ALS AND LOOK AT THE DRUG COMPOUND FOR SPG4 SPECIFICALLY AND INCLUDING THE PROJECT UPDATES AND STATUS AS OF MAR%H. I THINK IN CONCLUSION WE ARE HERE SPG4 HERE TO SUPPORT ALL PATIENTS AND FAMILIES AFFECTED WITH SPG4 AND ALSO TO SUPPORT ALL RESEARCHERS. I THINK OUR ROLE IS TO HELP CONNECT THE DOTS THE BEST WE CAN. WE'RE NOT THE EXPERTS BUT WE CAN ENSURE THINGS LIKE NATURAL HISTORY STUDIES ARE ONGOING AND IN PROGRESS BECAUSE WE KNOW THAT'S AN IMPORTANT PART TO FINDING A CURE OR HAVE THE FOUNDATION IN PLACE TO BE ABLE TO FIND A CURE OR FOR EXAMPLE WE WERE ABLE TO HELP CONNECT DR. ESTEVEZ OUT OF U-MASS WITH THE DREXEL TEAM WITH SPG4 MOUSE MODEL. WE'RE A LITTLE BIT MORE BEHIND THE SCENES IN DOING WHAT WE CAN TO HELP MOVE RESEARCH AND PROGRESS FORWARD AND THE RESEARCHERS AND EXPERTS ON THE LINE WE'RE HERE TO HELP AND SUPPORT YOU IN ANY WAY WE CAN AND ARE SO GRATEFUL FOR YOUR DEDICATION ON SPG4. >> THANK YOU SO MUCH, ANDREA AND ERIN FOR YOUR PERSPECTIVES AND THAT INFORMATION. AND NEXT WE'LL MOVE ON TO RE-DRR RE-DRR RE-DRR RE-DRRE -- DR. REBECCA SCHULE. >> I'M HONORED TO BE PART OF THIS AND I STRONGLY BELIEVE IF WE ALL BAND TOGETHER AND COLLABORATE TRANS-ATLANTICALLY WE CAN MAKE PROGRESS. I'M AN ADULT NEUROLOGIST SO I SEE MAINLY ADULT PATIENTS. I THINK WE ALL IN THIS ENVIRONMENT ROOM ARE UNITED BY THE GOAL THIS WE WANT TO IMPLEMENT ACCESSIBLE AND EFFECTIVE THERAPIES FOR SPG4. WHAT WE HAVE ALSO LEARNED AND KNOW THE WAY TO THERAPIES LEADS BY CLINICAL TRIALS. SO BEFORE I TALK ABOUT OUR SPG4 COHORT, I'D LIKE TO GIVE YOU A LITTLE BACKGROUND ABOUT THE AFRICA INFRASTRUCTURE WE SET UP FOR HOW WE COORDINATE OUR SPG4 CLINICAL RESEARCH. SO WE ESSENTIALLY NEED TO FIGURE OUT TWO LARGE AND COMPLEX PROBLEMS TO BE READY FOR A CLINICAL TRIAL. WE NEED TO FIGURE OUT CLINICAL DEVELOPMENT AND THAT MEANS WE NEED GOOD CLINICAL TRIAL OUTCOME PARAMETERS THAT CAN MEASURE THERAPY RESPONSE FOR QUESTIONS AND OTHER THINGS AND THIS IS A COMPLEX ISSUE. ON THE OTHER HAND WE NEED GOOD THERAPEUTIC TARGETS AND NEED TO DEVELOP THE THERAPIES PRE-CLINICALLY AND THIS IS ALSO A PROCESS THAT INVOLVES MANY STEPS AND VERY COMPLEX. ONLY IF THE TRUE LINES OF WORK ARE AT THE SAME TIME WE CAN PROCEED TO CLINICAL TRIAL. WHAT WE TRIED TO DO IN THE TREAT HSP NETWORK WHICH I COORDINATE AND IT'S A NETWORK OF CLINICIANS AND RESEARCHERS AND TRY TO COORDINATE OUR RESEARCH IN A GOAL-ORIENTED WAY. WE TRIED TO AVOID DUPLICATION OF EFFORTS AND BE AS EFFICIENT AS POSSIBLE ALWAYS WITH THE TRANSLATIONAL TREATMENT GOAL IN MIND. AND WE TRY TO ALLOCATE OUR RESOURCES WHERE NEED AND THE RESOURCES WE TRIED TO COLLECT ARE REALLY A CLINICAL AND RESEARCH NETWORK ON THE ONE HAND. AND TO DISCUSS IDEAS AND THEN AN INFRASTRUCTURE WHICH WE SHARE WITH A CLINICAL DATABASE AND BIO BANK AND COLLECT BIO SAMPLES FROM PATIENTS INCLUDING SPG4 AND A DEPOSITORY TO LINK DATA AND DATA SETS THAT CAN BE USED FOR MULTIPLE PROJECTS AND SHOULD BE AS ACCESSIBLE AS MANY PEOPLE AS POSSIBLE. YOU CAN SEE THERE'S A STRONG FOCUS IN EUROPE CURRENTLY AND I HOPE WE ARE GOING TO GROW ALSO ON THE OTHER SIDE OF THE ATLANTIC AND JUST IN THE PAST FEW DAYS I HAVE TALKED TO SEVERAL PEOPLE IN THE U.S. INCLUDING OTHERS THAT ARE SPEAKERS TODAY THAT HAVE AGREED TO JOIN OUR EFFORT SO THIS IS REALLY A GROWING NETWORK OF DEDICATED PEOPLE TRYING TO FIND TREATMENT OPTIONS SPASTIC PARAPLEGIA. WE'RE TRYING TO HARMONIZE OUR CLINICAL APPROACH AND HARMONIZE DATA COLLECTION. COLLECT PHENOTYPIC INFORMATION IN A STANDARDIZED WAY AND COLLABORATE ON PROJECT AND HAVE A BROADER AGGRESSIVE SHARING POLICY FOR DATA SAMPLES AND RESOURCES. AND THERE'S A WEB-BASED DATABASE SO EVERY MEMBER OF THE NETWORK CAN LOG ON AND DIRECTLY ENTER DATA FOR THEIR PATIENTS. PATIENTS ARE USING A GLOBAL UNIQUE IDENTIFIER MAKING IT IDENTIFIABLE AND WE CAN DIRECTLY ALSO USE THAT FOR CLINICAL TRIAL. AND WHAT YOU IMPLEMENTED IS EVERY USER CAN DOWNLOAD THE DATA AND IF YOU WANT IT USE OTHER PEOPLE'S DATA YOU HAVE TO ASK AND THERE'S A COMMITTEE THAT DECIDES ON THAT REQUEST. THAT WAY YOU ALWAYS SEE WHAT DATA IS THERE BECAUSE THAT REALLY SIMULATES RESEARCH BECAUSE YOU SEE OPPORTUNITIES. THIS DATABASE IS CONNECTED TO A BIO BANK THAT IS RATHER UNIQUE BECAUSE IT IS DIRECTLY CONNECTED TO THE CLINICAL DATA. FOR EACH SAMPLE YOU HAVE A TIME POINT IN WHICH CLINICAL INFORMATION AND ALSO WE HAVE A LARGE VARIETY OF SAMPLES AND SAMPLE PATIENTS LONGITUDINALLY AND HAVE PLASMA SAMPLES IN INTERVALS. WITHIN THE INFRASTRUCTURE WE HAVE ALSO RECRUITED A QUITE A SIZABLE SPG4 COHORT ALMOST 500 PATIENTS FROM 340 FAMILIES ABOUT EQUAL PROPORTIONS OF FEMALES AND MALES AND RECRUITED OVER 20 YEARS NOW. JUST TO GIVE YOU AN IDEA ABOUT THE PATIENTS I'LL BE TALKING ABOUT IS THAT YOU SEE HERE THE AGE DISTRIBUTION. THERE'S A TIME POINT WHEN THEY FIRST COME TO ONE OF THE CLINICS AND YOU CAN SEE THEY HAVE A MEDIUM AGE OF 50. I THINK THIS SHIFT TOWARDS MORE ADULT SPECTRUM IS HARDLY REFLECTING THE BIOLOGY OF THE DISEASE BECAUSE OFTEN SPG4 IS AN ADULT ONSET DISEASE BUT IT MAY ALSO PARTLY BE A RECRUITMENT BIAS BECAUSE FOR A LONG PERIOD THE RESEARCH NETWORKS IN SPG4 HAVE VERY MUCH BEEN DOMINATED BY ADULT NEUROLOGY CLINICS AND ONLY IN THE RECENT TWO OR THREE YEARS HAVE THEY REALLY ACTIVELY CONTACTED PEDIATRIC NEUROLOGISTS TO OVERCOME THIS BIAS AND COLLABORATE TOGETHER ACROSS THE SPECTRUM. IT USUALLY TAKES MORE THAN 10 YEARS FOR PATIENTS FROM THEIR FIRST SYMPTOMS BEFORE THEY REACH A SPECIALIZED OUT-PATIENT CLINIC REFLECTING THE SLOW ONSET AND ALSO THE DELAY IN RECEIVING A DIAGNOSIS FOR THE SLOW PROGRESS ADULT ONSET OF SPG4. SO IF WE LOOK AT THIS WE SEE A CURIOUS BIMODAL DISTRIBUTION A PEAK IN THE EARLY YEARS OF LIFE AND BROAD DISTRIBUTION ACROSS THE LIFE SPAN WITH THE MEDIAN OF 38 YEARS. FOR THE PURPOSE OF THE TALK I TRIED TO SEPARATE THE TWO GROUPS BECAUSE I HYPOTHESIZE THESE REALLY ALMOST REFLECT TWO DIFFERENT FLAVORS OF SPG4 IN AN INFANTILE FORM AND DEGENERATIVE ONSET WHERE THEY HAVE MOTOR SKILLS THAT ARE NORMAL AND OVER TIME SYMPTOMS APPEAR. FOR WHAT THE REASONS MAY BE FOR THE BIMODAL ONSET LET ME TELL YOU MORE ABOUT THE GENETIC MAKEUP OF OUR COHORT. IF WE LOOK AT THE MUTATION TYPES REPRESENTED IN OUR SPG4 COHORT, YOU CAN SEE THAT SHY OF 20% OF CASES ARE CAUSED BY MUTATIONS. THEN WE HAVE ABOUT 20% EACH IN GENOMIC DELETIONS AND THAT MEANS THAT ABOUT 80% OF ALL MUTATIONS WE OBSERVE IN SPG4 ALSO CALLED TRUNCATING MUTATIONS AND ONLY 20% ARE THESE MUTATIONS. IF WE LOOK AT THE DISTRIBUTION OF THOSE MUTATIONS ACROSS THE PROTEIN, HERE YOU SEE A SCHEMATIC OF THE GENE WITH ALL THE IMPORTANT BINDING DOMAINS AND THE FUNCTIONAL DATA AND ON TOP OF THE SCHEMATIC HERE, ALL THE MISSING VARIANTS. SO EACH LINE REPRESENTS A VARIANT AND IF THE LINE GETS THICKER IT MEANS THERE'S MORE THAN ONE MUTATION AND CAUSES THE LINES TO OVERLAP. YOU CAN SEE REALLY ALMOST EXCLUSIVELY THE MUTATIONS ARE LOCATED IN THIS DOMAIN AND THE TRUNCATED MUTATIONS BELOW THIS ARE REALLY SPREAD ALL OVER THE PROTEIN AND THE SAME IS TRUE ALSO FOR THE EXOME DELETIONS WITH LARGE PORTIONS OF THE GENOME ARE MISSING AND HERE REPRESENTED BY THE LONG HORIZONTAL LINES AND AS THEY ALSO SPAN THE WHOLE PROTEIN. SO WHAT ARE POTENTIAL REASONS FOR THIS BIMODAL ONSET OF SPG4? I'LL GIVE YOU TWO VISUALIZATIONS OF BASICALLY THE SAME FACT. IF YOU LOOK AT THE TRUNCATIONS DIVIDED OR GROUPED BY INFANTILE VERSUS DEGENERATIVE AND THEY'RE TWICE AS FREQUENT AS INFANTILE CASES AND THIS MAY PREDISPOSE THEM. IF YOU LOOK AT THIS THE OTHER WAY AROUND, WE HAVE THESE MUTATIONS AND YOU SEE IT'S TRUE THE MEDIAN DISEASE ONSET IS IN THESE 5 YEARS EARLY IN THESE CARRIERS THAN IN CARRIERS OF TRUNCATING MUTATIONS. BUT YOU CAN SEE IN BOTH GROUPS WE HAVE VERY EARLY ONSET CASES AND ALSO IN THIS MUTATION THERE IS THE AGE OF ONSET REALLY CAN REACH LATE ADULTS. WHAT ABOUT DISEASE SEVERITY? 50 YEARS AGO WE HAD A RATING SCALE TO MEASURE DISEASE SEVERITY HSP AND CAN REACH A MAXIMUM OF 52 POINTS AND 0 ARE NO SYMPTOMS WHATSOEVER AND 52 IS MAXIMUM DISEASE SEVERITY. HERE YOU SEE THE DISEASE DURATION AT BASELINE ON THE Y AXIS THE TOTAL SCORE AS A MEASURE OF DISEASE. YOU CAN SEE THERE IS A HIGHLY SIGNIFICANT CORRELATION BETWEEN THOSE TWO PARAMETERS BUT THE DISEASE DURATION IS 20% OF THE VARIABILITY. WHAT'S THE REASON FOR THIS WE ARE PREDICTING? WE LOOKED AT A MIXED MODEL AT FACTORS INFLUENCING THE DISEASE SEVERITY AND IN ADDITION TO THE DISEASE DELETION WE FIND THE AGE OF ON SET SIGNIFICANTLY INFLUENCES DISEASE SEVERITY BUT IN A KIND OF COUNTERINTUITIVE WAY. USUALLY WE ARE USED TO ASSOCIATING EARLY ONSET DISEASE BUT AS SPG4 AS A GROUP NOT THE DE NOVOS BUT AS A GROUP LATER ONSET SEEMS TO BE A BAD PROGNOSTIC FACTOR BEING ASSOCIATED WITH MORE SEVERE DISEASE. AND THE PRESENCE OF MUTATIONS IS ALSO ASSOCIATED WITH MORE DISEASE AS COMPARED TO FRTRUNCATED MUTATIONS. IN OUR COHORT OF LEADS WE DON'T SEE AN EFFECT OF SEX ON DISEASE. I SPLIT OUR COHORT IN THREE GROUPS OF EQUAL SIZE BY AGE OF ONSET SO YOU CAN SEE THERE'S AN EARLY ONSET GROUP, THERE'S AN INTERMEDIATE ONSET GROUP AND LATE ONSET GROUP. SEE ON THE Y AXIS GETTING AN IDEA BY FORMING THE RATIO BETWEEN THE RATING SCALE AND THE DISEASE DURATION. THIS GIVES AN INDICATION OF THE PROGRESSION RATE. IF YOU COMPARE THIS AND IF YOU LOOK AT THE TOTAL SPG4 COHORT THE PROGRESSION RATE IS ONE PER YEAR. YOU CAN SEE IN EARLY ONSET CASES INDEED PROGRESSION IS SLOWER. MEDIAN AND INTERMEDIATE CASES BELEIF LIKE THE TOTAL COHORT AND LATE ONSET CASES THE RATE IS CONSIDERABLY FASTER THAN EARLY ONSET CASES. WE CAN ALSO LOOK AT THIS USING THE CONTINUOUS VARIABLES AND SEE THE SAME EFFECT HERE YOU CAN SEE THE RED DOTS EARLY IN EARLY ONSET CASES WITH LESS STEEP PROGRESSION RATES. SO WHICH EVERY WAY YOU LOOK AT THIS WE SEE SIMILAR AFFECTS LIKE FOR EXAMPLE, SPG5. ALL RIGHT, ANOTHER WAY TO LOOK AT AGE OF ONSET IS TO LOOK AT THOSE VERY EARLY ONSET INFANTS. IS THERE ANYTHING SPECIAL ABOUT THOSE THAT START FROM THE BEGINNING IN THE DEVELOPMENT? HERE YOU SEE THE SAME DATA AS ON THE LEFT. YOU HAVE A GRAPH ON THE RIGHT. THE ONLY DIFFERENCE IS THAT I COLOR-CODED THE AGE. THE RED GOT ARE INFAN TILE ONSET CASES AND THE BLACK ARE THE DEGENERATIVE ONSET CASES. THERE'S A SMALL GROUP WITH EARLY ONSET AND SEVERE DISEASE WHEREAS MOST OF THE INFANTILE ONSET CASES HAVE A LESS THAN AVERAGE DISEASE PROGRESSION RATE. SO THEY ARE ACTUALLY LESS SEVERE THAN THE AVERAGE SPG4 CASES. SO THERE'S TWO DISTINCT GROUPS. ON A HUNCH I LABELLED THOSE CASES IN OUR SPG4 COHORT WHERE WE KNOW WE HAVE DE NOVO INHERITANCE AND ALL THE CASES THAT HAVE THE SEVERE PHENOTYPE ARE INDEED DE NOVO SPG4. WE HAVE A MEASURE I FIND USEFUL WHEN CONSULTING PATIENTS OF DAILY PRACTICE AND WE SEE THE SAME EFFECT OF AGE OF ONSET AND PROGRESSION HERE. IF YOU CONCENTRATE ON THE RED LINE YOU LOOK AT THE TIME FROM ONSET OF THE DISEASE UNTIL A PATIENT USES A WALKER OR WHEELCHAIR ON A DAILY BASIS. AND FOR THE TOTAL SPG4 COHORT IT TAKES A MEDIAN OF 23 YEARS FROM ONSET TO LOSS OF INDEPENDENT WALKING. YOU CAN SEE THE TIME IS CONSIDERABLY LATER FOR THE EARLY ONSET CASES SO MORE THAN 10 YEARS LATER AND WE SEE EXACTLY THE SAME PATTERN FOR INDEPENDENCE HERE. THERE'S THERE'S A CONSISTENT ONSET. WE'RE WORK TO LOOK AT THE DATA FROM OUR COHORT AND WE HAVE VISITS FROM MORE THAN 400 PATIENTS SPAN INING THE TIME AND LOOKING AT INDIVIDUAL DISEASE PROGRESSION RATES. NOW WE HAVE IDENTIFIED MUTATIONS AND AGE IN ONSET AS MODIFIERS MUCH THE PHENOTYPE IN SPG4 BUT STILL THE TWO FACTORS HAVE A SMALL PROPORTION OF THE ENORMOUS VARIABILITY WE SEE. HOW CAN WE EXPLAIN THIS AND FOR THIS WE LAUNCHED A PROJECT WHICH I'VE HELPED COORDINATE WITH THE UNIVERSITY OF MIAMI AND THEY'RE COLLECTING SPG4 CASES TO UNDERSTAND WHY THE DISEASE MAN TESTS IN SO MANY WAYS. WE'RE FOLLOWING THREE HOPEFULLY COMPLIMENTARY APPROACHES. THE FIRST APPROACH IS TO COLLECT THE LARGEST POSSIBLE SPG4 COHORT WITH A TARGET OF AT LEAST 1,000 CASE AND NICK EXTREME CASES FROM THE MILDEST AND MOST SEVERE AND TRY TO FUND THE FACTORS THEY HAVE IN COMMON THE SECOND APPROACH IS A FAMILY-BASED APPROACH AND THE AGE OF ONSET CAN VARY BY DECADES. WE'RE COLLECTING THESE WE CALL DISCORDANT FAMILIES AND WE HAVE A LARGE FAMILY IN SWITZERLAND WITH MORE THAN 60 AFFECTED FAMILY MEMBERS IDEAL FOR STUDYING THE ADDITIONAL GENETIC INFLUENCES THAT CAN MODIFY THAT PHENOTYPE. MANY OF THE PEOPLE HERE IN THE ROOM HAVE ACTUALLY ALREADY PLEDGED THEIR COLLABORATION FOR THE PROJECT AND I'M EXCITED BECAUSE THIS IS AN EXAMPLE OF A PROJECT WE CAN ONLY PULL OFF IF WE COLLABORATE GLOBALLY TO FIND ENOUGH PATIENTS. THIS RECRUITMENT FOR THE LARGEST COHORT IS A TRUE CHALLENGE AND THIS IS WHY WE LAUNCHED THE EDGE TRY AND I HAVE SHOWN A COMPANION REGISTRY THE SPG4 PATIENT REGISTRY LINKED TO THE HSP REGISTRY TO COMBINE THE DATA FROM BOTH DATABASES. SO WHAT IS THE PATIENT REGISTRY DO? PATIENTS CAN SIGN UP THEMSELVES AND REGISTER THEIR INTEREST FOR CLINICAL TRIALS AND CAN ENTER HEALTH-RELATED INFORMATION AND REPORT LONGITUDINAL OUTCOMES THAT ALLOW US TO DETERMINE PROGRESSION RATES. OF COURSE THIS NEEDS TO BE IMPLEMENTED IN A MULTI-LANGUAGE. WE HAVE ENGLISH, ITALIAN, DUTCH, GERMAN AND TURKISH AND WE HAVE COME A LONG WAY BUT A LONG WAY TO GO. WE'RE TESTING THE PILOT VERSION WITH THE HELP OF PATIENTS COLLECTING THEIR FEEDBACK AND I HOPE THIS WILL BE ONLINE BY AUGUST 2022. THIS BRINGS ME TO ONE LAST ASPECT I WANT TO SHARE WITH YOU AND THAT'S A QUESTION OF OUTCOME PARAMETERS. THIS IS A LARGE CHALLENGE STILL. WE NEED MUCH BETTER OUTCOMES AND NEED TO UNDERSTAND WHICH OUTCOMES HAVE MEANING FOR PATIENT. WE STARTED A PROJECT TOGETHER WITH MANY PATIENT ORGANIZATIONS AND YOU SEE THE LOGOS ON THE RIGHT TO UNDERSTAND WHAT ARE THE MEANINGFUL ASPECTS OF HEALTH THAT ARE AFFECTED BY HSP. I MEAN ASPECT OF HEALTH IN THE BROADEST SENSE BECAUSE THEY CAN COMPRISE SOCIAL INTERACTION AND LOTS OF PARTICIPATION. I MEAN THIS IN A BROAD SENSE. ONLY IF WE UNDERSTAND THE HOLISTIC DISABILITY WE CAN EXTRACT CONCEPTS WE CAN MEASURE THAT REPRESENT THE DISABILITY CAUSED BY THE DISEASE AND ONCE WE HAVE EXTRACTED THOSE CONCEPTS WE NEED TO FIND MEASURES AND THOSE ARE CALLED OUTCOME PARAMETERS. THERE WE HAVE DIFFERENT MODALITIES THAT WE CAN PULL FROM TO MEASURE OUR CONCEPT OF INTEREST. WE HAVE A NUMBER OF PROJECTS AND I LISTED A FEW TO WORK ON THE OUTCOME PARAMETERS. ONE DEDICATED PARTICULARLY THE CHILDREN BECAUSE I THINK WITH CHILDREN THE SITUATION IS VEEP MORE CHALLENGING AND I'D LIKE TO DRAW PARTICULAR ATTENTION TO THE OBSERVE THE PATIENT-REPORTED OUTCOMES AND THIS IS A LINK TO THE REGISTRY AND THE OUTCOMES THAT WILL POPULATE AND GIVE CONTENT TO THE PATIENT REGISTRY. WE HAVE A FRAMEWORK FOR THE WORK BECAUSE IT IS VERY CHALLENGING TO VALIDATE NOVEL OUTCOME PARAMETERS IN THE TIMELY FASHION AND WE'RE TRYING TO BUILD A PLATFORM MODELLED AFTER THE IDEA OF ADAPTIVE TRIALS USED IN RESEARCH TO TEST NOVEL PRECISION THERAPIES AND MUCH OF THIS THINKING AND INFRASTRUCTURE CAN BE USED FOR OUTCOME NAVIGATION. WITH THAT I'D LIKE TO ENCOURAGE ALL OF YOU THAT IF YOU SEE POTENTIAL POINTS OF COLLABORATION AND IF YOU HAVE QUESTIONS, DON'T HESITATE TO SEND ME AN E-MAIL AND WOULD LIKE TO THANK ALL THE GROUPS OF PEOPLE BECAUSE THE NAMES WOULDN'T FIT ON A SLIDE THAT HAVE SUPPORTED AND CONTINUED TO SUPPORT THIS WORK INCLUDING FUND FROM INSTITUTIONS. THANK YOU VERY MUCH. >> THANK YOU VERY MUCH. >> WE'RE GOING TO SHIFT OUR BREAK BY A FEW MINUTES AND TAKE OUR BREAK NOW AND REJOIN EVERYONE AND RESTART AT 11:25 EASTERN STANDARD TIME. >> WE'LL HAVE A PRESENTATION BY DR. TORO AND THEN HEAR FROM DARIUS EBRAHIMI-FAKHARI AND THEN HEAR FROM MICHELLE CHRISTIE AND I'LL INTRODUCE ARIANE HAS BEEN LEADING THE CHARGE FOR THE MEETING. SHE'S A PHYSICIAN SCIENTIST AT THE NIH AND INVESTIGATOR IN CLINICAL TRIALS INCLUDING THE THERAPIES FOR ULTRA RARE DISEASES AND WE'LL HAVE POLICY AND RSP AND I WELCOME THEIR INPUT. WE HAVE A NEURO OLOLOGY DISORDER AND RESEARCH INTERESTS AND TARGET ON DE GENE -- DEGENERATIVE DISEASES AND LOOKS AT CHILD ONSET FORM OF PATHWAYS. THE CURRENT WORK IS A NATURAL HISTORIES STUDIES AND DR. CHRISTIE LEADS A PRACTICE FOR NEURAL PHYSIOLOGY AND LOOKS AT GENETICS FOR CHILD MLS WITH NEURO GENETIC CONDITIONS ANDAGE LOOKING AT OTHER DISORDER AND LOOKING AT OTHER PROTOCOLS. I'LL LET ARIANE. >> I'LL PRESENT BRIEFLY SO WE'RE BACK ON TIME AND I'M PRESENTING ON BEHALF OF DR. SCHOR AND ALTER WHO ALSO EVALUATED THE PATIENTS AND TO EXPLAIN HOW THIS CAME ABOUT IN TERMS OF OUR INVOLVEMENT IN THE SPACE. SO MANY YEAR AGO MY COLLEAGUE DR. SCHOR AND ALTER SAW SPENCER WOULD IS NOW A 34-YEAR-OLD YOUNG MAN EVALUATED IN 2012 WHEN HE WAS 25 YEARS OF AGE AND HAD A HISTORY OF GROSS MOTOR MILESTONES AND CHILD ONSET RIGIDITY AND A WALKER AND LENG N -- LENGTHENING AND HAD CLEANING OF THE SPINAL CORD ON IMAGING AS WELL AS SPASTIC QUADRIPARESIS AND WE EVALUATED MATTHEW AND WE EVALUATED HIM WITH HIS BROTHER WHO ALSO HAD A NEUROLOGICAL DISEASE BUT ENDED UP HAVING SEPARATE NEUROLOGICAL DISEASES WHICH SOMETIMES HAPPENED IN THE UDP. HE BASICALLY HAD SPASTIC QUADRIPARESIS AND HAD A SIMILAR HISTORY AND DIAGNOSED WITH DE NOVO MUTATION OF SPG4. THERE WAS ANOTHER PATIENT WHEN WE LOOKED BACK IN THE PROGRAM WHO HAD A MUTATION AT THE SAME REGION BUT A DIFFERENT AMINO ACID SUBSTITUTION AND THERE WAS SOME IN VITRO ASSAYS TO TRY TO SEE WHAT THE DIFFERENTIAL IMPACT OF THE AMINO SUBSTITUTION WAS. SO WE WROTE UP THE TWO PATIENTS IN A POSTER A FEW YEARS AGO AT THE AMERICAN COLLEGE OF GENOMIC MEETING BECAUSE IT SEEMED LIKE AN UNUSUAL PHENOTYPE AND SHORTLY AFTER THE LITERATURE THEY PUBLISHED A LETTER TO THE EDITOR DETAILING HOW THE MUTATION COULD COST THIS COMPLEX SPG4 PHENOTYPE SIMILAR TO WHETHER WE HAD BEEN SEEING IN THE PATIENTS IN THE SERIES HAD SEEN A MUTATION WE HAD SEEN IN OUR PATIENTS. SO LAST YEAR A LOCAL GENETICISTS REFERRED THE TWO LITTLE GIRLS WE HEARD FROM EARLIER BLAIR AND LILLY AND AWAY WHAT'S INTERESTING IS THEY WERE NOT SEEKING OUT SPECIFIC PATIENTS WITH A CERTAIN FEENLT IT'S UNUSUAL TO HAVE THE SAME PATIENTS RECRUITED OVER YEARS WITHOUT EMPHASIS ON A SPECIFIC PHENOTYPE. IT SEEMED QUITE UNUSUAL TO US AND BASED ON THE TWO LITTLE GIRLS WE SAW WE FELT TO GET THE COMMUNITY TOGETHER TO SEE WHY THE DE NOVO CONDITIONS MAY PRESENT DIFFERENTLY AND WHAT THE NATURAL HISTORY MAY OCCUR AND I'LL PASS IT TO DARIUS WHO CAN DETAIL MORE ABOUT HIS COHORT HE FOLLOWED. >> THANK YOU, ARIANE. THANK YOU FOR THE INVITATION TO BE HERE. I'M DARIUS EBRAHIMI-FAKHARI AND A SPECIALIST AT BOSTON'S CHILDREN HOSPITAL WHERE I LEAD A RESEARCH PROGRAM FOR EARLY ONSET FORMS OF SPASTIC PARAPLEGIA. IT'S NICE TO SEE THE COMMUNITY COME TOGETHER AROUND THIS QUESTION AND I'M DELIGHTED TO SHARE SOME OF OUR WORK IN THE SPACE. THESE ARE MY DISCLOSURES. BEFORE I GO INTO FINDINGS I WANT TO GIVE CREDIT TO MY TEAM MEMBERS WHO PUT THIS TOGETHER AND WHO WORKED ON THIS THIS INCLUDES ALISA AND CATHERINE WHO MANY FAMILIES HAVE MET AND AFSHIN WHO HELPS WITH THE MOLECULAR ANALYSES I'LL PRESENT TODAY. IN THE NEXT 15 TO 20 MINUTES I HOPE TO COVER FOUR AREAS. I'LL TALK ABOUT THE CHALLENGES OF STUDYING ULTRA RARE DISEASE AND I REALIZE I'M PREACHING TO THE CHOIR TODAY. IN THE SECOND PART I'LL SPEAK ABOUT OUR APPROACH TO ESTABLISHING CLINICAL TRIAL READINESS FOR ONSET FORMS OF HEREDITARY SPASTIC PARAPLEGIA AND TALK ABOUT OUR PATIENTS WITH DE NOVO SPG4 WE'VE MED AND IN THE LAST PART I'LL TALK ABOUT FUTURE DIRECTIONS. I HOPE THIS WILL STIMULATE DISCUSSION WE'LL HAVE LATER ON. THE FIRST NOTE AND I JUST WANT TO REVIEW SOME OF THE FRAMEWORK THAT WE OPERATE IN AND I THINK DR. SCHOR HIT ON A LOT OF THE POINTS THAT WE ALL THINK ABOUT IN THE RARE DISEASE SPACE. FIRST WE HAVE TO ACKNOWLEDGE RARE DISEASE AFFECTS A SMALL NUMBER BUT WORLDWIDE IT AFFECTS A LARGE NUMBER AND MOST PRESENT DURING CHILDHOOD AND THE VAST MAJORITY DOES NOT HAVE A SPECIFIC TREATMENT. I THINK THE PROBLEM IS ILLUSTRATED IN THE GRAPH THE RARE DISEASES IN THE BLUE LINE AND THERAPIES AND YOU SEE THE POSITIVE TREND BUT THE GAP REMAINS QUITE WIDE. THAT I THINK HAS IN PART TO DO WITH THE FACT THAT WE'VE SEEN REMARKABLE SUCCESS IN GENE DISCOVERY. WE'RE NOW ABLE TO UNCOVER THE GENETIC ETIOLOGY OF MANY RARE DISEASES BUT BEYOND GENE DISCOVERY, ARE MOLECULAR UNDERSTANDING. THE UNDERSTANDING OF THE PATHWAYS AND MOLECULES REMAINS QUITE LIMITED. DISEASE MODELS AND REAGENTS STILL NEED TO BE DEVELOPED AND LOOKING AT NATURAL HISTORY DATA AND HISTORICALLY THERE'S LIMITED INTEREST IN FUNDING THE RESEARCH AND LIMITED COMMERCIAL INTEREST IN DEVELOPING THERAPIES. THOUGH THIS HAS CHANGED IN RECENT YEARS. AS A PHYSICIAN SCIENTIST I THINK TWO KEY AREAS WHERE WE CAN HELP THE RARE DISEASE COMMUNITY. I'M SUMMARIZE THEM. ONE IS CLINICAL TRIAL READINESS. I'LL EXPLAIN THAT IN A MOMENT AND SECOND MOLECULAR TREATMENTS. WHEN I THINK OF CLINICAL TRIAL READINESS I THINK OF THE NETWORK. YOU NEED TO BUILD A COMMUNITY TO DEVELOP A SUSTAINABLE AND SUCCESSFUL RARE DISEASE RESEARCH PROGRAM AND IT INCLUDES THE PATIENTS AND FAMILIES AND ADVOCATES AND RESEARCHERS AND THERE ARE KEY PIECES OF INFRASTRUCTURE THAT NEED TO BE BUILT TO REALLY TAKE DEVELOPMENT THROUGH DIFFERENT STAGES THAT INCLUDES EARLY INVESTMENT IN NATURAL HISTORY STUDIES AND INCLUDES BIOMARKER DISCOVERY AND DEFINING OUTCOME MEASURES, LOOKING AT QUALITY OF LIFE WHICH I THINK IS A VERY IMPORTANT AREA AND IN TERMS OF PRE-CLINICAL DEVELOPMENT THE DISEASE MODELS AND TOOLS AND LINING UP TOXICOLOGY STUDIES AND SOME OF THESE FACTORS NEED TO BE IN PLACE AND I THINK THIS IS TRUE FOR MANY RARE DISEASES AND A COMMON THEME. AND THIS TABLE BREAKS DOWN THE QUESTION OF THERAPY DEVELOPMENT INTO VERY SIMPLE CATEGORIES. IF YOU THINK ABOUT IT, WE ONLY HAVE REALLY 5 DIFFERENT TREATMENT MODALITIES AVAILABLE. FIRST IS SMALL MOLECULES WHICH IS STILL THE MAINSTAY OF TREATMENT FOR MANY DISEASES. WE HAVE PROTEIN REPLACEMENT STRATEGIES FOR AND ANTIBODY-BASED TREATMENTS FOR IMMUNE MEDIATED DISORDERS AND TWO EMERGING CATEGORIES OF MOLECULAR TREATMENTS THAT SUMMARIZE OLIGO NUCLEOTIDES AND MOLECULAR TREATMENTS AND THE APPROACH WE TOOK AT BOSTON CHILDREN'S HOSPITAL IS TO SAY WE'RE GOING TO TRY TO FILL SOME OF THESE GAPS FOR THIS GROUP OF DISORDERS. WE CAME UP OVER THE LAST YEARS WITH A PROGRAM IN CLINIC RESEARCH AND WE STARTED A NATURAL HISTORY STUDY SPECIFICALLY FOR CHILD ONSET SPG BECAUSE WE NOTED THERE WAS A GAP FOR THAT KIND OF RESEARCH AND THAT NOW INCLUDES A LONGITUDINAL NATURAL HISTORY STUDY LOOKING AT CLINICAL OUTCOME PARAMETERS, NEUROIMAGING AND QUALITY OF LIFE AND BIOMARKERS. AND THIS COMES FROM MY OWN CLINICAL PRACTICE, MANY ARE NOW ABLE TO RECEIVE SOME FORM OF SEQUENCING BUT DON'T ALWAYS FIND A DIAGNOSIS AND WE USE MORE ADVANCED MOLECULAR TESTING IN THESE CASES TO DETERMINE THE ETIOLOGY AND ON THE BASIC SCIENCE SIDE WE'RE CONDUCTING SMALL MOLECULE SCREENS AND WORKING WITH MANY COLLABORATORS ON THERAPIES WITH GENE REPLACEMENT APPROACHES. WE HAVE THE TWO PARTS OF OUR PROGRAM MOST OF THE BASIC SIGNI SCIENCE WORK IS DIRECTED AT OTHER FORMS OF HSP BUT IN PRINCIPLE THE SAME INFRASTRUCTURE I THINK WE AS A COMMUNITY NEED TO BUILD FOR SPG4. I WANT TO SPEND TWO MINUTES QUICKLY TALKING ABOUT THE WAY WE CONDUCT OUR NATURAL CASE STUDY AND MOVE TO OUR FINDINGS. IN OUR NATURAL HISTORY STUDY WE HAVE THE INITIAL VISIT AND WE TAKE A BROAD CLINICAL APPROACH THROUGH 169 IN A CLINICAL QUESTIONNAIRE AND THE GOAL IS TO HAVE A BROAD REPRESENTATION OF ALL POSSIBLE SYMPTOMS. WE TAKE THIS APPROACH BECAUSE WE ACKNOWLEDGED THAT IN MANY CASES OUR INDUSTRYING OF THE PHENOTYPIC SPECTRUM OF THE DISEASE HAS LIMIT. SO WE WANT TO BE AS BROAD AS POSSIBLE AT THIS EARLY STAGE. THEN AS REBECCA INTRODUCED, WE USED A NUMBER OF RATING SCALES INCLUDING THE SPASTIC PARAPLEGIA SCALES AND INCLUDE A HEALTH-RELATED QUALITY OF LIFE ASSESSMENT. WE ALSO REVIEW BRAIN MRI SCANS OBTAINED ON A CLINICAL AND COLLECT BLOOD SAMPLES AS PART OF A BIO REPOSITORY AND THEN SELECT CASES OF FIBROBLASTS. THEN WE MOVE TO OUR FOLLOW-UP AND LONGITUDINAL PHASE AS A MORE CLINICAL QUESTIONNAIRE AND WE USED THE SAME AND COLLECT BLOOD SAMPLES. THAT'S THE FRAMEWORK AND IN OUR WORK WITH THE NATURAL HISTORY STUDY WE CAME ACROSS A NUMBER OF YOUNG PATIENTS WITH SPG4 AND NOTED THAT MANY HAD DE NOVO VARIANTS AND THAT LED US SIMILAR TO THE NIH TEAM TO THIS PUBLICATION THAT FIRST PRESCRIBED THAT CHILDREN WITH DE NOVO MUTATIONS OR INDIVIDUALS WITH DE NOVO MUTATIONS TEND TO HAVE FEATURES NOT AS COMMONLY SEEN IN THE CLASSIC FAMILIAL FORMS AND BROUGHT US TOGETHER. I'LL BE PRESENTING IN OUR EXPERIENCE FROM 17 INDIVIDUALS WITH DE NOVO SPG4 VARIANTS. SO THIS IS JUST A BASIC OVERVIEW OF THE DEMOGRAPHIC INFORMATION HERE AND I SHOULD SAY THIS IS CROSS-SECTIONAL ANALYSIS. THERE ARE LIMITATIONS TO CONCLUSIONS ONE CAN DRAW FROM THE DATA. THESE 17 PARTICIPANTS CAME MOSTLY FROM THE U.S. ABOUT TWO-THIRDS AND A THIRD FROM OUTSIDE THE UNITED STATES. YOU SEE WE HAD ROUGHLY EQUAL REPRESENTATION OF MALE AND FEMALE AND I WANT TO DRAW YOUR ATTENTION TO THE AGE AT LAST FOLLOW UP REPRESENTING THE AGE SPECTRUM AND THE COHORT. THE AGE OF SYMPTOM ONSET. WHAT WAS THE FIRST REPORTED SYSTEM? PARENT REPORTED. THEN LASTLY, THE AGE AT A MOLECULAR DIAGNOSIS. I THINK A LOT OF INFORMATION CAN BE GAINED FROM THE THREE NUMBERS. SO FIRST THE AGE OF FOLLOW UP AND VICTORY AGE OF 9 YEARS. YOU SEE THE DISTRIBUTION OF AGES HERE RANGING FROM TWO YEARS OF AGE TO 19 YEARS OF AGE AT THE TIME OF ENROLLMENT. THE AGE AT SYMPTOM OUTSET IS MUCH EARLIER. ALL PATIENTS PRESENT IN THE FIRST TWO YEARS OF LIFE USUALLY WITH MOTOR DELAY AND IN CONTRAST YOU SEE THE AGE AT THE MOLECULAR DIAGNOSIS WHICH IN THIS COHORT GRANTED MOSTLY PATIENTS WITH ACCESS TO HEALTH CARE AND TERTIARY CARE THE MEAN AGE WAS STILL 6 YEARS SO THERE'S A SIGNIFICANT DIAGNOSTIC DELAY STILL AND THAT'S SOMETHING WE NEED TO WORK ON. WHEN WE LOOKED AT THE MOLECULAR SPECTRUM THE VAST MAJORITY OF DE NOVO ARE CAUSED BY MUTATIONS AND IT'S IMPORTANT TO DISCUSS TODAY AND TOMORROW BECAUSE IT DOES RAISE THE QUESTION WHETHER CLASSIC FAMILIAL FORMS AND THE NOBLE VARIANTS SHARE THE SAME ETIOLOGY AND YOU SEE BASED ON THE COMPUTER MODELLING MISSING VARIANTS ARE TOLERATED VERSUS NOT TOLERATED IN THE COMPUTER MODELS AGREE WITH OUR FINDINGS IN THAT MOST OF THE MISSING VARIANTS AND THE TRIPLE A DOMAIN IS PREDICTED TO BE DISEASE. IN ITS COHORT WE ONLY HAVE ONE TRUNCATED VARIANTS. ALL OTHERS ARE MISSING VARIANTS AND IN A PARTICULAR VARIANT WAS RELATIVELY COMMON OCCURRING IN FIVE INDIVIDUALS IN THIS COHORT. SO WHAT DID LEARN ABOUT THE CLINICAL SPECTRUM AND AGAIN THIS IS A CROSS-SECTIONAL ANALYSIS SO THERE'S A LOT OF LIMITATIONS HERE. THE FIRST SYMPTOM IS USUALLY MOTOR DELAY. YOU SEE ON THE LEFT YOU SEE THE MILESTONES AND THE PERCENTAGE OF INDIVIDUALS THAT ACHIEVE THESE MILESTONES AND SEE THE AVERAGE AGE AT WHICH THEY'RE ACHIEVED. YOU SEE, FOR EXAMPLE, A MAJORITY OF PATIENTS ACHIEVE ASSISTED WALK AND AT A SIGNIFICANTLY DELAYED AGE. SO MOTOR DELAY REALLY IS THE FIRST SYMPTOM IN THE SYNDROME. AND I THINK IT'S ONE THAT NEUROLOGISTS NEED TO PICK UP EARLY AND REFER TO GENETIC TESTING FOR. THE SECOND LESSON WE LEARNED ABOUT MORE DEVELOPMENT CAME FROM A CROSS-SECTIONAL ANALYSIS OF THE LEVEL OF AMBULATION AT ENROLLMENT AND WHAT WE LEARNED IS THAT THE MAJORITY OF PATIENTS REQUIRE WHEELCHAIR FOR LONGER DISTANCES AND YOU SEE THE AVERAGE AGE AT WHICH WALKING OR WHEELCHAIR WERE MORE COMMONLY USED AND THAT'S QUITE EARLY. THERE SEEMS TO BE A LOT OF PROGRESSION EARLY ON AND THAT'S ALSO REFLECTED IN THIS RETROSPECTIVE ANALYSIS OF MOTOR DISABILITY. THIS IS A 7 POINT SCALE THAT BASICALLY QUANTIFIES THE DEGREE AND CHANGES WITH AGE QUICKLY AT STAGE 6 IT'S WHEELCHAIR DEPENDENT. THAT'S OFTEN PRESENTED EARLY. THE DEFINING FEATURE OF THIS DISEASE IS SPASTICITY AND WE FOUND UPPER LIMB SPASTICITY WAS PRESENT IN A QUARTER OF THE PATIENTS AND THE AVERAGE AGE AND THIS IS CROSS SECTIONAL WAS HIGHER THAN THE AVERAGE AGE OF PATIENTS WHO ONLY HAD LOWER LIMB SPACTICITY AND WE SEE THE TYPICAL SIGNS TO LOOK FOR AND WE SAW HYPERREFLEXIA AND IN A MAJORITY OF PATIENTS, CONTRACTURES AND THIS MAY BE BECAUSE WE'RE ATTUNE TO LOOKING AND WE FOUND EVIDENCE OF MOVEMENT DISORDERS INCLUDING DYSTONIA IN 40% OF PATIENTS. LOOK BEING AT OTHER DOMAINS OF DEVELOPMENT WE FOUND SPEECH DELAY WAS ALMOST UNIVERSAL. ABOUT A QUARTER OF PATIENTS WERE MOSTLY NON-VERBAL AND PATIENTS WITH VERBAL COMMUNICATION WE FOUND DYS-PAIGE DISPAGIA WAS COMMON AND THIS WAS CLINICIAN RATED AND AT A DISTRIBUTION OF A THIRD, A THIRD AND A THIRD. MEANING A THIRD OF PATIENTS HAD NO COGNITIVE DEFICITS AND A THIRD OF PATIENTS WERE JUDGED TO HAVE MILD COGNITIVE DEFICITS AND A THIRD JUDGED FOR AWHILE DEFICITS. THEY ASKED DO THEY THINK THE DEFICITS HAVE PROGRESSED OVER THE YEARS AND A THIRD OF FAMILIES SAID THEY FELT THE DEFICITS WERE INDEED PROGRESSIVE. NOW, IN TERMS OF OTHER SYMPTOMS THAT WE LOOKED FOR WE FOUND THE NEURO GENETIC BLADDER DISORDER WAS COMMON AND INCONTINENCE AND AT SOME STAGE OF THE DISEASE IT WAS PRESENT AND PATIENTS WHERE THIS WAS PRESENT A THIRD HAS EVIDENCE OF ABNORMAL SWELLING AND IN CONTRAST TO THE CLASSIC FAMILIAL FORM AND TO ME SPEAKS TO ME AS SOMETHING THAT POINTS A DIFFERENCE IN ETIOLOGY ABOUT A THIRD OF PATIENTS WITH DE NOVO SPG4 HAD SEIZURES WHICH IS QUITE UNCOMMON IN THE FAMILIAL FORM AND A QUARTER QUALIFIED FOR A DIAGNOSIS OF EPILEPSY BASED ON TWO UNPROVOKED SEIZURES OR TREAT TREATED WITH ANTIEPILEPTIC DRUGS AND TREATMENT INCLUDED THE USUAL SYMPTOMATIC TREATMENT APPROACHES TO SPACTICITY INCLUDING MEDICATIONS AND IN SOME CASES BOTOX INJECTIONS WITH A BACLOFEN PUMP AND RATED ON THE SPASTIC PARAPLEGIA RATING SCALE WE FOUND A MODERATE LEVEL OF DYSFUNCTION BY AN AVERAGE SCORE OF 30. I'M PLOTTING OUT HERE THE SPR ITEMS TO SHOW 11, 12 AND 13 HAD LOWER SCORES, CONTRACTURES AND PAIN AND BLADDER DYSFUNCTION. A LITTLE BIT OF A DIFFERENCE IN THE DE NOVO AND FAMILIAR CASES POTENTIALLY. I ALSO WANT TO POINT OUT AND THIS IS SOMETHING THE SPASTIC PARAPLEGIA RATING SCALE IS A GREAT OUTCOME SCALE AND HAS NOD BEEN VALIDATED IN CHILDREN UNDER AND THAT'S AN IMPORTANT LIMITATION HERE. AND IN THE LAST MINUTE I WANT TO TALK ABOUT FUTURE DIRECTIONS FOR OUR TEAM. FOR THE CURRENT CROSS-SECTIONAL ANALYSIS WE'RE HOPING TO PULL INFORMATION FROM SEVERAL COHORTS. WE HAD DISCUSSIONS WITH OUR COLLABORATE E COLLABORATORS THE QUESTION IS CAN WE DERIVE MORE GENERAL TRENDS FROM THE CROSS-SECTIONAL ANALYSIS AND HOPING TO ANSWER THAT QUESTION. WE'RE ALSO REACHING OUT TO COLLECT BLOOD SAMPLES FOR BIOMARKER DISCOVERY AND I THINK IT WILL BE IMPORTANT FOR US IN THE ROOM TRYING TO ANSWER HOW MUCH OF THE EARLY PRESENTATION IS INDEED PART OF THE PHENOTYPES AND WANTING TO LOOK AT MARKERS IN BLOOD SAMPLES AND THAT'S AN ONGOING EFFORT AND WE'RE HOPING TO USE A QUESTIONNAIRE WE USED IN OTHER FORMS OF ONSET TO GET A SENSE OF WHAT AREAS ARE IMPORTANT TO FAMILIES ON A DAY TO DAY BASIS AND TO PROVIDE THIS AS A QUANTITATIVE OUTCOME MACHINE. -- MEASURE AND WE'RE HOPING TO EXTEND TO A LONGITUDINAL PHASE AND CONTINUE ENROLLMENT AND AGAIN THE GOAL IS TO PROMOTE AND SUPPORT CLINICAL TRIAL READINESS TO DESCRIBE THE SYMPTOMS AND WE CAN RATE THEIR IMPORTANCE AND MAKE THE CASE THAT WE NEED TO DEVELOP THERAPIES FOR THIS CONDITION QUICKLY. WITH THIS I'LL COME TO MY SUMMARY AND I HOPE I WAS ABLE TO SHOW YOU DE NOVO SPG4 IS A COMPLEX DISEASE IN CHILDREN AND IT HAS A BROAD RANGE WHEN IT COMES TO SYSTEMS DIFFERENT FROM SPG4 AND I HOPE I WAS ABLE TO SHOW AN INTERNATIONAL EFFORT A REGISTRY OF NATIONAL HISTORY STUDY CAN HELP THE END POINTS OF FUTURE TRIALS AND A WANT TO THANK MY TEAM AND THE MANY COLLABORATORS WHO CONTRIBUTED TO THIS AND FUNDING SOURCES AND OUR CONTACT DETAILS. SO THANKS FOR YOUR ATTENTION. >> THANKS MUCH, DARIUS. UP NEXT IS MICHELLE CHRISTIE. >> THANK YOU, I'M HONORED TO BE PART OF THIS. I KNOW I'M PROBABLY A NEW FACE FOR MANY. LET ME GO AHEAD AND SHARE MY SCREEN. SO DARIUS HAD REACHED OUT TO ME AND I'M SO GRATEFUL THAT HE DID. DOWN IN TEXAS WE ACTUALLY FOLLOW A LARGE NUMBER OF PATIENTS WITH HEREDITARY SPASTIC PARESIS AND I HAVE NO FINANCIAL DISCLOSURES. I HAVE A SECONDARY BOARD CERTIFIED IN CHILD NEUROLOGY AND CLINICAL NEUROPHYSIOLOGY AND MY DAUGHTER'S ILL TODAY SO SHE'S IN MY LAP. I HAVE AN ASSISTANT PROFESSORSHIP WITH UT SOUTHWESTERN IN A SMALL ROLE BUT IN THE GENE THERAPY PROGRAM. WE ARE TALKING TO TRY TO CREATE A GENE THERAPY. AND THIS WAS PRESENTED AND THAT'S BEEN MY ROLE TO DO THE NERVE STUDIES FOR THE DATA. I WORK FOR AN ORTHOPEDIC HOSPITAL. WE'RE IN DALLAS, TEXAS. WE HAVE A LAB AND JUST SO YOU KNOW ABOUT PEDIATRIC HSP WHERE I WORK AND IT'S ONE OF THE LARGEST CLINICS WE FOLLOWED PATIENTS FOR GREATER THAN 25 YEARS. AND WE HAVE 13 PATIENTS WHO HAVE AN INFANTILE ONSET WITH 8 HAVING THE DE NOVO MUTATIONS AND WE DON'T SEE IN THE COHORT A LARGE DIFFERENCE BETWEEN DE NOVO MUTATIONS AND INHERITED IN A PURE FORM ORCALLY -- OR COMPLICATED FORM. WE HAVE ONE PATIENT WHO HAD AN AND MUTATIONS HAVE BEEN BROUGHT UP BY OTHER SPEAKERS. I KNEW DARIUS WAS GOING TO DO SUCH A GREAT JOB TALKING ABOUT THE COHORT IN GENERAL AND THE INFORMATION SHARES A LOT OF THE SAME THING WE SEE IN OUR PATIENTS SO I WANT TO FOCUS ON THE LONG-TERM DATA WE HAD. SO I WANTED TO LOOK AT THE HEREDITARY AND THE DE NOVO. WE HAVE THREE PATIENTS PRESENTED WITH HEREDITARY ONSET SPG4. SOME INTERESTING PARTS AND THE END VERY SMALL BUT THERE WAS MATERNAL INHERITANCE WITH ALL OF THEM. SYMPTOMS WERE FIRST NOTED ABOUT THE SAME TIME AS THE DE NOVO. BETWEEN 4 AND 16 AND 18 MONTHS. SO SCORES WERE 2 TO 3 FOR ALL OF THEM AND ALL REQUIRED HAMSTRING LENGTHENING AND ACHILLES STRETCHING AND WITH GROWTH YOU NOTE INCREASED CROUCHING OVER THE YEARS. WE DIDN'T SEE MAJOR DIFFERENCES WITHIN THEIR AMBULATION. I WANTED TO SHOW THIS BECAUSE IT'S MORE THAN ANYTHING AND THIS IS A PATIENT WITH AN INHERITED FORM AND YOU SEE A SPASTIC GAIT AS WE START WALKING. AGAIN ALL THESE PATIENTS WILL BE GREATER THAN 10-YEAR FOLLOW-UP ON THE VIDEOS. TO ME IT APPEARS LOWER BUT ARE STILL WALKING WITHOUT ASSISTING DEVICES AND THIS PATIENT HAS OUR LONGEST FOLLOW-UP OF ACTUALLY ALMOST 30 YEARS. HERE'S ONE THAT NEEDED A WALKER. AND THEN HIS GREATER THAN 10-YEAR FOLLOW-UP AND HE GOES BETWEEN HIS WHEELCHAIR AND CRUTCHES BUT DOES STILL MOVE WITH HIS CRUTCH USE. HE ENJOYS PLAYING BASKETBALL AND IS A REAL PLEASURE. ONE OTHER HEREDITARY LONG-TERM FOLLOW-UP. YOU CAN SEE VERY MILD GAIT DISTURBANCE WHEN THEY INITIALLY PRESENTED TO US. AND AGAIN THESE ARE ALL SPG4s. FOR MORE THAN A 10-YEAR PERIOD MAINTAINED A SPASTIC BUT DIDN'T NEED DEVICES OVER A LONG-TERM PERIOD. SO THIS IS OUR DE NOVO COHORT AND WE HAVE LONG-TERM FOLLOW-UP OF PATIENTS 10 TO 19 YEARS WORTH OF FOLLOW-UP ON PATIENTS WITH DE NOVO SPG4 MUTATIONS. AND WHAT WE SEE SO WE SEE A MIX OF BOTH CURE AND COMPLICATED PHENOTYPES. THEY ALL HAVE MUTATIONS IN DIFFERENT AREAS. THE PURE FORM WAS AN EYE PREDICTIONS DELETION WHERE OTHERS WERE UP IN OTHER DISCUSSIONS AS WELL. AND I THINK THE POINT I WOULD LOVE TO BE CHALLENGED ON IT AND SEE VIDEOS TOO BUT IF WE ACTUALLY DIDN'T SEE A LARGE IN A GOOD WAY, A LARGE PROGRESSION IN THE PATIENTS SO SOME OF THEM WOULD CHOOSE AS THEY GROW TO SPEND MORE TIME IN THEIR WHEELCHAIR TO INCREASE THEIR INDEPENDENCE AND THEIR SPEED. HOWEVER, WE DID NOT SEE A GREAT CHANGE WITHIN THEIR AMBULATION WHEN YOU WATCH THEIR VIDEOS FOR A SPLIT SECOND. SO HERE'S ONE OF OUR FIRST PATIENTS. I DO THINK IT WOULD BE NECESSARY TO GET TIME TO WALK TEST ON OUR PATIENTS TO SEE ARE THEY SLOWER, WHAT'S HAPPENING BUT THEY OVERALL REQUIRE THE SAME ASSISTIVE DEVICES THAT THEY HAVE BEEN SINCE EARLY CHILDHOOD. HERE'S AND THIS IS A PATIENT WITH DE NOVO AGAIN. LONG-TERM FOLLOW-UP. A PATIENT 3 DE NOVO OVERALL. YOU CAN SEE SHE'S STILL WALKING, STILL AMBULATING WITHOUT THE USE OF ASSISTIVE DEVICES. I THINK WE CAN ALL APPRECIATE THERE IS A SLIGHT CHANGE IN HER GAIT BUT THERE'S NO EXTRA DEVICES BEING USED. AND IN OUR LAST PATIENT IS SIMILAR. SIMILAR ON OVER 10 YEARS OF FOLLOW-UP. WE'RE NOT REQUIRING ADDITIONAL ASSISTIVE DEVICES ON OUR SHORT AMBULATION STUDIES. SO AGAIN THIS IS A SMALL VALUE AND IT'S IMPORTANT TO HAVE CONFERENCES LIKE THIS AND PULL ALL OF OUR PATIENTS TOGETHER. ONE THING I NOTICED IS AND IT WAS WRITTEN ABOUT BEFORE AND PUBLISHED IN ONE CASE WITHIN FAMILIES THERE JUST SEEMED TO BE AN ELEMENT OF ANTICIPATION WITH SPG4s WHERE PARENTS WOULD PRESENT MUCH LATER ON AND AS GENERATIONS GO BY THEIR CHILDREN PRESENT VERY EARLY. THIS WOULD BE VERY NEW. WE USUALLY LOOK AT THE DISORDERS AND SO I WOULD BE FASCINATED BY PEOPLE WHO UNDERSTAND GENETICS FULLY WHY ARE THESE MUTATIONS SHOWING AN ELEMENT OF ANTICIPATION AND CAN THAT THEN HELP US UNDERSTAND WHY SOME OF OUR DE NOVO PATIENTS ARE PRESENTING SO EARLY. IS THERE SOMETHING ELSE GOING ON WITH TRANSCRIPTION OR TRANSLATION OR WITH THE PROTEIN ITSELF THAT IS AFFECTING THEM SO EARLY. I HAVE A SECOND QUESTION WHICH I KNOW WILL GENERATE A LOT OF DISCUSSION AND HOME IT DOES LATER ON BUT IS OUR INFANTILE FORM OF HSP PROGRESSIVE AT A FUNCTIONAL LEVEL FOR LONG DISTANCES? YES, WE DO SEE A SLIGHT CHANGE BUT IS THIS DIFFERENT THAN WHAT WE WOULD DUE TO GROWTH IN PATIENTS WITH SOMETHING LIKE CEREBRAL PALSY WHERE WE KNOW THE NEUROLOGIC INJURY IS STAFFIC AND FROM OUR CHILDREN'S POINT OF VIEW IT WON'T MATTER WHY BUT AS WE HAVE WHICH THERAPIES TO USE FOR WONDERFUL PATIENTS AND BECAUSE GENE THERAPIES ARE AMAZING AND I WANT TO ADVANCE THEM VERY MUCH I'M PROUD TO BE PART OF THE GENE THERAPY PROGRAM. CURRENTLY THOUGH ALL THE AAB9s WE'RE STUDYING ARE FOR FATAL DISEASE AND I JUST WANT TO BE EXTRA CAREFUL AS A MOTHER MYSELF THAT WE'RE SAFE WITH OUR PATIENTS WITH HSP BECAUSE THEY'RE BEAUTIFUL PATIENTS. THEY'RE WONDERFUL AND WE WANT TO MAKE SURE WE BALANCE THE SIDE EFFECT PROFILES WE'RE GIVING THEM TO MAKE SURE WE'RE PROLONGING AND IMPROVING THEIR LIVES. THAT'S MY MAIN POINT. I HOPE ALL THOSE POINTS GENERATE A LOT OF DISCUSSION LATER ON WHEN WE CAN OPENLY TALK AND THANK YOU SO MUCH FOR ALLOWING US TO BE PART OF THIS DISCUSSION. >> THANK YOU FOR THE BEAUTIFUL PRESENTATION AND THANKS FOR PARTICIPATING UNDER THE CIRCUMSTANCES. SO WE'RE GOING TO HAVE A LUNCH BREAK. AND IF WE CAN TRY TO BE BACK FOR 12:35 THAT WOULD BE WONDERFUL. THE VIDEOCAST CAN'T BE PAUSED. BE MINDFUL IF YOU TURN YOUR CAMERA ON IT WILL BROADCAST BUT I'LL MUTE THE VIDEOCAST IN A FEW MINUTES IN CASE ANYBODY WANTS TO CHITCHAT OVER LUNCH AND OTHERWISE WE'LL BE BACK AT 12:35 >> SO I'M GOING TO INTRODUCING OUR MODERATOR FOR THE SECOND SESSION. THE SECOND SESSION WILL BE ON THE TOPIC OF GENETICS. THE MODERATOR IS CAMILO TORO A NEUROLOGIST SPECIALIZED IN MOVEMENT DISORDER AND HAS BEEN THE CLINIC DIRECTOR UP HIS DEPARTMENT AND ACQUIRED INFORMATION ON BIOINFORMETIC TOOLS AND HAS SEEN MORE CLASSIC HSPs. I'LL PASS IT LONG TO INTRODUCE OUR SPEAKERS FOR THE AFTERNOON. >> THANK YOU VERY MUCH FOR THE INTRODUCTION. NOT ONLY THE INTRODUCTION BUT FOR PUTTING TOGETHER THE SYMPOSIUM. I THINK WE OWE THE INCREDIBLE EFFORT TO YOU I'M TO INTRODUCE OUR TWO SPEAKERS FOR THE AFTERNOON AND THEY'RE PERFECT ON THE TOPIC TO ADDRESS THE DAY AND WHAT IS THE DIFFERENCE BETWEEN DE NOVO AND INHERITED SPG4 AND IS THERE GAI EXPLANATION OR WAYS AND WE CAN UNDERSTAND THE DIFFERENCE AND UNDERSTANDING THE DISEASE AND BETTER THE DE NOVO VERSION OF THE DISEASE AND WITH THAT KNOWLEDGE TO BE TRANSLATED TO MODERATE THE DISEASE. THE TWO SPEAKERS WE'RE FORTUNATE TO HAVE DR. JENNIFER POSEY ASSISTANT PROFESSOR IN THE DEPARTMENT OF MOLECULAR AND HUMAN GENETICS AT BAYLOR AND HAS INCREDIBLE EXPERIENCE IN THE USE OF MOLECULAR GENETICS AS IT RELATES TO CORRELATING WITH PATIENT'S CLINICAL PRESENTATIONS AND WHERE THERE CAN BE VARIATIONS IN THE SAME TEAM. THE NEXT SPEAKER WILL BE HEATHER McLAUGHLIN AND IS ALSO A BOARD CERTIFIED CLINICAL MOLECULAR GENETICIST. HAS A REALLY INTERESTING VANTAGE POINT THAT IS INFORMATIVE TO ALL OF US AND THE FACT SHE WORKS NOW A PLACE THAT DOES A LARGE AMOUNT OF MOLECULAR SEQUENCING AND SHE'LL BE ABLE TO TELL US IN HER EXPERIENCE WITH THIS LARGE DATA SETS THE INCIDENT OF SPG4 MUTATIONS DIAGNOSES IN THE SAMPLES IN AN ACTIVE MOLECULAR SEQUENCING GROUP. WITHOUT FURTHER ADO I WILL GO FORTH AND WE HAVE OPEN SESSION FOR DISCUSSION IN WHICH WE ARE GEE TO ADDRESS QUESTIONS REGARDING BOTH THE MORNING AND THE AFTERNOON SESSION AND I THINK THIS IS GOING TO GENERATE A FAIR AMOUNT OF INTERESTING CONVERSATIONS. THANK YOU. >> THANK YOU VERY MUCH DR. TORO AND FOR THE OPPORTUNITY TO SPEAK TO THE GROUP TODAY. I FOUND AS I WAS PREPARING MY SLIDES THERE WAS MORE I WANTED TO TALK ABOUT AND SAY THAN PERHAPS THERE WOULD BE TIME DURING THE INITIAL MEETING. I TRIED TO PUT TOGETHER A PRESENTATION THAT HOPEFULLY PROVIDES A LITTLE BIT OF AN OVERVIEW OR FRAMEWORK FOR MAYBE HOW TO THINK ABOUT SOME OF THE QUESTIONS WE HAVE ABOUT THE ROLE OF DE NOVO MUTATIONS AND SPG4 AND MORE COMPLEX DISEASE. SO I WANTED TO BACK UP AND KIND OF QUICKLY REMIND THE GROUP AND MANY ON THE CALL WILL ALREADY BE FAMILIAR WITH THIS BUT FROM A RARE DISEASE GENOMIC STANDPOINT WHICH IS WHERE I'M COMING FROM AS A PHYSICIAN SCIENTIST AND RARE DISEASE RESEARCHER WE LIKE TO STEP BACK AND LOOK AT THEM IN TERMS OF THE MECHANISMS IN WHICH THEY FORM AND THEIR CHARACTERISTICS AND LEARN FROM THERE FOR THE MEANS OF THE EXPECTED DISEASE AND THE EXPECTED PHENOTYPIC EXPRESSION. SO I WANTED TO JUST FRAME SOME OF THE TALK IN TERMS OF WE OFTEN THINK ABOUT DE NOVO MUTATIONS AS BEING INFLUENCED BY SOME OF THE STATIC PROPERTIES OF OUR GENE POEM I THINK A GREAT EXAMPLE IS CPG NUCLEOTIDES WHICH HAVE A HIGHER LIKELIHOOD OF BEING MUTATED AND I THINK THE R499 A AMINO ACID RESIDUE OCCURS IN THE CPG NUCLEOTIDES NOT SURPRISING WE SEE THAT AS A RECURRENT NEW MUTATION PRESENTED IN RELATED FAMILIES. WE KNOW DURING DNA REPLICATION YOU CAN HAVE ERRONEOUS NUCLEOTIDES AND CERTAIN GENOMES CAN BE EXPOSED AND WE HAVE EXAMPLES AND WE KNOW THE SPAST GENE ITSELF SITS VERY PROXIMAL TO SEVERAL REPEATS THAT CAN MEDIATE NON-ALLELIC EVENTS AND THERE'S CELL SPECIFIC PROPERTY MAY INCREASE THE LIKELY HHS THE MUTATION OR HOW IT'S EXPRESSED AND CHROMATIN STATE AND GENE EXPRESSION AND THINGS LIKE THIS. I PROBABLY DON'T HAVE TO REMIND THIS GROUP BUT WHEN WE'RE THINKING ABOUT INHERITED VERSUS DE NOVO FROM A BIG PICTURE PERSPECTIVE OF COURSE EACH OF US HAVE FAR FEWER DE NOVO MUTATIONS THAN WE HAVE INHERITED VARIANTS. WE OFTEN CONCEPTUALIZE FROM A POPULATION STANDPOINT MOST INHERITED VARIANTS WILL HAVE A SMALL IF ANY EFFECT SIZE ON OUR HEALTH ON OUR CLINICAL PHENOTYPE WHEREAS WE EXPECT THAT DE NOVO MUTATIONS IN GENERAL ARE MORE LIKELY TO IMPACT HEALTH IN ALL OF US AND WITH THAT, ONE OF THE THINGS THAT WE BEGAN TO CONSIDER IN THE CLINICAL REALM WORKING WITH ONE OF THE DIAGNOSTIC LABORATORIES AT BAYLOR GENETICS, WE WANTED TO GET A LITTLE BIT OF A SENSE FOR HOW FREQUENT ARE MUTATIONS AND RARE DISEASE AND THIS HAS BEEN IN STUDIES OVER A DECADE NOW AND WE STEPPED BACK AND ASK FOR INDIVIDUALS REFERRED BY THEIR PHYSICIANS FOR RARE DISEASE OF ANY KIND, MANY OF THESE INDIVIDUALS WILL HAVE NEUROLOGIC CONDITIONS. SOME WILL NOT. BUT FOR THOSE INDIVIDUALS REFERRED FOR DIAGNOSTIC XM SEQUENCING WHICH I ARGUE IS IN SOME WAYS AN UNBIASSED ANALYSIS OF THE GENOME TO SOME EXTENT. WE'RE LOOKING AT THE MAJORITY OF THE DISEASE GENES, THE CODING REGIONS. HOW FREEBLQUENTLY DO YOU IDENTIFY NEW MUTATIONS AND THIS IS IMPORTANT FOR THOSE WHO COME AWAY WITH THE DIAGNOSIS MEANING AN AUTOSOMAL VARIANT ON ONE OR TWO COPIES OR AFFECTING THE GENE ON THE FEMALE ALLELE AFFECTED AND LOOK AT TO THE TOTAL OF DIAGNOSES FROM FULL SEQUENCING COHORTS AND WE CALCULATOR COUNT THE NUMBER DE NOVO WHERE WE WERE ABLE TO DEMONSTRATE AND IT WAS NOT INHERITED FROM EITHER PARENT AND IN PRIMARILY PEDIATRIC COHORTS, ALMOST-QUARTERS OF THOSE INDIVIDUALS HAVE DE NOVO MUTATIONS. IN ADULT COHORTS SO INDIVIDUALS WHO ARE OVER 18 YEARS OF AGE, THAT GETS CLOSER TO A LITTLE MORE THAN HALF OF INDIVIDUALS WILL HAVE A DE NOVO MUTATION. OF THOSE, IF YOU LOOK AT THE AGE BREAKDOWN THE INDIVIDUALS IN THIS PARTICULAR COHORT THAT HAD A DE NOVO MUTATION POSITIVE OF THEIR CONDITION, THEY WERE ALL BETWEEN 18 YEARS AND 30 YEARS. THESE WERE ADULTS NO HOLDER THAN 30 YEARS OF AGE AND THERE'S PROBABLY A COUPLE REASONS FOR THAT. ONE VERY PRACTICAL REASON IS THAT ADULTS COME TO MY GENETICS CLINIC THE OLDER THEY ARE THE LESS LIKE LIE WE'RE ABLE TO GET SAMPLES FROM THEIR PARENTS AND THERE'S VERY MUCH IN THE FIELD IN ADULT GENETICS THE IDEA THAT A LOT OF ADULT ONSET GENETIC DISEASE IS LESS LIKELY TO BE DE NOVO BECAUSE DE NOVO MUTATION LIKELY TO BE CONFERRING A MORE SEVERE PHENOTYPE. AGAIN, THIS IS VERY BROAD STROKES NOT SPECIFIC TO SPG4 BUT I WANTED TO PROVIDE A LAY OF THE LAND HOW WE THINK CLINICALLY FROM THE MEDICAL GENETIC STANDPOINT ABOUT MUTATION. THE OTHER THING I WANTED TO BEGIN TO TALK ABOUT WITH THIS GROUP TODAY WAS TO FRAME SOME OF THIS THINKING WITHIN HOW WE APPROACH THE GENOMIC ARCHITECT ARCHITECTURE OF DISEASE. YOU CAN SEE A FAMILY PEDIGREE. SO WE HAVE AN INDIVIDUAL SHOWN HERE IN GREEN AND FATHER AND MOTHER HERE AND THEN ADDITIONAL FAMILY MEMBERS FURTHER UP THE FAMILY TREE. AND WHEN WE THINK ABOUT NEW MUTATION WE THINK OF THE DE NOVO MUTATION OR ONE THAT OCCURRED RECENTLY IN A FAMILY TREE OR PEDIGREE AND WE EXPECT THAT TO HAVE A LARGE PHENOTYPIC EFFECT SIZE WHEREAS FOR MORE COMMON VAS VARIANTS PERHAPS THE PARENTAL OR GRANDPARENTAL WE EXPECT A LESS INFLUENCE AND IT'S IMPACTING ONLY THIS INDIVIDUAL NEITHER OF HIS OR HER PARENTS HAVE THE VARIANT AND THIS IS WHAT I WAS JUST TALKING ABOUT WE SEE FREQUENTLY IN OUR DIAGNOSTIC LABORATORY COHORT. THESE TYPES OF OBSERVATIONS ACTUALLY PROMPTED THE CLAN GENOMIC HYPOTHESIS AND PUBLISHED MORE THAN A DECADE AGO AND POSITED THERE'S A CONTRIBUTION OF NEW METATIONS TO HUMAN RARE DISEASE. WHILE THIS IS VERY MUCH THOUGHT OF IN ALLELE VARIANTS WE'VE BEEN ABLE TO DEMONSTRATE RECENTLY SOME ARE BROUGHT TO HOMO ZYGOCI ZYGOCITY. I WANT TO MOVE ON AND TALK ABOUT THE CHALLENGE OF INCOMPLETE PENETRANTS. I'M GOING TO USE CONGENITAL SCOLIOSIS TO MAKE SOME POINTS I THINK COULD BE RELEVANT FOR THE GROUP. SO A TEAM AT ORTHOPEDIC SURGEONS ARE CLOSE COLLABORATORS OF OURS AND THEY'VE BEEN STUDYING CHILDREN WITH THIS EARLY ONSET CONGENITAL SCOLIOSIS. THEY SEE THE INDIVIDUALS AFFECT INTERESTED A DELETION OF 16P.1.2 SHOWN BY THE INTERRUPTED RED LINE. WHAT WAS FRUSTRATING TO THEM INITIALLY WAS IN MANY CASES THE DELETION AND LOSS OF FUNCTION EXPERIENCE WAS INHERITED FROM AN UNAFFECTED PARENT LIKE THIS FATHER HERE. THEY EVENTUALLY FIGURED OUT WHAT WAS CAUSING THIS INCOMPLETE PENETRANTS AND TURNED OUT THE INDIVIDUALS AFFECTED WITH CONGENITAL SCOLIOSIS HAD A LOSS OF ALLELE AND THE OTHER HAD A HYPOMORPHIC GENE SO SOME EXPRESSION BUT NOT FULL AND YOU NEED THAT VARIANT AND THE HYPOMORPHIC EXPRESSION ON THE ALLELE TO HAVE CONGENITAL SCOLIOSIS. THAT VARIANT IS ACTUALLY A COMMON ALLELE IN THE CHINESE HUN POPULATION. AND THE HYPOTHESIS WAS ULT FATLY IF YOU HAD TWO WILD TYPE ALLELE WITH THIS ALLELE IN BLUE YOU STILL HAVE THE TBX EXPRESSION THAT YOUR RISK OF CONGENITAL SCOLIOSIS IS LOW. THAT'S TRUE EVEN WITH TWO HYPOMORPHIC EXPRESSION OR ONE VARIANT AND ONE LOSS OF FUNCTION VARIANT, YOU STILL HAVE JUST ENOUGH TBX6 EXPRESSION TO SQUEEZE BY AND PROBABLY NOT HAVE CONGENITAL SCOLIOSIS. BUT YOUR PENETRANTS FOR SCOLIOSIS IS SPECIALLY INCREASED ONCE HAVE YOU HAVE A COPY ON ONE ALLELE OPPOSITE WHERE YOUR TBX6 EXPRESSION IS STILL DETECTABLE BUT SUBSTANTIALLY REDUCED. THIS IS AN IMPORTANT KIND OF LESSON FOR US BECAUSE IT TAUGHT US TO THINK CRITICALLY NOT ONLY ABOUT THE GENE CAUSING WHAT APPEARS TO BE A DOMINANT CONDITION WITH INCOMPLETE PENETRANTS BUT TO UNDERSTAND HOW OTHER VARIANTS EITHER THIS LOCUS OR OTHER EXAMPLES I WON'T HAVE TIME TO DISCUSS TODAY WHERE THERE'S OTHER LOCI TO UNDERSTAND GENE DOSAGE AND WHAT'S HAPPENING BEHIND THE SCENES IN RELATION TO THE SEVERITY OF THE PHENOTYPE OR PENETRANTS OF THE PHENOTYPE. I WON'T BELABOR THIS POINT BECAUSE IT WAS MENTIONED EARLIER WITH REBECCA SCHOLES TALK BUT IN COLLABORATION WITH BAYLOR, OUR GROUP HAS BEEN LOOKING AT THE BURDEN OF THIS AND ONE DRIVING REASON IS HE HAD SEEN IN HIS OWN PEDIATRIC NEUROLOGY CLINIC WHERE SOME INDIVIDUALS IN THE SAME FAMILY HAVE THE SAME MUTATION AT THE REST OF THE FAMILY MEMBERS PRESENTED MUCH GREATER THAN EXPECTED AND THE QUESTIONS IS WHY ARE THEY HAVING MORE SEVERE DISEASE AND HOW CAN WE HELP FAMILIES TO KNOW WHAT TO EXPECT FOR A NEW MEMBER OF THE FAMILY WHO HAS THE VARIANT. HOW SEVERE IS THIS GOING TO BE AND HOW CAN THEY PLAN? WHAT HE LEARNED WAS THAT THERE ARE MANY VARIANTS AND GENES ASSOCIATED WITH NEUROON -- NEUROPATHY AND MANY TIMES UNAFFECTED INDIVIDUALS WOULD HAVE VARIANTS IN THE FAMILY BUT ARE UNAFFECTED PARENTS AND HAVE VARIANTS BUT WHEN YOU LOOK AT THE CHILDREN SEVERELY AFFECTS YOU WOULD SEE A DRIVING MUTATION AND THIS YOUNG MALE HAS AN VARIANT AND HAD MUCH MUCH MORE SEVERE DISEASE THAN YOU WOULD EXPECT FOR INDIVIDUALS WITH THIS VARIANT IN MFN2 AND WHAT JIM WAS ABLE TO SHOW IS THE VARIANT INHERITED FROM PARENTS MODERATE THE SEVERITY OF THE PHENOTYPE. THIS NEW MUTATIONAL BURDEN. ONE THING PROPOSED BUT NOT DEMONSTRATED IN THE HUMAN RARE DISEASE RESEARCH WORLD AT LEAST NOT DEFINITIVELY IN ANY WAY I CAN FIND IN THE LITERATURE IS THE POSSIBILITY WITH NEW MUTATIONS VERSUS INHERITED YOU CAN HAVE COMPENSATORY LOCI RATHER THAN DIALING UP THE SEVERITY COULD DIAL DOWN THE SEVERITY OF THE CONDITION AND IN A SETTING WHERE YOU HAVE AN INHERITED VARIANT OVER MULTIPLE GENERATIONS THERE'S THE THEORETICAL POSSIBILITY COMPENSATORY VARIANTS MAY MAKE THE PHENOTYPE LESS SEVERE. IN A SITUATION WHERE YOU HAVE A NEW MUTATION THE GENOME HASN'T HAD AN OPPORTUNITY TO HAVE OTHER VARIANTS TAKE PLACE. WHETHER THIS REALLY OCCURS IN A SMALL INDIVIDUAL FAMILY LEVEL WE DON'T KNOW BUT KNOW IT CAN OCCUR IN A POPULATION LEVEL BUT OVER MANY GENERATIONS. I THINK IT'S AN INTERESTING HYPOTHESIS TO CONSIDER IN TERMS OF WHETHER MUTATIONAL BURDEN CAN ALSO WORK THAT WAY. I ALSO WANT TO TALK BRIEFLY ABOUT DUAL MOLECULAR DIAGNOSES. THESE ARE CONDITIONS IN WHICH AN INDIVIDUAL RATHER THAN HAVING ONE CONDITION WITH ADDITIONAL VARIANTS WITH THE PHENOTYPE MAY HAVE TWO CONDITIONS THAT SEGREGATE INDEPENDENTLY WHERE ONE SIBLING HAS ONE CONDITION AND MAYBE THE CHILD HAS THE OTHER AND INDEPENDENT SEGREGATION OF TWO OR MORE RARE DISEASE PHENOTYPES. AND IN THE EXAMPLE I'M SHOWING YOU HERE ON THE LEFT IS AN INDIVIDUAL WHO ACTUALLY HAS TWO GENETIC FORMS OF DEVELOPMENT ENCEPHALOPATHY WE HAVE IN OUR LABORATORY DATABASE AND YOU'D EXPECT SOMEBODY LIKE THIS MIGHT ACTUALLY PRESENT WITH AN EVEN MORE SEVERE PHENOTYPE FOR DEVELOPMENT ENCEPHALOPATHY ALONE. THEY'RE IMPORTANT SCENARIOS TO IDENTIFY. THEY MAY INFLUENCE TREATMENT BUT CAN ALSO EXPLAIN SCENARIOS IN WHICH YOU MAY HAVE SOMEONE WHO APPEARS TO HAVE A MORE SEVERE PHENOTYPE THAN EXPECTED. YOU MAY THINK THESE ARE INCREDIBLY RARE BUT IT TURNS OUT IF YOU TAKE ALL COMERS WHO HAD A DIAGNOSTIC WHOLE EXOME SEQUENCING STUDY AT LEAST 5 OR MORE WILL HAVE TWO OR MORE DIAGNOSES. IT CAN COME IN TWO FLAVORS. THE EXAMPLE I SHOWED YOU A MOMENT OKAY NOW HERE ON THE RIGHT IS THE OVERLAPPING FLAVOR WHERE A PERSON HAS TWO SIMILAR CONDITIONS AND YOU EXPECT THEM TO HAVE A PHENOTYPE THAT'S EVEN MORE SEVERE. YOU CAN SEE THE OPPOSITE WHERE SOMEONE MAY HAVE A MELDING OF TWO CONDITIONS UNRELATED TO EACH OTHER BUT CLINICALLY WHEN THEY COME IN TO SEE YOU, WHAT YOU'LL SEE IS A COMBINATION OF PHENOTYPES YOU MAY NEVER HAVE SEEN BEFORE AND UNTIL YOU'VE DONE THE APPROPRIATE TESTING, YOU MAY NOT REALIZE FOR EXAMPLE THIS PERSON WITH ABSENT SKIN PIGMENTATI PIGMENTATION DOES NOT HAVE A SINGLE UNIFIED DIAGNOSIS. THE LAST THING I WANTED TO MENTION IS I WANTED TO BRING UP THE IDEA OF MOSAICISM AND HOW THAT CAN INFLUENCE DISEASE TRAIT EXPRESSION. MANY OF US THINK OF IT IN TERMS OF WHAT POINT IN AN INDIVIDUAL'S DEVELOPMENT A NEW MUTATION OCCURS. SO IF IT OCCURS SORT OF AT THE FIRST MITOSIS OR IF IT OCCURS LATER ON AFTER LEFT-RIGHT PATTERNING HAS OCCURRED OR A MUTATION THAT OCCURS ONLY IN THE GERM LINE BUT COULD BE PASSED ON TO THE NEXT GENERATION. AND AS YOU CAN KIND OF ENVISION FROM WHAT YOU CAN SEE HERE, THAT CAN GREATLY INFLUENCE THE PHENOTYPE THAT MAY BE EXPRESSED FROM THE IMPACTED CELLS. ONE OF THE REASONS I BRING THIS UP IS BECAUSE IN THINKING ABOUT THE QUESTION OF DE NOVO MUTATIONS AND SPAST, I RAN ACROSS A VERY INTERESTING PARADOX AND WHAT I CALL THE PARADOX OF DISEASE, SEVERITY AND CRANIOFRONTAL NASAL SYNDROME. THIS PARTICULAR CONDITION IS X LINKED WHICH MAKES IT A LITTLE BIT DIFFERENT. AND IT'S COVERED BY DAMAGING OR PATHOGENIC VARIANTS IN EFNV1. WHAT'S CURIOUS ABOUT IT IS HETER HETE HETEROZYGOUS FEMALES ARE MORE AFFECTED AND IT MAY SEEM COUNTERINTUITIVE AND HERE'S A DAUGHTER AND HER FATHER AFFECTED AND YOU CAN APPRECIATE FROM THE IMAGE SHE AS A MORE SEVERE PHENOTYPE THAN HER FATHER THOUGH SHE HAS ONE EXTRA CHROMOSOME OF THE VARIANT AND ONE THAT IS WILD TYPE. HER FATHER ONLY HAS ONE AND IT'S VARIANT. ONE OF THE IMPORTANT THINGS TO THINK ABOUT IN THIS PARTICULAR CONDITION IS THAT WE KNOW THAT FOR SEASONS YOU CAN HAVE MOSAICISM FOR GENE EXPRESSION FOR THE RELEVANT GENE. WE KNOW IN CFNS THAT WOMEN ARE MOSAIC FOR EFNB1 EXPRESSION IN FEMALES BECAUSE OF THEIR CHROMOSOMIC ACTIVATION. THEY'LL HAVE A POPULATION OF CELLS WHERE A SUBSET ARE EXPRESSING THE WILD TYPE GENE. THIS IS IMPORTANT IN THIS PARTICULAR CONDITION BECAUSE OF THE FACT THAT IT RELATES TO RECEPTORS AND THEIR ROLE. SO EFNB1 IS ONE OF THE EPHRONS AND THIS CLASS OF RECEPTORS IS IMPORTANT FOR EMBRYONIC TISSUE AND THERE'S SUBCLASSES A AND B AND THEY'RE DEFINED WHETHER THEY'RE THEY BIND TO EPHRIN RECEPTORS AND YOU CAN HAVE CELL ADHESION ON ONE AND CELL REPULSION IN THE OTHER. IN THIS PARTICULAR CASE, THIS WAS OF NOTE BECAUSE SCIENTISTS HYPOTHESIZED THE REASON WHY THE MOSAIC FEMALES WITH CFNS WERE MORE SEVERELY AFFECTED WAS BECAUSE OF TWO POPULATIONS OF CELLS. ONE EXPRESSING THE WILD TYPE COPY AND ONE PRESUMABLY NOT EXPRESSING IT WELL. WHEREAS THE MALES ONLY HAD ONE CELL LINE. THEY WERE NOT MOSAIC AND THEY WERE PRESUMABLY EXPRESSING A KNEW -- MUTANT COPY OR NOT EXPRESSING WELL AT ALL. THE GROUP FOUND IF YOU MIX CELLS THAT SHOWED THE STAIN EPHRIN EXPRESSION LEVELS EITHER WILD TYPE 2 POPULATIONS WITH WILD TYPE OR WILD TYPE POPULATIONS WITH MUTANTS, THE CELLS WOULD CONTINUE TO INTERACT THROUGH THEIR EPHRIN LIGANDS AND MIX AND DO THE SIGNALLING NEEDED. BUT WHEN YOU MIX A CELL LINE WITH A MUTANT EXPRESSING CELL LINE SIMILAR TO WOMEN WITH ACTIVATION OF GENE, YOU WOULD SEE CELL SEGREGATION AND THE GREEN AND PURPLE ARE NO LONGER MIXING APPROPRIATELY. ONE OF THE HYPOTHESES THEN YOU WOULD PREDICT MALES WHO ARE GERM LINE MOSAIC FOR AN EPHRIN B1 VARIANT WOULD BE JUST AS SEVERELY AFFECTED AS FEMALES. I DON'T HAVE ENOUGH TIME TO SHOW THIS BUT NOW MULTIPLE MOSAIC MALES HAVE SHOWN THEY'RE EQUALLY AS AFFECTED AS FEMALES MORE THAN THOSE WITH THE MUTATION. THIS IS A GREAT EXAMPLE OF HOW MOSAICISM CAN INFLUENCE PHENOTYPES SOMETIMES IN PARADOXICAL WAYS. I HOPE I'VE CONVINCED YOU AT A POPULATION LEVEL WE CONCEPTUALIZE THEM TO HAVE A LARGER PHENOTYPIC IMPACT. WE KNOW MUTATIONAL BURDEN AND COMPOUND BURDEN CAN INFLUENCE THE SEVERITY OF DISEASE EXPRESSION AND POTENTIALLY INFLUENCE PENETRANTS AS WELL AND KIND OF RAISES THE QUESTION WHETHER THERE COULD BE MECHANISMS INVOLVING COMPENSATORY MUTATIONS ALSO HERE. I HOPE I'VE CONVINCED YOU DUAL MOLECULAR DIAGNOSES CAN BE DIFFICULT TO CLINICALLY RECOGNIZE AND WHEN THEY MIGHT SHARE A RELATIONSHIP THEY CAN INFLUENCE PHENOTYPE AND PARADOXICALLY IN SOME CASES MAY LEAD TO A MORE SEVERE PHENOTYPIC PRESENTATION. WITH THAT I'LL WRAP UP. OUR RARE DISEASE RESEARCH GROUP IS LARGER THAN WHAT I SHOW HERE BUT THESE ARE THE MOVERS AND SHAKERS THAT CONTRIBUTED TO THE WORK I'VE PRESENTED HERE AND MY FUNDERS AS WELL. >> I'M HEATHER McALAU LAUGLAUGHLIN ONE OF THE MEDICAL AFFAIRS DIRECTORS AND I'LL TALK ABOUT THE DATA WE HAVE ON SPAST RELATED HSP IN CHILDREN WITH CP SPECTRUM DISORDERS. SO A LITTLE BIT ABOUT CEREBRAL PALSY FIRST, WHAT WE KNOW ABOUT THE DISORDER OR GROUP OF DISORDERS IT'S THE MOST COMMON CAUSE OF MOTOR DISABILITY IN CHILDREN AND INCIDENTS OF 23 PER 1,000 LIVE BIRTHS IN THE UNITED STATES. THE TERM REPRESENTS A HETEROGENEOUS GROUP OF CONDITIONS CHARACTERIZED BY IMPAIRMENT OF MOVEMENT POSTURE AND OR MOTOR FUNCTION AND ONSET OCCURS TYPICALLY BETWEEN TWO TO THREE YEARS OF AGE AND IN UNDERLYING GENETIC ETIOLOGY CAN BE DETERMINED FOR 20% TO 60% OF PATIENTS DEPENDING ON THE COHORT I WANT TO SHARE ABOUT THE MOLECULAR DIAGNOSTICS TODAY. FORTUNATELY IT TAKES AN AVERAGE OF 4.8 TO 5 YEARS FOR AN INDIVIDUAL TO RECEIVE AN ACCURATE DIAGNOSIS. THE REASONS ARE MULTIFOLD AND WE HAVE INDIVIDUALS TRYING TO ACCESS AND RECEIVE GENETIC TESTING. IF PATIENTS ARE HAVING TO PAY OUT OF POCKET OR HAVE POOR INSURANCE COVERAGE THIS CAN BE A VERY LARGE BARRIER FOR MANY MANY FAMILIES. AND THERE ARE REIMBURSEMENT CHALLENGES SO EVEN FOR THOSE THAT HAVE INSURANCE THAT MAY PAY FOR THIS TYPE OF TESTING OFTEN THE OUT OF POCKET COSTS ARE SO HIGH IT'S UNREASONABLE FOR THE FAMILY TO BE ABLE TO AFFORD THAT AND FINALLY WE HAVE AN ISSUE OF LACK OF COMFORT WITH GENETIC DISORDER AND MANY ARE BEING SEEN BY THEIR PEDIATRICIAN AND A LACK OF COMFORT WHERE THEY'D LIKE TO ORDER THE TEST AND FEEL COMFORTABLE EXPLAINING THE TEST TO A PATIENT. THE COHORT IS FROM OUR CP SPECTRUM PANEL AND I'LL TALK ABOUT THE GENETIC TESTING PROGRAM AND WANTED TO PROVIDE BACKGROUND ON WHAT THE TESTING PROGRAM IS SO THE GROUP CAN BETTER UNDERSTAND THE COHORT AND THE WAY THE TESTS ARE DESIGNED. PHYSICIANS ARE MADE AWARE OF THESE AND WE HAVE PATIENT WE SUSPECT HAVE BEEN DIAGNOSED WITH A SPECIFIC GENETIC DISORDER AND IF THEY MEET CRITERIA THE TEST IS ORDERED THROUGH THE PROGRAM VIA THEIR CLINICIAN. THE CLINICIAN IS THE ONE THAT DECIDES WHETHER THIS IS AN APPROPRIATE TEST AND THE PATIENT CAN DECIDE WHETHER THEY WISH TO PARTICIPATE IN THE PROGRAM DEPENDING ON WHETHER THEY'D LIKE TO SHARE SPECIFIC DATA WITH OTHER PROGRAM SPONSORS. THE SAMPLES THAT ARE SUBMITTED TO INVITAE ARE TEST RESULTS DELIVERED TO THE ORDERING CLINICIAN AND CLINICIAN AND THEY'RE COLLECTED ON OUR QUEST REQUISITION FORM. THEY'RE SEND REPORTS AND A REGULAR CADENCE AND CHARGED DIRECTLY FOR THE TEST SO THERE'S NO COST INCURRED BY THE PATIENT OR FAMILY AND THE SPONSOR HAS THE OPTION TO FOLLOW-UP WITH THE CLINICIAN NOT THE PATIENT FOR THE PROGRAM AND IT'S A WAY WE TRY TO GET AROUND THE FACT THAT ACCESS TO GENETIC TESTING TODAY IS SO DIFFICULT FOR MANY FAMILIES. SO WE'VE BEEN TRYING TO PROVIDE PATIENT TO MEET CERTAIN CRITERIA WITH NO CHARGE TESTING IN ORDER FOR THEM TO RECEIVE A MOLECULAR DIAGNOSIS. I WANTED TO BRIEFLY TOUCH BEFORE WE START TALKING ABOUT SPAST A LITTLE BIT MORE ABOUT WHAT DO I MEAN WHEN I SAY DE-IDENTIFIED INFORMATION AND THE FIRST IS CLINICIAN INFORMATION AND THE CLINICIAN'S NAME AND E-MAIL ADDRESS OR PHONE NUMBER AND MPI NUMBER AND INSTITUTION NAME AND ADDRESS. NO PATIENT NAME IS EVER SHARED IT'S JUST THE CLINICIAN IDENTIFYING INFORMATION THAT MAY BE SHARED AND CLINICIANS ARE AWARE OF THIS AND ATTEST TO IT WHEN THEY SEND THEIR PATIENTS FOR TESTING THROUGH THE PROGRAM. VARYING INFORMATION WE MIGHT SHARE WOULD BE THE GENE, THE NOMENCLATURE AND VARIANT, THE ZYGOCITY AND ARE THEY PATHOGENIC OR INSIGNIFICANT VARIANTS AND CLINICAL INFORMATION. WE'RE NOT PROVIDING SPONSORS A WHOLE CLINIC NOTE IT'S JUST THE CLINICAL INFORMATION PROVIDED THROUGH THE SPONSOR TESTING PROGRAM REQUISITION PROGRAM LIKE AGE IN YEARS, CLINICAL SYMPTOMS AND WE ASK WHAT TYPE OF CARDIO MYOPATHY THEY HAVE IS IT HYPERTROPHIC, FOR EXAMPLE, SPECIFIC LAB AND TEST RESULTS THAT MIGHT BE PERTINENT TO THE PROGRAM SPONSORS, TREATMENT HISTORY SO WE HAVE AN EPILEPSY DRUG AND WE'LL ASK HOW MANY EPILEPSY DRUGS HAS THE PATIENT TRIED SO FAR AND TESTING ARE THERE SIMILARLY AFFECTED FAMILY MEMBERS AND ANY SUSPECTED CLINICAL DIAGNOSES FROM THE PHYSICIAN. NOW I'LL TALK ABOUT DATA FROM THE PINPOINT GENETIC TEST PROGRAM. THIS SAY PROGRAM THAT IS A SPONSORED TESTING PROGRAM THAT IS PERFORMED BY INVITAE. SO PDC SPONSORS THE PROGRAM BUT WE'RE PERFORMING ALL THE TESTING IN OUR CLINICAL LABORATORY MUCH LIKE ALL THE OTHER GENETIC TESTING WE PERFORM. FOR INDIVIDUALS TO BE ELIGIBLE THEY MUST RESIDE WITHIN THE U.S. OR CANADA AND MUST HAVE SYMPTOMS SUGGESTIVE CEREBRAL PALSY. THE FIRST THING YOU'LL NOTICE IS FOR MANY SPONSORED TESTING PROGRAM WE PURPOSELY MADE THE INCLUSION OR THE ELIGIBILITY CRITERIA QUITE BROAD SO WE CAN IMPACT THE LARGEST NUMBER OF PATIENTS. NEXT I WANTED TO SHARE A LITTLE BIT MORE ABOUT THE PANEL ITSELF. THIS IS A VERY LARGE PANEL. IT HAS 425 GENES AND SO UNFORTUNATELY I'M NOT ABLE TO SHOW ALL THE GENES THAT ARE INCLUDED IN THE PANEL IN A SINGLE SLIDE BUT I DID PROVIDE A WEBSITE AT THE BOTTOM OF THIS PAGE SHOULD ANYONE WANT TO GO REVIEW THE GENES FURTHER THE TURN AROUND TIME FOR THIS TEST IS 10 AND 21 DAYS AND WE HAD TO ACCEPT MULTIPLE TYPES OF SPECIMENS INCLUDING BLOOD, SALIVA OR GENOMIC DNA IF THAT'S AVAILABLE AS WELL. AND REALLY WHAT WE'RE TRYING TO ACHIEVE WITH THIS PANEL IS OFFERING A BROAD PANEL OF GENES THAT MIGHT BE ABLE TO DETERMINE THE ETIOLOGY OF CEREBRAL PALSY. BECAUSE IT'S SUCH A HETEROGENEOUS GROUP OF DISORDERS WE ALSO INCLUDED GENES ASSOCIATED WITH HEREDITARY SPASTIC PARAPLEGIAS AND ATAXIAS AND OTHER DISORDERS THAT CAN MIMIC CEREBRAL PALSY. AND WE'RE PERFORMING NEXT GENERATION SEQUENCING AND WE HAVE WHOLE GENE SEQUENCING AND DUPLICATION ANALYSIS OF ALMOST EVERY AXON IN EVERY GENE OFFERED ON THE PANEL. WE HAVE HIGH AVERAGE COVERAGE IN THE ANALYSIS ALSO INCLUDES AND WE'RE ABLE TO IDENTIFY SEQUENCE VARIANCE AND COPY NUMBER VARIANTS IN THE ASSAY. THE COHORT I WOULD LIKE TO SHARE MORE INFORMATION ABOUT TODAY IS THE COHORT OF CHILDREN OR INDIVIDUALS THAT HAVE BEEN TESTED -- SORRY, NOT JUST CHILDREN, TESTED THROUGH THE PTC PINPOINT CP SPECTRUM PANEL AND THE DATE RANGE IS 9/15/2020 TO 12/15/21 AND THE AVERAGE RANGE OF TESTING WAS 8 YEARS OLD BUT THERE WAS QUITE A RANGE OF AGES AT THE TIME RANGING FROM ZERO TO 74 YEARS. WE HAD PROVIDERS WHO ORDERED THROUGH THE PROGRAM COMING FROM 18 UNIQUE SPECIALTIES. I'M PROVIDING MORE INFORMATION ABOUT THE EXPERIMENTS HERE. A LOT OF THESE MAKE SENSE. WE'RE LOOKING AT SOME PEDIATRIC SPECIALISTS AND NEUROMUSCULAR MEDICINE SPECIALISTS AND HAVE MORE MOLECULAR GENETIC AND CLINICAL GENETIC FOCUSSED SPECIALISTS AS WELL. THIS IS TYPICAL OF WHAT WE SEE FROM AND MANY ARE BEING SEEN BY PROVIDERS AND THERE'S MANY TYPES OF PROVIDERS PARTICIPATING IN THE PROGRAM. IN TERMS OF THE DIAGNOSTIC YIELD, THIS IS A PROGRAM WHERE THERE ARE OBVIOUSLY MANY DIFFERENT CAUSES OF CEREBRAL PALSY. SOME ARE GENETIC AND SOME ENVIRONMENTAL AND SOME MAY BE A MIX OF BOTH. WHAT WE SEE THIS PERCENTAGE AND THERE'S A LARGE NUMBER OF INDIVIDUALS THAT MAY NOT ACHIEVE A MOLECULAR DIAGNOSIS THAT MAY BE FOUND TO BE A CARRIER FOR AUTOSOMAL RECESSSIVE DISORDER OR HARBOR A VARIANT OF SIGNIFICANCE. THERE ARE FEW PATIENTS AND THERE'S OVER 425 GENES SO THE PROBABLE THAT AN INDIVIDUAL DOES NOT HARBOR A SINGLE VARIANT REPORTABLE IN ANY ONE OF THOSE GENES ARE QUITE LOW. YOU'RE SEEING THIS SPREAD FOR THIS PARTICULAR PROGRAM. NEXT I WANT TO TALK ABOUT THE MOST COMMON MOLECULAR DIAGNOSES THROUGH THE PROGRAM. YOU CAN SEE PART OF THE REASON WE'RE HERE TODAY IS THE SPAST GENE DOESN'T COUNT FOR THE MAJORITY OF THE DIAGNOSES WE SEE IN THE PROGRAM AND WE'VE IDENTIFIED AT THE TIME OF THIS DATA CUT 19 INDIVIDUALS. I THINK WE'RE ALMOST NEARING 25 NOW AT THIS POINT. SO WHAT THIS MEANS IS 1.1% OF ALL MOLECULAR DIAGNOSES ARE ATTRIBUTED TO SPAST IN THIS COHORT AND SPAST MAKES UP 11% OF POSITIVE OF ALL MOLECULAR DIAGNOSES RECEIVED IN THE COHORT AND IT'S QUITE INTERESTING. NEXT I WANTED TO PROVIDE MORE INFORMATION. I KNOW IN A FEW TALKS TODAY I WANTED TO SHARE WHICH PATHOGENIC VARIANTS WE'VE IDENTIFIED SO FAR IN THE COHORT AND POINT YOUR ATTENTION TOWARDS THIS WHICH APPEARS TO BE A RECURRING PATHOGENIC VARIANT IN THE COHORT. YOU'LL NOTICE WE TALKED ABOUT LOSS OF FUNCTION VARIANTS AND THERE'S QUITE A NUMBER ON THIS LIST. THIS IS A FEMALE CHILD WITH SPASTIC DYSPLASIA AND THE VARIANT IS AT A HIGHLY CONSERVED RESIDUE AND NOT DATABASE AND IT'S BEEN REPORTED IN THE LITERATURE IN MULTIPLE INDIVIDUALS AND FAMILIES AFFECTED WITH SPASTIC PARAPLEGIA AND WE HAVE IDENTIFIED IT AS BEING DE NOVO IN THIS PATIENT AND OTHERS AS WELL. AND THERE'S A STRONG PATHOGENIC VARIANT AND ONE RECURRENT IN OUR POPULATION. I WANT TO MAKE SURE WE HAVE TIME FOR THE OVERALL DISCUSSION OF THE GROUP. I WANTED TO SHARE THE SPECTRUM PANEL CAN BE A MOLECULAR TOOL UTILIZED BY A VARIETY OF PROVIDERS. IT MAY HELP IDENTIFY THE UNDERLYING GENETIC CAUSE WITH ETIOLOGY AND MAY NEED TO CAUTION THEY MAY GET MORE THAN ONE SIGNIFICANCE GIVEN THE PANEL SIZE. THE DIAGNOSTIC YIELD IS EXPECTED TO IMPROVE WITH FAMILY STUDIES WE ARE ABLE TO PERFORM BY TESTING AAFFECTED AND UNAFFECTED RELATIVES AND DATA PUBLISHED IN THE LITERATURE AND THIS NO-CHARGE SPONSORED TESTING PROGRAM CAN BE A PART OF A TIERED DIAGNOSTIC APPROACH FOR PATIENTS WITH CEREBRAL PALSY AND I'LL END THERE. >> THANK YOU SO MUCH, HEATHER FOR A WONDERFUL PRESENTATION. THIS COULD BE A GOOD TIME FOR US TO OPEN THE ENTIRE PANEL FOR DISCUSSION INCLUDING DISCUSSIONS ABOUT THE TOPICS THAT WERE COVERED IN THE MORNING. >> IF PEOPLE CAN INTRODUCE THEMSELVES AND I SEE SOME PART INITIATIVE THAT HEATHER WAS TALKING ABOUT AND I THINK JEFF MENTIONED HE HAD A QUESTION SO MAYBE WE CAN OPEN WITH THAT IF AVAILABLE. >> A LOT OF MY QUESTION WAS NOT ABOUT THAT TOPIC THOUGH HEATHER DID A FABULOUS JOB REVIEWING THAT. MY QUESTION WAS ABOUT THE HYPOMORPHIC VARIANT REVIEWED AND WONDERING IF THE PRESENTER CAN SPEAK TO HOW THAT HYPOMORPHIC VARIANT WAS PROVEN AS SUCH. WE'RE INTERESTED IN A HYPOMORPHIC IN THE DDC GENE SO WE'RE TRYING TO UNDERSTAND THE THEORY OF A HYPOMORPHIC VARIANT SIMILAR TO WHAT YOU PRESENTED, DR. POSEY. >> ABSOLUTELY. SO BRIEFLY THE TEAM THAT MADE THAT DISCOVERY, THEY DID TWO THINGS. THE FIRST WAS SET UP CELLULAR ASSAYS TO TEST LOCALIZATION AND FOUND THE HYPOMORPHIC VARIANT DID NOT LOCALIZE OR EXPRESS TO THE SAME LEVEL AND HAD EVIDENCE IT WAS UP FRONT AND THE IMPORTANT NEXT THING THEY DID WAS BUILT THAT PARTICULAR ALLELE IN MICE. AND I TAKE THE SLIDE OUT OF MY PRESENTATION SO I DON'T HAVE IT HANDY QUICKLY BUT ESSENTIALLY THEY DID THE SAME EXPERIMENT IN MICE THEY'VE BEEN OBSERVING IN HUMANS. FOR BOTH MOUSE AND HUMANS IF YOU HAVE A DOUBLE KNOCKOUT OF TBX6 WAS LETHAL SO THAT WAS NOT AVAILABLE AND COMPARED IT TO THE SINGLE HYPOMORPH TO THE COMPOUND LOSS TO FUNCTION PLUS HYPOMORPH AND THEN ALSO A HOMOZYGOUS HYPOMORPH AND IT WAS ONLY THE MICE THAT HAD THE LOSS OF FUNCTION WITH THE HYPOMORPH WITH A SKELETAL PHENOTYPE AND WHAT WAS CURIOUS WAS THE MICE AND HUMANS HAVE A SIMILAR SKELETAL PHENOTYPE. THE SCOLIOSIS INVOLVES THE LOWER SPINE WHICH WAS IMPORTANT TO THEM BECAUSE THEY WERE ABLE TO OPERATE ON THE PATIENTS MORE READILY AND MORE ACCESSIBLE THAN THE THORACIC SPINE WHERE YOU HAVE TO WORRY ABOUT THE RIBS AND THINGS BECOME MORE CHALLENGING. THEY SIMPLY DID CELLULAR ASSAYS AND FOLLOWED IT UP WITH MOUSE GENOMICS AS WELL. >> THANK YOU. VERY HELPFUL. WE HAVE A GROUP IN ITALY DOING THE CELLULAR FUNCTIONAL STUDIES BUT I DON'T KNOW IF ANYONE'S LOOKED AT ANIMAL MODELS. THANK YOU FOR EXPLAINING. >> AND LOOKING HOW THE MUTATIONS CAN LEAD TO THE PHENOTYPE AND HAVE TROUBLE UNDERSTANDING WHERE THE INHERITANCE MECHANISM SHOULD CAUSE A DIFFERENT PHENOTYPE. AT FIRST I THOUGHT IT'S THE VERY NATURE OF THE SPECIFIC MUTATIONS THAT LEAD TO A SEVERE PHENOTYPE AND THE SEVERITY OF THE PHENOTYPE IN TURN LEADS TO A MORE COMMONLY OBSERVED DE NOVO INHERITANCE AND FIND THE SAME MUTATIONS IN DE NOVO IN OUR ADULT POPULATIONS WITH A MILDER PHENOTYPE. THIS IS SOMETHING I REALLY DON'T UNDERSTAND. I'M WONDERING WHETHER ANYBODY HAS IDEAS THERE. >> I GUESS I CAN GO FIRST. I DEFINITELY DON'T HAVE A DEFINITIVE ANSWER FOR YOU BUT THERE'S A COUPLE THINGS I WONDER ABOUT WHEN I LOOK AT SOME OF THE DATA THAT HAVE BEEN PRESENTED ON INDIVIDUALS WITH A MORE SEVERE PHENOTYPE. ONE OF THE FIRST THINGS THAT I WONDER IS HAS ANYBODY LOOKED AT ADDITIONAL VARIANTS IN THEIR EXOMES OR EVEN GENOMES THAT MAY BE MODIFYING THE PHENOTYPE? AND ONE OF THE REASONS IT'S SO COMPELLING TO ME IS FOR THIS TYPE OF PHENOTYPE AND FOR SIMILAR RELATED NEUROLOGICAL PHENOTYPES WE HAVE SUCH A LONG LIST OF GENES. MANY OF WHICH HAVE EITHER EPI EPISTAFFIC -- EPISTATIC INTERACTIONS AND THE COMBINATION OF THEIR MUTATION PLUS THE SECOND HIT COULD BE LEADING TO MORE SEVERE DISEASE. YOU COULD KIND OF COUNTER THAT AND SAY WHY IS IT ONLY THE DE NOVOS. IT'S POSSIBLE WE HAVEN'T LOOKED EXTENSIVELY ENOUGH. THAT'S ONE THING TO CONSIDER. I DON'T HAVE A GOOD SENSE AND KNOW FROM A CLINICAL GENETIC PERSPECTIVE IT'S EASY TO GET SAMPLES FROM THEM AND THEY HAVE SEVERE DISEASE AT LEAST IN THE U.S. AND ARE MORE LIKELY TO GET EXOME SEQUENCING CLINICALLY COVERED SO THE TEST AVAILABILITY IS LESS LIMITING BUT EVEN HERE WE'RE LEFT WITH THE QUESTION OF NON-CODING VARIANTS AND WE'RE NOT FREQUENTLY LOOKING FOR THOSE AND IT'S TOUGH TO GET TRIOS. THE QUESTION OF COULD THERE BE A MUTATIONAL BURDEN AND I HAVE TO SAY I WAS SURPRISED TO COME ACROSS THE STORY OF THE CRANIONASAL SYNDROME AND IF YOU HAVE DE NOVO MUTATIONS AND IF SOME OF OUR PATIENTS WITH DE NOVO MUTATIONS HAPPEN TO BE MOSAIC, WHETHER IT'S FOR THAT VARIANT OR MOSAICISM FOR OTHER VARIANTS AND IT'S SUPER TOUGH TO , COULD WE BE SETTING UP SCENARIOS WHERE THERE'S SOME ASPECT CAUSING A MORE SEVERE PHENOTYPE? THAT'S A BIG HYPOTHESIS. WE'D HAVE TO STUDY A LOT BUT I THINK IT WOULD BE REALLY INTERESTING TO LOOK AT THE NEW MUTATIONS IN INDIVIDUALS THAT WE HAVE AND TRY TO TRY TO UNDERSTAND WHERE THOSE INHERITED FROM A PARENTAL GERM LINE OR AT THE TIME OF CONCEPTION OR ACTUALLY POST-ZYGOTIC AND ARE WE SEQUENCING DEEPLY ENOUGH TO DETECT IT AND LOOKING AT THE RIGHT TISSUES TO DETECT THAT. IT'S NOT GOING TO BE EASY BUT TO ME IT MAY BE VERY COMPELLING TO LOOK AT. >> I'LL ADD TO THAT THAT YOU CAN THINK OF IT AS AN OPPORTUNITY. AND THERE'S A SIZABLE NUMBER OF PATIENTS WITH MUTATIONS ON THE SAME LOCUS. SOME DE NOVO, SOME INHERITED OR PROVEN INHERITED THAT COULD BE A POPULATION WHERE ONE CAN BEGIN STUDYING THAT PARTICULAR QUESTION. I DON'T KNOW WHICH ONE WOULD BE THE 409 OR THE ONES THAT ARE FREQUENTLY FOUND IN BOTH SETTINGS THAT MAYBE THAT POPULATION IS HOMOGENOUS ENOUGH IN TERMS OF THE MOLECULAR FINDINGS TO BE ABLE TO ASK THIS PRECISE QUESTIONS. >> I THINK GETTING TO THE QUESTION OF GENETIC MODIFIERS IS NOT JUST TO DETERMINE THAT FROM AN ETIOLOGY STANDPOINT AND THIS WILL BE A QUESTION FOR TOMORROW. I THINK THE WHOLE QUESTION OF GAIN OF FUNCTION VERSUS LOSS OF IS I THINK HOVERING OVER ALL THIS BECAUSE THE REAL IMPLICATION HERE IS WHAT'S THE MECHANISM AND HOW IT WILL BE TARGET FROM A THERAPEUTIC STANDPOINT. AND IF THERE'S A GENETIC MODIFYING GREAT IT MAY GIVE AN ADDITIONAL TARGET. IT'S VERY IMPORTANT TO THINK OF STUDYING THAT AND GOING GENOME SEQUENCING. WE HAVE DIFFERENT APPROACHES. I WANTED TO SAY THAT AND ALSO ASK A SIMPLE QUESTION OF THE PROGRAM FOR HEATHER, DO YOU EVER GO BACK AND TEST THE PARENTS AND DO YOU KNOW IF THESE ARE DE NOVO OR INHERITED AND IS THERE A MECHANISM WHERE THEY MAKE FAMILIES AWARE OF ONGOING RESEARCH? IS THIS A WAY A COMMUNITY CAN BE INFORMED OF ONGOING PROJECTS? >> ANY TIME A PATIENT IS IDENTIFIED TO HAVE A POSITIVE MOLECULAR FINDING OR DIAGNOSIS, WE OFFER NO CHARGE TESTING UP TO TWO FAMILY MEMBERS AND THE SAME COULD BE SAID FOR CERTAIN VARIANTS OF UNCERTAIN SIGNIFICANCE. LET'S SAY WE SEE A SINGLE VARIANT IN A CHILD AND IT VERY MUCH FITS THEIR PHENOTYPE WE CAN ACCEPT UP TO TWO BIOLOGICAL RELATIVES. THE BEST THING WOULD BE THE PARENTS BUT SOMETIMES THOSE AREN'T AVAILABLE. AND WE ARE ABLE USING OUR DATA TO BE ABLE TO CONFIRM MATERNITY AND PATERNITY SO WE'RE ABLE TO TELL THE SAMPLES ARE COMING FROM THE BIOLOGICAL PARENTS. IN TERMS OF RESEARCH OPPORTUNITIES AND THAT WITH PATIENTS WE HAVE A LOT OF RESEARCHERS WHO WILL CONTACT US AND THEY'RE INTERESTED IN SPECIFIC GENES OR COHORTS OF PATIENTS THAT WANT TO MAYBE REACH OUT TO THEIR ORDERING PROVIDERS TO PERFORM ADDITIONAL STUDIES OR INVITE THEM FOR SEARCH RESEARCH OPPORTUNITIES. THAT'S SOMETHING THAT OUR LABORATORY IS INTERESTED IN FACILITATING AND WOULD BE HAPPY TO DISCUSS FURTHER. >> THANK YOU. >> NEXT TO MICHELLE. >> THESE ARE GENETICALLY IT'S ALL REALLY IMPORTANT QUESTIONS WE'RE ASKING AND I'M WONDERING IF WE CAN TAKE LIKE STEP 1, STEP 2, STEP 3 APOACH -- APPROACH WHAT I HEARD FROM OUR WONDERFUL FAMILIES THEY GET THE DIAGNOSE AND DON'T GET THE OUTLOOK AND IT SOUNDS LIKE THEY'RE ALMOST WORRIED THEIR CHILD WOULD PASS AWAY ON THEM IS WHAT I TOOK FROM IT. DO YOU THINK WE HAVE ENOUGH PATIENTS TOGETHER TO GET THAT ANSWERED BECAUSE THAT'S POWERFUL IN ITSELF. ARE WE SEEING SLIGHT CHANGES FOR THESE PATIENTS IN THEIR FUNCTION DURING GROWTH? ARE WE SEEING TRUE DECLINE LATER IN LIFE AND THAT HAS A LOT OF POWER TO IT AND AT THE SAME TIME DEFINITELY WE NEED TO BE PULLING OUR GENETICS TOGETHER AND WORKING ON AND IT'S COMPLEX GENETICALLY WHEN YOU START THINKING OF IT WHICH ACTUALLY JENNIFER YOU BROUGHT UP WONDERFULLY AND WHY DO PATIENTS WITH THE SAME MUTATION AND LOOK DIFFERENTLY AND WHY DID MOM PRESENT SO LATE WHEN IT'S EXACTLY THE SAME MUTATION. THOSE ARE MY THOUGHTS AND MY HOPES TOGETHER WE CAN ALL WORK DEATH START ASKING WHAT IS THE NATURAL HISTORY AND WORK FURTHER TOGETHER. >> I SEE A QUESTION CAN THE PROTEOMICS WITH DE NOVO PATIENTS WITH INHERITED BE INSIGHTFUL TO LOOK AT THE GENETIC MODIFIERS? >> I THINK TRANSCRIPTOMICS AND LOOKING AT EXPRESSION AND PERHAPS AT THE EXPRESSION OF AND IF YOU CAN LINE UP A SET OF INDIVIDUALS WITH THE EXACT SAME VARIANT AND SEPARATE THEM BY DIFFERENCES IN THEIR PROTEOMIC AND OMIC PROFILES YOU CAN START TO ASK THE QUESTION WHAT'S DIFFERENT BETWEEN THE TWO WE'RE SEEING A CLEAR MOLECULAR SIGNATURE AND NOW LET'S ASK THE QUESTION WHAT'S DIFFERENT. THAT COULD BE POWERFUL. >> YOU SAY LOSS OF FUNCTION. AND THERE'S A CATEGORIZATION OF LOSS OF FUNCTION AND VARIANTS. CAN YOU CLARIFY HOW YOU USE THE TERMS? MY USE OF THE TERM WOULD BE MOST MUTATIONS AS LOSS OF FUNCTION. >> WE CAN'T DETERMINE WHETHER IT'S LEADING IT GAIN OF FUNCTION SO WE HAVE FUNCTIONAL STUDIES IN THE LITERATURE AND I CALL THEM VARIANTS AND TRY NOT TO INFER. THE MOLECULAR MECHANISM OF THE GENE IS LESS OF A FUNCTION THAN WE EXPECT LOSS OF FUNCTION BUT I THINK AS WE SEE WITH OTHER GENETIC DISORDERS THE MECHANISM OF DISEASE IS LOSS OF FUNCTION AND SEE A DIFFERENT PHENOTYPE WITH LOSS OF FUNCTION. I DON'T KNOW IF WE CAN REALLY SAY WHAT'S HAPPENING HERE RIGHT NOW. >> I WANT TO INTERJECT ONE AUDIENCE FROM THE ONLINE AUDIENCE AND THEN GO BACK TO THE CHAT. WE HAVE JOINING US A PEDIATRIC NEUROLOGIST AND SPECIALIZES AT MOVEMENT DISORDER AND HAS A STRONG INTEREST IN DYSTONIA AND CEREBRAL PALSY AND AS A PARENT OF A CHILD THAT WAS MISDIAGNOSED I ASK WE BE CAUTIOUS OF USING THE LABEL CEREBRAL PALSY AND A MAJOR AND WE FIRST HEARD OF HSP. THE IMPACT HAS BEEN PROFOUND. IT'S IMPERATIVE WE WORK WITH PROFESSIONALS AND FAMILIES AND I UNDERSTAND THIS CHANGE IN LABELLING IS IMPACTED BY THE FACT CEREBRAL PALSY IS LOOKED AT THE CAUSE OF CP. I WONDER IF YOU HAVE COMMENTS FOR THIS MOTHER. >> THANK YOU AND THANK YOU FOR HAVING ME TODAY. THE QUESTION'S AN IMPORTANT ONE DIFFERENTIATE IG DIFFERENTIATING I THINK DIFFERENT PEOPLE HAVE DIFFERENT DEFINITIONS. WHEN I THINK OF THIS WE THINK OF THIS AND THINK OF DISORDERS THAT MAY INITIALLY PRESENT WITH A NON PROGRESSIVE MOTOR DISABILITY THEN LATER MAY DECLARE ITSELF FOR A NEURO DEGENERATIVE DISORDER AND BY THE TIME YOU'RE 6 IT'S CLEAR IT'S A PROGRESSIVE DISORDER. THERE'S A CONCEPT OF HAVING A PROVISIONAL CP DIAGNOSIS THAT IS THEN CONFIRMED AS YOU AGE THEY'LL GIVE A DIAGNOSIS IN AGE 2 AND GIVE A DIFFERENT DIAGNOSIS AT AGE 5. THE EARLY DIAGNOSIS IS IMPORTANT. AND I THINK BEING AWARE OF WHAT THE MIMICS COULD BE AND WHICH MIM IBS REQUIRE EARLY IS CRITICAL. FOR THE EARLY DIAGNOSIS IN MANY PARTS OF THE WORLD ESPECIALLY IN THE U.S. IS ACCESS TO THERAPIES. ACCESS TO SERVICES. ACCESS PERIOD TO THINGS CHILDREN NEED TO SUCCEED BUT THINKING OF REVISITING THE DIAGNOSIS EARLY IN LIFE TO SEE IF PROGRESSION IS OCCURRING IS IMPORTANT. I'M NOT SURE WHAT THE SITUATION WAS WITH DONOVAN BUT WONDERING IF THAT HELPED CLARIFY THE DIFFERENCE FOR THE FAMILY. AND I THINK IT'S VALUABLE TO THINK ABOUT IT IN THE CONTEXT OF OTHERS IN A COMPARABLE WAY IN THE WAY WE LOOK AT EPILEPSY AND AUTISM WHERE WE CAN SAY SOMEONE HAS AND CARRY BOTH LABELS SIMULTANEOUSLY. AND I THINK THAT SHOULD ALSO BE TRUE FOR CP AND THEN WE CAN GET INTO THE DEBATE ARE THERE SOME TYPES THAT ARE SLOW PROGRESSING AND NOT AND FIT A PHENOTYPE AND HAVE MAYBE AN INFANTILE DIAGNOSIS AND CP DIAGNOSIS AT THE SAME TIME AND THAT'S NUANCED AND OPEN TO DEBATE AND IN THE EARLY YEARS IT SHOULDN'T BE A ONE AND DONE PHENOMENON AND SHOULD BE REASSESSED WITHIN THE FIRST YEARS OF LIFE. >> TO ADD TO THE BEAUTIFUL POINT, IT'S ONE THING WITH RESIDENTS I HARP ON ACTUALLY IS I SAY CP DUE TO WHAT? AND THE DEFINITION SAY MOVEMENT DISORDER EARLY ON AT BIRTH BUT DOESN'T TELL US THE ETIOLOGY AND IT'S SO IMPORTANT. I IT'S A HOT TOPIC AND WE NEED TO MOVE TOWARDS CP DUE TO WHAT AND IF WE DON'T KNOW THE WHAT YET WE NEED TO KEEP LOOKING. >> THIS IS KIM MOM OF OWEN. SHE HAS A QUESTION I'LL SAVE FOR TOMORROW AND ALSO SAID SHE LOVED SEEING THE VIDEOS OF THE CHILDREN YOU SHOWED. HER SON HAS A MORE SEVERE PHENOTYPE AND SOME OTHER PARENTS ALSO MENTIONED THAT WHAT SOME OF THE S WHO PRINTED WERE SLOWER PROGRESSION THAN SOME CHILDREN AND WONDERED WHY IS THAT. AND THEN THEY ALSO HOPED YOUR DAUGHTER FEELS BETTER SOON. >> WELL, THANK YOU, EVERYONE FOR THAT. I ALSO FOLLOW PATIENTS. WE DIDN'T HAVE THE LONG-TERM DATA ON THEM WHO PRESENT WITH A VERY COMPLEX FORM. WHERE YOU KNOW THEY DON'T REACH AMBULATION AND THEY DON'T REACH TYPICALLY THEY HAVE A LOT OF EPILEPSY ALONG WITH THAT AS WELL. AND I THINK THAT REALLY WAS -- I AGREE WITH YOU THE QUESTIONS I HAVE FOR OUR AMAZING GENETICISTS AND BENCH SIDE RESEARCHERS, WHY ARE WE SEEING MUTATIONS EVEN WITHIN THE SAME REGION OF THE GENE THE MAJORITY ARE WITHIN THAT TRIPLE A SET AND WHY WHERE HE GETTING SOME BEAUTIFUL CHILDREN WHO HAVE AND THE ONES I PRESENTED LONG-TERM DATA ON WHERE THEY PRESENTED IN INFANCY AS WELL AND THEY REACHED AMBULATION FOR SHORT DISTANCES AND THINGS LIKE THAT. HOPEFULLY I'LL HAVE SOME MORE WE'LL KEEP GATHERING TOGETHER THAT'S THE IMPORTANCE OF THESE MEETING TO SEE WHAT'S THE AND A HALF HISTORY FOR THE MORE SEVERE PHENOTYPES AND I HOPE YOUR CHILDREN ARE DOING WELL AS WELL. WE ALL WANT TO CARE FOR THEM DEEPLY. >> WE HAVE NON-MOTOR SYSTEMS WITH SPASTIC PARAPLEGIA AND TO THE EXTENT THEY'RE CAPTURED IN THE SCALES IT SEEMS PARTICULARLY IMPORTANT FOR THE PATIENTS DE NOVO SINCE THEY SEEM TO HAVE A PHENOTYPE THAT ENCOMPASSES OTHER DOMAINS BESIDES PLASTICITY. IF YOU CAN ANSWER THAT QUESTION. THANK YOU. >> AND I'LL SAY THE POINT IS WELL TAKEN I THINK THE SYMPTOMS OF THE SPECTRUM GOES BEYOND MOTOR DISABILITY AND SPACTICITY AND IT'S IMPORTANT TO RECOGNIZE. IT DOES MAKE THINGS MORE COMPLICATED WHEN WE THINK ABOUT OUTCOME MEASURES THAT ARE RELIABLE AND CHANGING IN A TIME FRAME THAT WOULD BE AMENABLE FOR USING THIS OUTCOME MEASURE IN THE CLINICAL AND INTERVENTIONAL TRIAL. IT'S DEFINITELY A CHALLENGE. THE WAY WE APPROACHED THIS IN OUR NATURAL HISTORY STUDY WAS ENROLLMENT AND IN DESIGNING THE FOLLOW-UP QUESTIONNAIRES AND THE FOLLOW-UP STUDY VISITS, WE INITIALLY TOOK THE APPROACH THAT WOULD BE ADAPTED TO MANY OF THE NON-MOTOR FEATURES. AND THAT PROVED TO BE COMPLICATED FOR PRACTICAL REASONS. SO WE HAVE NOW A ONE SIZE FITS ALL APPROACH FOR THE FOLLOW-UP QUESTIONNAIRE BUT WE DO PAY CLOSE ATTENTION TO NON-MOTOR FEATURES. IT'S A GENERAL PROBLEM AND MAY BE A SEGUE TO WHAT REBECCA CAN SPEAK ABOUT FOR THE SPASTIC PARAPLEGIA RATING SCALE. IT'S A CHALLENGE FOR US BECAUSE MANY ASSESSMENTS WE USE DEPEND ON THE LEVEL OF COGNITIVE ABILITIY IEY IES AND DEPEND ON THE ABILITY TO PARTICIPATE AND IN CHILDREN WITH DEVELOPMENT DELAYS. WE NEED TO ADAPT SOME OF THE TOOLS. I THINK WE NEED TO ADAPT THEM FURTHER FOR A SPECIFIC SCENARIO. I DO WANT TO SAY I THINK THE MOTOR OUTCOMES AS CLINICIANS AND RESEARCHERS ARE IMPORTANT BECAUSE WE CAN QUANTITATE THEM AND ASSESS THEM ON A CLINICAL BASIS EVERY DAY. I DO WANT TO EMPHASIZE THAT'S THE REASON WHY WE'RE CHOOSING THOSE AND PUTTING THOSE UP FRONT BUT WE RECOGNIZE THAT MANY CHILDREN WITH HEREDITARY SPASTIC DISPLAGIA MAY HAVE THIS. >> AND WHILE TALK ABOUT THE SITUATION IS CURRENTLY WHAT WE KNOW NOW AND WHAT SHOULD BE DONE. SO CURRENTLY I THINK WE'RE NOT CAPTURING THE SYMPTOMS ENOUGH. WHAT WE KNOW ABOUT THIS TYPE IS ERECTILE DYSFUNCTION AND BLADDER DISTURBANCES ARE QUITE COMMON. I HAVE LOOKED AT THE FIRST ANALYSIS OF A NEUROPSYCHOLOGY STUDY WHICH WAS COMPLETED WITH AN EXTENSIVE NEUROPSYCHOLOGY BATTERY IN SPG4 PATIENTS COMPARED TO CONTROLS WHERE WE SEE ACROSS THE BOARD ADULT PATIENT WITH SP4 ARE COGNITIVE DEFICITS IN MEMORY AND EXECUTIVE FUNCTION. IN THE WAY THEY CAN STILL FUNCTION BUT IT INTERFERES WITH FUNCTION AND ACTIVITIES AND FUNCTION. THAT'S WHAT WE KNOW NOW. WHAT WE HAVE TO FIND OUT I THINK IS WHAT THE RELEVANCE FOR DISEASE BURDEN IS OF THESE ADDITIONAL SYMPTOMS. SO WE HAVE TO FIND OUT THE SPECTRUM AND WHAT THE MEANINGFUL IS BECAUSE IF WE'RE TALKING ABOUT CLINICAL TRIALS DO WEE HAVE TO MAKE A GOOD DECISION WHAT THE SYMPTOMS ARE THAT AFFECT PATIENTS MOST. AND THIS IS WHY WE ARE CURRENTLY PUTTING SO MUCH EFFORT IN DEVELOPING THESE PATIENT-REPORTED PARAMETERS AND STARTING FROM SCRATCH FROM A CONCEPT OF DISABILITY AND ASK PATIENTS TO DO TWO LARGE SURVEYS IN SEVERAL LANGUAGES WITH A THOUSAND RESPONDENTS TO FIND OUT THE MOST RELEVANT SYMPTOMS AND SOMETHING WE'RE CURRENTLY ANALYZING. I THINK WE HAVE TO BE MORE CAREFUL TO HAVE A MORE COMPREHENSIVE VIEW NOT A MOTOR PREDOMINANT VIEW AND THIS IS THE MAIN WAY WE HAVE TO START WITH THE PATIENT VIEW AND THEN ADAPT OUR THINKING. BECAUSE WHAT WE THINK MIGHT BE THE MOST IMPORTANT FEATURE MAY BE ISN'T THE MOST IMPORTANT FEATURE AT ALL. BECAUSE THERE ARE MANY WAYS TO OVERCOME YOUR IMPAIRED MOBILITY. IT'S MUCH HARDER IF YOU'RE IMPAIRED LANGUAGE WISE AND YOUR COGNITION IS IMPAIRED TO FIND SOLUTIONS TO STILL PARTICIPATE. >> THANK YOU. >> I THINK KATHARINE ALTER HAD A QUESTION. >> HI, EVERYONE. I HAD A COMMENT AND A QUESTION. ONE IS I'LL GO WITH MY COMMENT FIRST. IF ALL THE WE'RE DOING IS FOCUSSING ON SPACTICITY WE'RE MISSING THE BOAT BECAUSE THE FUNCTION IS IMPAIRED MORE BY HYPERTONIA THAN SPACTICITY. ALL THE PATIENTS WHOSE VIDEOS WE SAW TODAY AND THE COHORT WE'VE SEEN AT NIH THE PREDOMINANT SYMPTOM WE SEE IS LOW MUSCLE TONE IN THE CORE MUSCLES AND AXIAL MUSCLES AND THOSE CHILDREN JUST LIKE WHAT YOU WANT TO CALL TYPICAL CP, AS THEY AGE THE IMPACT OF WEAKNESS HAS A BIGGER IMPACT ON FUNCTION OVER TIME BECAUSE YOUNG CHILDREN ARE ACTUALLY STRONGER THAN WHEN CHILDREN GET OLDER AND IT'S COUNTER INTUITIVE BUT YOU'RE STRONGER THAN 3 AND 4 THAN 13 AND 14. YOU CAN'T JUST MEASURE SPACTICITY. YOU HAVE TO MEASURE HYPERTONIA AND WEAKNESS WHICH WE AREN'T REALLY GOING. AND THE OTHER THING WITH SPACTICITY YOU HAVE TO MEASURE IT CORRECTLY AND MOST THE TIME WE AREN'T MEASURING IT CORRECTLY. THE QUESTION WAS FOR HEATHER WHICH WAS THE INVITAE AND THE GENE TEST. YOU'RE TESTING KIDS WHO PRESENT WITH A CP PHENOTYPE BUT NO KNOWN CAUSE OR RISK FACTORS FOR IT BUT ARE WE AGAIN MISSING SOMETHING HERE BECAUSE THEY'RE LIKELY GOING TO BE KIDS WHO HAVE THEY HAD PERINATAL ASPHYXIA OR PRE TERM AND HAVE PBL BUT HAVE SOME GENETIC CAUSE AS WELL AND THAT MAY INFLUENCE THE SEVERITY OF THEIR CONDITION OR THE LONG-TERM IMPACT. SO IF WE JUST KEEP SAYING AND I'VE HAD THIS HAPPEN THROUGH MY CAREER MULTIPLE TIMES WHERE A CHILD WAS DIAGNOSED WITH CP THEY WERE PRETERM AND HAD CRANIAL HEMORRHAGE WE ATTRIBUTED IT TO THIS AND THEN DIAGNOSED WITH SOMETHING ELSE AND YOU CAN HAVE BAD LUCK TWICE. SHOULD WE BE TESTING EVERY CHILD WITH CP? >> THAT'S A GREAT POINT AND MAYBE I DIDN'T DO A GREAT JOB EXPLAINING SO CERTAINLY THE PROGRAM ELIGIBILITY FOR THE PTC SPONSORED PROGRAM I DISCUSSED TODAY REQUIRES ABSENT OF RISK FACTORS FOR AN ACQUIRED BRAIN INJURY AND THERE'S OUTSIDE SPONSORED TESTING AS WELL SO PATIENTS WHO MAY NOT QUALIFY FOR THAT TESTING CAN STILL ORDER THE TESTING THROUGH THEIR INSURANCE OR PATIENT PAY OR THINGS LIKE THAT AS WELL AND I TOTALLY AGREE WITH YOUR POINT THAT SOMETHING THAT MIGHT SEEM LIKE A RISK FACTOR, I THINK THERE'S COMMON, LIKE YOU SAID, PREMATURE BIRTH AND OTHER FACTORS WE COMMONLY SEE. THANK YOU SO MUCH FOR YOUR COMMENTS. >> THIS IS A QUESTION FROM SOMEONE WHO HAS A DAUGHTER WITH COMPLICATED HSPA AND FOR THE REGISTRY, DO YOU HAVE PLANS TO RECRUIT MORE PATIENTS FROM OTHER POPULOUS COUNTRIES LIKE CHINA, INDIA AND INDONESIA, ETCETERA AND CAN RESEARCH IN THOSE COUNTRIES COLLABORATE FOR EARLY ONSET ESP TO GET THE MOST PATIENTS FOR THE ENDEAVORS. >> WE'D LIKE TO HAVE AS BROAD REPRESENTATION AS POSSIBLE AND CERTAINLY WOULD LOVE TO COLLABORATE WITH RESEARCHERS IN THE COUNTRIES. I THINK THAT BRINGS UP THE POINT OF COLLABORATION HOW IMPORTANT IT IS. WE AS A COMMUNITY WE HAVE TO GET TOGETHER AND BUILD THE BIGGEST NETWORK POSSIBLE TO ALLOW ACCESS IN DIVERSE REPRESENTATION FRANKLY BECAUSE ALL OF US WHO PRACTICE IN TERTIARY CARE MEDICAL CENTERS AND RESEARCH INSTITUTIONS THERE'S A BIAS HERE. I THINK THE PATIENTS THAT WE'RE SEEING ARE NOT NECESSARILY REPRESENTATIVE OF THE BROAD PROPOSITION. SO YES, ABSOLUTELY, WE WOULD LOVE TO COLLABORATE. WE HAVE CERTAINLY IN THE EARLY DAYS WE REACHED OUT AND ON A SCIENTIFIC LEVEL HAVE HAD A LOT OF COLLABORATIONS BUT I THINK WE NEED TO FORMALIZE THAT AND THIS IS EXACTLY WHAT WE'RE HOPING TO DO. >> THERE IS A QUESTION FROM DR. CHANG. HE HOPE TO HAVE HIM SPEAK AT A FUTURE CONFERENCE AND WORKS IN THE FIELD AND HAD A QUESTION FOR ANYBODY IN THE PANEL. CONSIDERING THE VAST HETERO HETEROGENEITY WOULD YOU PREDICT THERE'S A DOSE DEPENDENT MECHANISM BEHIND THE ETIOLOGY OF THE DISEASE? >> MAYBE I'LL PROVIDE A QUICK ANSWER. WE DON'T STUDY SPAST IN THE LAB SO I HAVE NO TRUE MOLECULAR INSIGHTS INTO THIS BUT YOU ARE RIGHT. YOU BRING UP I THINK THE QUESTION -- THE HE WILL -- ELEPHANT IF THE ROOM IS THIS GAIN OF FUNCTION AND WE CAN SPECULATE ABOUT THE MUTATIONS A LOT BUT THE ONLY WAY TO REALLY GET TO THIS IS TO TEST EXPERIMENTALLY. AND THE HYPOTHESIS YOU'RE PROPOSING IS CERTAINLY POSSIBLE BUT TO MY KNOWLEDGE AND AGAIN I'M NOT IN THE FIELD AND FROM A MOLECULAR STANDPOINT I DON'T KNOW IF ANY CONVINCING STUDIES HAVE SHOWN A DOSE-DEPENDENT EFFECT. >> THE ONLY GENE DOSAGE STUDIES REALLY RELATE TO THE RECURRENT DELETIONS WHERE YOU DO PREDICT YOU HAVE FULL LOSS OF FUNCTION OF ONE OF THE TWO COPIES THOUGH I DON'T KNOW WHETHER SOMEONE LOOKED AT GENE EXPRESSION DISEASE REDUCED BY HALF BUT I AGREE THERE COULD EASILY BE LOSS FUNCTION AND GAIN OF FUNCTION OR EVEN DOMINANT/NEGATIVE AND SOME VARIANTS WE'RE LOOKING AT RIGHT NOW MIGHT FALL INTO DIFFERENT FUNCTIONAL IMPACTS AND THAT MIGHT LEAD TO SOME VERY NUANCED PHENOTYPIC DIFFERENCES. IT MOST DEFINITELY WARRANTS FURTHER STUDY. >> I MISSED A QUESTION IN THE CHAT. PETER, WOULD YOU LIKE TO UNMUTE OR WOULD YOU LIKE ME TO READ YOU'RE QUESTION. >> I CAN READ IT IF I CAN FIND IT. >> I'LL READ IT FOR YOU. FOR DARIUS, DO ALL THE PATHOGENIC MUTATIONS IN THE TRIPLE A DOMAIN ABOLISH THE ENZYME FUNCTION? >> THE SHORT ANSWER IS WE DON'T KNOW. WE HAVEN'T DONE ANY EXPERIMENTAL TESTING OF THESE VARIANTS TO REALLY KNOW IF IT'S ABOLISHING THE TRIPLE A DOMAINS FUNCTION. I THINK THAT'S ALL I CAN SAY. THAT'S EXACTLY THE QUESTION I THINK WE NEED TO ANSWER. >> AND THE SECOND QUESTION IS FOR REBECCA. DO YOU EVER SEE PATIENTS WITH A COMPLETE ARE SPAST GENE DELETION AND WHAT ARE THEIR SYMPTOMS LIKE COMPARED TO TRUNCATING MUTATIONS. >> WE ALREADY DISCUSSED THIS OVER THE CHAT. I'LL NEED TO CHECK MY DATABASE BUT THIS IS AN EXCELLENT QUESTION FROM PETER BECAUSE THIS WILL HELP US FIGURE OUT EXACTLY THE GAIN OF FUNCTION, LOSS OF FUNCTION MECHANISM AND SEE WHETHER A COMPLETE LOSS OF FUNCTION BY LOSS OF THE WHOLE GENE CAUSES A SIMILAR PHENOTYPE THAN THE OTHER MORE REGULAR SPAST MUTATIONS WE SEE SO I'LL FOLLOW-UP ON THAT. >> AND THE LAST QUESTION FROM PETER, ARE THERE ANY PEOPLE IN FAMILIES WITH A GENE MUTATION THAT LIVE INTO OLD AGE WITH NO SYMPTOMS WHATSOEVER? >> DO YOU MEAN REGULAR RUN OF THE MILL SPG4 MUTATIONS OR WHOLE GENE DELETIONS? >> RUN OF THE MILL. >> WE SEE THAT. SO WE COMMONLY HAVE -- NO, NOT COMMONLY BUT WE HAVE A FEW PERCENT IN THE SINGLE DIGITS OF PARENTS WHERE WE FIND THE MUTATION THAT'S VERY SUBTLE OR NO CLINICAL SIGNS OF THE DISEASE. IT'S NOT COMMON. IT HAPPENS. I CAN'T SEE A PATTERN WHERE IT WOULD HAPPEN MORE OFTEN. >> I HAD A QUESTION FOR REBECCA. I WAS ACTUALLY REALLY INTERESTED IN YOUR DATA ON PROGRESSION AND HOW THE PEOPLE THAT HAD LATER ONSET DISEASE SEEMED TO HAVE A FASTER PROGRESSION AND I WONDER IF YOU HAVE AN EXPLANATION OR HYPOTHESIS TO ACCOUNT FOR IT. >> I DON'T HAVE AN ANSWER. I CAN JUST SHARE MY BOX ON THIS AND I SEE BASICALLY TWO POSSIBLE EXPLANATIONS. ONE WOULD BE AN EXPLANATION THAT HAS NOTHING TO DO WITH THE DISEASE ITSELF AND MORE A FUNCTIONAL EXPLANATION. AND IT MIGHT CONTRIBUTE. IF YOU HAVE EARLIER ONSET MOTOR DYSFUNCTION THE COMPENSATORY MECHANISMS ARE MORE ABLE TO COMPENSATE THAT. WE SEE THAT IN CEREBRAL PALSY CHILDREN FOR EXAMPLE. WE HAVE A STATIC NEUROLOGICAL INJURY AND WHEN THE PATIENTS AGE WE SEE THAT MULTI-DETERIORATION AND THE COMPENSATION STRATEGIES OF SOMEONE OLDER AND MOTOR DYSFUNCTION WOULD BE A MORE GENERAL EXPLANATION. WHAT SPEAKS AGAINST THAT IS IN OTHER NEUROLOGICAL DISEASES IT'S THE OTHER WAY AROUND, EARLY ONSET IS SEVERE AND LATE ONSET IS MILDER DISEASE. SO IT ARGUES AGAINST IT. THE OTHER EXPLANATION IS IT HAS SOMETHING TO DO WITH DISEASE ITSELF. BUT WHAT IT IS I'M AFRAID I DON'T KNOW. IT WOULD BE REALLY INTERESTING TO FIND OUT. IF ANYBODY ELSE HAS BETTER IDEAS THAN I HAVE FOR THE QUESTION I'D BE INTERESTED TO HEAR. >> THE LAST QUESTION IN THE CHAT FROM MIGUEL, ACCORDING TO G TEX IT APPEARS X ON 4 IS SPLICED BETWEEN THE GENOFORM HAS ANYONE LOOK AT ISO FORM EXPRESSION LEVELS? >> I HAVE A PARTIAL COMMENT. WE HAVE CHECKED THE EXPRESSION LEVELS. I CAN COMMENT HOWEVER THAT THERE ARE NO DISEASE CAUSING MUTATIONS KNOWN LOCATED IN EXOME 4 AND THE OTHER THING WE HAVE DONE IS WE TRIED TO DONE ISOFORM SPECIFIC ANALYSIS. WE TRIED TO FIND OUT WHETHER THERE'S INTERACTIONS WHERE IT'S MEDIATED SOMEHOW BY THE PIECE OF SEQUENCE ENCODED BY EXON 4 BUT IT DOESN'T SEEM TO BE THE CASE. THESE ARE THE TWO PIECES OF INFORMATION I CAN OFFER BUT IT DOESN'T EXACTLY ANSWER THE QUESTION. >> IS THERE DIFFERENTIAL ALLELIC USE? >> NOT THAT I KNOW OF. JENNIFER, MAYBE YOU KNOW MORE. >> FOR THIS LOCUS NOT THAT I'M AWARE OF BUT I THINK IT'S DEFINITELY WORTH DIGGING BACK INTO AND INVESTIGATE. I KNOW IN OUR RARE DISEASE COHORT WE HAVE PREVIOUSLY STUDIED CASES MOST WITH DELETIONS IN THE REGION BECAUSE THEY WERE ASCERTAINED BY CLINICAL ARRAY BUT IT WOULD BE INTERESTING TO GO BACK AND LOOK AT SOME OF THOSE INDIVIDUALS AND TRY TO GET A SENSE FOR WHETHER THAT COULD BE THE CASE. >> THANK YOU EVERYBODY. WE'RE AT THE 2:00 HOUR. THANKS SO MUCH FOR A WONDERFUL DISCUSSION AND Q&A SESSION AND WE THANK EVERYBODY FOR PARTICIPATING AND WE LOOK FORWARD TO SEEING YOU TOMORROW SO WE'LL MEET AGAIN TOMORROW AT THE SAME TIME, 10:00 A.M. EASTERN STANDARD TIME TO 2:00 P.M. AND TOMORROW WE HAVE TWO SYMPOSIUMS. THE FIRST ON TRANSLATION YAL RESEARCH AND THE SECOND WILL BE ON THERAPEUTICS. WE HOPE TO BUILD UPON WHAT WAS DISCUSSED TODAY AND WE THANK EVERYBODY SO MUCH FOR THEIR TIME AN EXPERTISE. WE'LL SEE YOU ALL TOMORROW. THANK YOU SO MUCH.