>> 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-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.