>> HELLO AND WELCOME TO THIS

SESSION OF DEMYSTIFYING

MEDICINE.

THOSE OF YOU WHO ARE ASTUTE

REALIZE I'M NOT WIN ARIAS --
THOSE ARE BIG

SHOES TO FILL BUT I'VE HAD TO

FILL THEM ALMOST EVERY YEAR

WE'VE RUN THIS COURSE.

I WAS INVOLVED IN BRINGING WIN

ORIGINALLY TUESDAY NIGHTS TO RUN

THIS COURSE.

AS PAY BACK, HE'S ASKED ME TO BE

COMMUNICATOR AND FILL IN FOR HIM

HAD WHEN HE WASN'T AVAILABLE.

TODAY'S A PARTICULAR PLEASURE TO

TALK ABOUT SOMETHING THAT WE'RE

ALL I THINK ACUTELY AWARE OF DUE

TO IN PART THE POPULAR PRESS.

IF I COULD HAVE THE FIRST SLIDE.

SO THE TOPIC WE'LL BE DISCUSSING

TODAY IS STUTTERING.

AND I DON'T KNOW HOW MANY OF YOU

CAN SEE OR RECOGNIZE THE IMAGE

AT THE TOP IN SPEECH.

HOW MANY PEOPLE SAW IT?

OKAY, BEAUTIFUL.

IT WAS ONE OF THE BEST MOVIES OF

THE YEAR IN MY OPINION.

WE'VE LISTED HERE WITH THE HELP

OF WOMEN, WE'VE ASSEMBLED SOME

FAMOUS STUTTERERS.

OF YOU KNOW SOME OF THE MORE

INSTRUMENTAL IN CREATING TOUCH

THING AS THE TEN COMMANDMENTS.

KING GEORGE V WHO OF COURSE WAS

FEATURED IN THE FILM, AND ONE

THAT I WAS UNAWARE OF, ACTUALLY,

WAS LEWIS CARROLL.

BECAUSE HIS PROSE IS SO ES

QUISITE AND YOU WONDER WHAT THE

CONNECTION MIGHT BE THERE.

SO TODAY WE'RE REALLY HONORED TO

HAVE THREE COLLEAGUES WHO ARE

GOING TO DO THE PRESENTATIONS

TODAY.

THE FORMAT IS GOING TO BE VERY

INTERESTING BECAE WE WILL NOT

HAVE A BREAK BUT WE'RE GOING TO

KEEP THIS FAIRLY BRIEF.

THE DISCUSSION WILL BE SHARED

AMONG THE THREE AND THE

QUESTIONS CAN BE DIRECTED TOWARD

THE THREE.

AND OUR SPEAKERS TODAY WILL BE

DENNIS DRAYNA AND PENNY FRIEDMAN

FROM THE CLINICAL CENTER, AND

DONNA KRASNEWHICH.

DRAYNA IS FROM THE UNIVERSITY OF

WISCONSIN AND PH.D. FROM HARVARD

IN 1981.

HE'S CURRENTLY THE SENIOR

INVESTIGATOR AT THE NATIONAL

INSTITUTE OF DEAFNESS AND OTHER

COMMUNICATIVE DISORDERS AND HE

PURSUED THE GENETIC OF

COMMUNICATION DISORDERS WITH AN

EMFUTSEMPHASIS ON STUTTERING.

PENNY IS FROM THE OFFICE OF THE

DIRECTOR FOR FACILITATING -- AND

I THINK WE OWE A DEBT OF

GRATITUDE IN HOPING BRING THESE

TOGETHER AND I THINK YOU'LL SEE

WHAT I MEAN IN A FEW MOMENTS.

AND THEN FINALLY DONNA

KRASNEWHICH IS GOING TO BE

TALKING ABOUT SOME OF THE

MOLECULAR DETAILS OF WHAT WE

KNOW ABOUT THE GENE THAT WE'LL

BE DISCUSSING.

AND DONNA JOINS THE GENERAL

MEDICAL SCIENCE AT NIGNS IN 19,

IN 2009 AFTER SPENDING A CAREER

IN HUMAN JA GENETICS.

SHE IS THE CLINICAL GENETICIST

AND HELD SEVERAL INTRAMURAL

POSITIONS MOST OF WHICH I

REMEMBER, INCLUDING FACULTY AT

THE WESTERN DMPLEGHTS C.

METROPOLITAN AREA GENETICISTS.

M GOING TO BEGIN THE

DISCUSSION AND INVIT I GUESS

WE'RE GOING TO BEGIN FIRST WITH

DENNIS.

>> THANK YOU VERY MUCH FOR THAT

VERY NICE INTRODUCTION.

IT'S INDEED A GREAT PLEASURE TO

PARTICIPATE AS PART OF THE TEAM

THAT HAS ACTUALLY DONE SOME, I

THINK, VERY FUNDAMENTAL WORK IN

UNDERSTANDING STUTTERING.

SO IF I COULD JUST ... SO THE

SUBJECT OF THE DISCUSSION TODAY

IS STUTTERING WHICH I AM GOING

TO DEFINE AS A DISORDER

AFFECTING THE FLOW OF SPEECH

CHARACTERIZED BY UNCONTROLLABLE

REPETITIONS OR PROLONGATNS OF

WORDS OR SYLLABLES OR BY SILENT

SPRUPPIONINTERRUPTIONS OF SPEECH
KNOWN AS

BLOCKS.

THIS IS THE NATURAL HISTORY OF

THE DISORDER IS THAT IT IS

COMMON.

IT TYPICALLY ARISES IN YOUNG

CHILDREN.

IT'S CONSIDERED A DEVELOPMENTAL

DISORDER.

THE ONSET TYPICALLY OCCURS JUST

AFTER CHILDREN LEARN HOW TO

SPEAK.

SO TYPICALLY AGE THREE TO FOUR.

AND HE DISORDER'S COMMON IN

THIS GROUP.

IT AFFECTS UP TO 5% OF CHILDREN.

NOW THE GOOD NEWS ABOUT THIS

DISORDER IS THAT IT FREQUENTLY

RESOLVES EITHER WITH THE HELP OF

SPEECH THERAPY OR SPONTANEOUSLY.

SO THREE QUARTERS OR FOUR FIFTHS

OF THESE CASES RESOLVE.

NOW, HOWEVER FEMALES TEND TO

RECOVER MORE FREQUENTLY THAN

MALES DO AND THAT RESULTS IN,

AMONG THE INDIVIDUALS WHO FAIL

TO RECOVER FROM THE DISORDER,

RESULTS IN A SKEWED SEX RATIO OF

THE AFFECTED INDIVIDUAL.

OWTYPICALLY IT HAS A RATIO OF

PERSISTENT STUTTERING IN THE

GENERAL POPULATION OF FOUR TO

ONE, SOMETHING LIKE THAT.

AND AN OVERALL POPULATION

PREVALENCE RATE OF ABOUT 1%.

NOW I SHOULD SAY THAT THAT 1%

NUMBER IS PRETTY INCLUSIVE

DEFINITION OF THE DISORDER.

AND IF YOU DON'T HAVE TRAINING

IN SPEECH LANGUAGE PATHOLOGY,

SOME OF THOSE PEOPLE YOU MIGHT

NOT RECOGNIZE.

SOME PEOPLE WHO HAVE HAD SPEECH

THERAPY AND ARE GOOD AT DEALING

WITH THEIR STUTTERING, ARE LEFT

WITH VERY SMALL RESIDUAL

PATHOLOGIES IN THEIR SPEECH THAT

MIGHT NOT NOTICE.

BUT CERTAINLY THIS GENERAL RANGE

OF FRANK STUTTERING OF THE

POPULATION IS A REASONABLE

ESTIMATE.

THE DISORDER OCCURS IN ALL

POPULATIONS AND ALL LANGUAGE

GROUPS.

IMPORTANTLY, WHICH I'LL PROBABLY

DISCUSS MORE AS WE GO ON, THE

SEVERITY OF THE DISORDER

AFFECTED BY OTHER FACTORS,

INCLUDING ANXIETY AND FATIGUE.

SO IF YOU HAVE AN INDIVIDUAL WHO

IS A VERY MILD STUTTERER, AN

ALMOST GUARANTEED WAY TO MAKE

THEM A SEVERE STUTTERER IS TO

PUT THEM UNDER SOME SORT OF

STRESSFUL SITUATION.

OKAY.

SO THE CAUSES OF THIS DISORDER

ARE NOT KNOWN.

ALTHOUGH A REMARKABLE VARIETY

HAVE BEEN SUGGESTED OVER THE

YEARS.

THE ONLY CONTRIBUTING CAUSE OF

THIS DISORDER WAS CONSISTENTLY

IDENTIFIED MORE GENETIC FACTORS.

AND THE EVIDENCE FOR THIS CAME

FROM SEVERAL DIFFERENT TYPES OF

STUDIES.

THERE HAVE NOW BEEN A TOTAL OF

SIX TWIN STUDIES OF STUTTERING

THAT HAVE BEEN PUBLISHED.

TWIN STUDIES ARE USED TO MEASURE

INHERITABILITY.

INHERITABILITY IS HOW MUCH OF

THE DISORDER IS INHERITED

FACTORS VERSUS HOW MUCH IS DUE

TO THE ENVIRONMENT, EITHER

SHARED ENVIRONMENT, THINGS LIKE

WHAT YOU EAT, WHERE YOU LIVE.

AND INHERITABILITY FROM THESE

TWIN STUDIES HAVE ESTIMATES ARE

BETWEEN 50 AND 80%.

IN OTHER WORDS, 50 TO 80% OF THE

RELIABILITY FOR THIS DISORDER

THEY WOULD SAY CAN BE ATTRIBUTED

TO GENES.

SO IT'S RELATIVELY STRONGLY

GENETIC IN NATURE.

THERE'S ANOTHER KIND OF STUDY

THAT WAS ADOPTION STUDIES THIS

OFTEN USED TO STUDY W MUCH IS

GENETIC OR ENVIRONMENTAL.

THERE ARE TWO STUDIES THAT ARE

PUBLISHED NEITHER OF THEM ARE

BIG ENOUGH TO COME TO STRONGLY

STATISTICALLY SIGNIFICANT

CONCLUSIONS.

BUT ONE STUDY DID HAVE QUITE THE

EVIDENCE OF THE FOLLOWING.

IT SHOWED THAT CHILDREN WHO ARE

ADOPTED BY STUTTERING PARENTS,

SO THESE ARE NOT THE BIOLOGICAL

CHILDREN OF THOSE PARENTS.

ADOPTED CHILDREN OF STUTTERING

PARENTS STUTTER AT A RATE NO

GREATER THAN THE GENERAL

POPULATION.

SO IT'S NOT THAT YOU LEARN TO

STUTTER BY LISTENING TO

STUTTERING PARENTS.

THERE DIDN'T SEEM TO BE EVIDENCE

OF THAT.

THERE ARE LOTS OF FAMILY

CLUSTERS IDENTIFIED WITH THIS

DISORDER.

MANY SMALL FAMILIES AND VERY

LARGE FAMILIES.

SOME OF THESE FAMILIES HAVE

AFFECTED MEMBERS WHO WERE RAISED

IN DIFFERENT STATES, OKAY.

AND DIDN'T INTERACT WITH OTHER

BRANCHES OF THE FAMILY.

AND IT'S VERY HARD TO ATTRIBUTE

THAT TO A CULTURAL OR AN

ENVIRONMENTAL ORIGIN FOR

DISORDER.

AND FINALLY STUDIES OF

SEGREGATION ANALYSIS, SO

SEGREGATION ANALYSIS IS AN

EXERCISE WHERE YOU ACCUMULATE

LATE A NUMBER OF PEOPLE WHO HAVE

GENETIC DISORDER.

YOU ASK DOES THIS ORDER IN THIS

COLLECTION OF FAMILY BEHAVE

ACCORDING TO SIMPLE RULES OF

INHAIRNLTS.

INHERITANCE.

LIKE THE RULE OF DISORDER -- THE

ANALYSIS OF STUTTERING HAVE NOT

COME TO ANY GENERAL CONCLUSION.

SO THE ONLY THING WE CAN SALES

THAT THE DISORDER FAIRLY

CLUSTERS IN FAMILIES BUT IT DOES

NOT PLAY A SIMPLE INHERITANCE

PATTERN LIKE WE WOULD EXPECT

FROM SOMETHING LIKE CYSTIC

FIBROSIS OR HEMOPHILIA, OKAY.

IF THERE'S STRONG EVIDENCE FOR

GENETIC ORIGINS TO A DISORDER,

THAT'S GOOD NEWS.

BECAUSE THAT MEANS THOSE OF US

WHO SPEND OUR TIMES DOING HUMAN

GENETICS HAVE AN AFFIDAVIT TO

THOSE UNDERLYING CAUSES OF

GENETICKIC FACTORS.

ONE WAS CALLED THE LINKAGE

STUDIES AND WHAT THESE STUDIES

DO IS IDENTIFY THE LOCATION OF

THE LOCATION OF A GENE THAT

CAUSES A DISORDER LIKE THESE

STUDIES ARE DONE IN FAMILIES.

WHAT THESE STUDIES INVOLVE IS

GENETIC MARKERS AERS AT KNOWN

LOCATIONS FOR COINHERITANCE

DISORDER.

NOW THE OBSERVATION OF

COINHERITANCE WHICH IS KNOWN AS

LINK-IT TELLS US THAT THE

CAUSATIVE THEME IS MORE THAT

MARKER.

THE REASON LINKAGE OCCURS IS

BECAUSE TWO CREATES ON A

CHROMOSOME ARE SO CLOALTS --
CLOSE

TOGETHER THAT -- THAT ALL GENES

UNDERGO AS THEY ARE PASSED FROM

PARENT TO OFFSPRING, ALL RIGHT.

SO THE FACT WHEN WE START WITH A

KNOWN LOCATION -- THEN THE

PROBLEM IS TO FIND THAT GENE,

OKAY.

SO I SHOULD TELL YOU THERE HAVE

BEEN A NUMBER OF LINKAGE STUDIES

OF STUTTERING WITH ALL OF THE

EVIDENCE.

PEOPLE WERE WILLING TO THIGH

LINKAGE DESPITE OF THE FACT THE

ANALYSIS -- IN SPITE OF THE FACT

IT DOESN'T SEEM TO SHOW CLEAR

SIMPLE PATTERNS OF INHERITANCE

IN FAMILIES, PEOPLE WERE STILL

TRYING LEEPGAGE.

THE SHORT APPEARS IS NOT VERY

SIMPLE.

I'M GOING TO TURN EVERYBODY INTO

A HUMAN GENETIC.

THE AFFECTED INDIVIDUALS ARE

FILLED IN AND THE UNAFFECTED

INDIVIDUALS ARE NOT FILLED IN.

SO BROTHERS AND SISTERS, SO THIS

IS FOR INSTANCE A FATHER AND A

MOTHER, AND THEY HAVE FIVE SONS,

RIGHT, FIVE AFFECTED BOYS.

THIS IS THE ELDEST THIS IS THE

YOUNGEST.

THESE ARE DOUBLE LINES

CONNECTING PARENTS.

THESE DOUBLE LINES MEANS THAT

THE FATHER AND THE MOTHER ARE

RELATED TO EACH OTHER.

SO TO GIVE YOU AN IDEA OF HOW

RELATED THEY CAN BE IN THIS

PARTICULAR FAMILY, THERE ARE TWO

BROTHERS AND A SISTER WHO

MARRIED TWO SISTERS AND A

BROTHER THAT ARE ALL THE YEAH

SPRING OF THEIR -- OFFSPRING OF

THEIR FIRST COUSIN.

THESE PATTERNS IN PAKISTAN HAVE

PERSISTED FOR A LONG TIME, AT

LEAST A THOUSAND YEARS.

AND SO THERE ARE CASES WHERE

PEOPLE ARE RELATED TO THEIR

SPOUSE, LIKE HERE'S A CASE WHERE

WE KNOW THIS WOMAN IS RELATED TO

THIS MAN.

WE JUST CAN'T TRACE BACK HOW.

BECAUSE THIS PART OF THE

PEDIGREE IS LOST TO US WITH NO

WRITTEN RECORDS.

OKAY.

SO THERE'S A GRADE GREAT DEAL OF

INTERMARRIAGE.

AND AS EVERYONE I THINK MAY BE

GENERALLY FAMILIAR WITH, THESE

SORTS OF FAMILIES TEND TO BRING

OUT GENETIC DISORDERS, OKAY.

THEY ARE TYPICALLY USED FOR A

TYPE OF DISORDER CALLED A RECESS

I GENETIC DISORDERS WHERE

CARRIES COPY ONE SET OF THE

GENES BUT HAVE NO SYMPTOMS

THEMSELVES.

ONLY WHEN TWO CARRIERS MARRY

EACH OTHER THEIR CHILDREN

UNLUCKILY WILL GET THE BAD

VURLINGS FROM VERSION FROM THEIR
FATHER AN
D

BAD CHROMOSOME FROM THEIR MOTHER

THEY HAVE NO GOOD COMPETENT OF

THE GENE AND THEY GET THE

DISEASE.

AS YOU CAN IMAGE SUCH INBRED OR

CONSANG WASNESS FAMILIES ARE

COMMON FOR THOSE TYPES OF

DISORDERS.

THEY WOULD BE GOOD FOR

DISOFERREDZ LIKE STUTTERING.

THEY DON'T SHOW A CLEAR PATTERN

OF INHERITANCE BUT IN FACT MIGHT

HAVE SOMEWHAT WE CALLED ADDITIVE

EFFECTS.

SO IF YOU HAVE ONE COPY OF A

STUTTERING GENE YOU MIGHT HAVE

SOME INCREASED RISK OF

STUTTERING.

AND IF YOU HAVE TWO COPIES, YOU

HAVE AN EVEN HIGHER INCREASED

RISK, OKAY.

AND SO IN FACT, A LINKAGE STUDY

IN A GROUP OF PAKISTANI

FAMILIES, THIS BEING THE LARGEST

OF THAT GROUP, PRODUCED VERY

STRIKING AND LARGE STATISTICALLY

SIGNIFICANT EVIDENCE TO LINKAGE

ON THE LONE AR LONG ARM OF
CHROMOSOME

12.

THE GOAL THEN BEGAN TO FIND THE

GENE OF CHROMOSOME 12 THAT WAS

POSITIVE OF THIS AND OTHER

PAKISTANI FAMILIES.

AND THAT WE WERE ABLE TO DO IN A

LARGE STUDY THAT ULTIMATELY

INVOLVED MANY PEOPLE AND WAS

PUBLISHED HERE IN THE NEW

ENGLAND JOURNAL OF MEDICINE.

AND YOU'LL NOTE MY COPRESENTERS

TODAY, DOCTORS KRASNEWHICH AND

FRIEDMAN ARE AUTHORS ON THIS

PAPER.

WHAT WE FOUND ARE MUTATIONS IN

THE GENE ON CHROMOSOME 12 CALLED

GMPTAB.

AND I'M NOT GOING TO BORE YOU

WITH WHAT THAT ALL STANDS FOR.

WE FOUND THAT MUTATION THAT, IN

THIS VERY LARGE PAKISTANI

FAMILY.

THERE'S A MUTATION, A PARTICULAR

MUTATION AT AMINO ACID POSITION

1200 IN THE PROTEIN ENCODE BY

THIS GENE.

WE FOUND THAT SAME MUTATION IN A

TOTAL OF FOUR APPARENTLY

UNRELATED PAKISTANI STUTTERING

FAMILIES I AND THE AFFECTED

MEMBERS OF THOSE FAMILIES.

WE ALSO FOUND OTHER MUTATIONS IN

OTHER STUTTERING FAMIES IN

THAT GENE.

SO WE SUBSEQUENTLY IDENTIFIED

ADDITIONAL MUTATIONS.

NOW, THIS GENE IT TURNS OUT

PARTICIPATE IN A BIOCHEMICAL

PATHWAY.

THIS GENE ENCODES PART OF AN

ENZYME.

THE OTHER PAR I PART IS ENCODED
BY A

GENE CALLED -- AND THE NEXT STEP

IS ENCODED BY A GENE CALLED

NIGPA.

WE BEGAN LOOKING AT THESE GENES

AND BEGAN TO FIND MUTATIONS IN

PEOPLE WHO STUTTER AND NO

MUTATIONS IN PEOPLE'S GENES WHO

DO NOT TUTOR.

WHAT DO THEY ENCODE?

THEY ENCODE SOMETHING CALLED THE

LYSOSOMAL TARGETING PATHWAY.

THOSE HOW FAR US INVOLVED IN

HUMAN GENETICS FOR A LONG TIME

KNOW THAT ONE OF THE MOST

REMARKABLE FEATURES OF THIS

LINKAGE-BASED APPROACH, THIS

SO-CALLED POSITIONAL APPROACH TO

FINDING DISEASE GENES YOU'RE

LOOKING FOR A GENE BASED ON ITS

POSITION AT A PARTICULAR

CHROMOSOME.

YOU GET SURPRISED, A LARGE

AMOUNT OF THE TIME.

IT'S VERY RARELY, IS THE

CAUSATIVE GENE SOMETHING YOU

WOULD HAVE SUSPECTED.

AND IN FACT, THIS IS CERTAINLY

THE CASE WHEN WE STUMBLED INTO

THIS PATHWAY.

BECAUSE MUTATIONS IN THIS

PATHWAY IN FACT HAD BEEN

PREVIOUSLY KNOWN.

AND THEY ARE PREVIOUSLY

ASSOCIATED WITH TWO DISEASES

KNOWN AS MUCO LIP DOSES TYPE TWO

AND THREE.

I THINK WITH THAT -- OH, I

SHOULD SAY, THE SECOND STEP IN

THIS IS AN ENSIEMED CALLED

NAGPA.

NO HUMAN HAS EVER BEEN

ASSOCIATED WITH MU TITIO
MUTATION IN THIS

GENE.

THAT'S A LITTLE BIT OF A

SURPRISE BECAUSE MUTATIONS IN

THIS GENE MIGHT EXPECTED TO

RESULT IN THOSE IN NEW

CO-LIPDOSES TWO AND THREE.

SO I BELIEVE, YES THERE'S STRONG

EVIDENCE THAT LINKS IN THESE

THREE GENES WITH STUTTERING.

IT'S A RARE INHERITED RECESSIVE

DISORDERS IN CHILDREN KNOWN TO

BE CAUSED BY MUTATIONS IN SOME

THESE GENES.

HOW DO WE RECONCILE THESE

FINDINGS?

SO, THAT WAS DONE BY MY

COPRESENTERS TODAY SO IT'S A

PLEASURE TO HAND THIS OFF TO

DR. DONNA KRASNEWHICH.

>> GOOD AFTERNOON.

AS DENNIS SAID, DENNIS HAS

ACTUALLY LINKED THIS GENE RIGHT

HERE TO STUTTERING.

AND WE ALSO KNEW HISTORICALLY

THAT THESE GENES WERE INVOLVED

IN THE BASIS OF RARE CHILDHOOD

GENETIC DISORDERS, RECESSIVE

DISORDERS.

AND SO THE CONUNDRUM WAS HOW  

DO YOU RESOLVE THESE TWO

PROBLEMS.

SO I THINK THAT THE ANSWER TO

THIS IS ACTUALLY TO UNDERSTAND

THIS YOU ACTUALLY HAVE TO ANY

ABOUT THESE GENES AND THE

PROTEINS THAT THEY ENCODE.

SO WE KNOW, WHAT WE NEED TO KNOW

IS WH
T PROTEINS ARE CODED FOR

BY GNPTB AND -- AND THAT'S THE

LAST TIME I'LL SAY ALL THREE OF

THEM.

THE PATHWAY ARE INVOLVED IN

THESE PROTEINS.

HOW DO CELLS CHANGE WHEN THE

PROTEIN DON'T WORK CORRECTLY.

AND WHAT WOULD YOU EXPECT TO SEE

IN AN INDIVIDUAL WHO DIDN'T HAVE

PROPER FUNCTIONING OF BOTH

PROTEINS.

SO IN ORDER TO UNDERSTAND WHERE

THESE PROTEINS WORK AND WHAT

WOULD HAPPEN IF SOMETHING WENT

WRONG, WE HAVE TO KNOW WHERE

THEY OPERATE.

SO IT TURNS OUT THEY OPERATE IN

A LYSOSOME AND LYSOSOMES ARE

ORGANELLES, MEMBRANE BOUND

ORGANELLES INSIDE OF CELLS WHOSE

JOB IT IS IS TO RECYCLE THE

PROTEINS AND GLYCO PROTEINS AND

GLYCO LIPIDS THAT ARE IN CELLS.

SO BASICALLY PROTEINS AND GLYCO

PROTEINS AND LIPIDS GO INTO THE

LYSOSOMES AND THE LYSOSOME IS

FILLED WITH ENZYME THAT BREAK

THESE DOWN TO VERY BASIC

BUILDING BLOCKS.

AND THOSE ENI' ENENZYMES ARE
CALLED

LYSOSOMAL ENZYMES.

ONE THOSE BUILDING BLOCKS ARARY

POURED OUT OF THE LYSOSO AND

BACK INTO THE CELL FOR THE CELLS

TO USE THEM.

VERY EFFICIENT SYSTEMS.

THE CELLS CAN BREAK DOWN LARGE

COMPOUNDS INTO THEIR BASIC

BUILDING BLOCKS AND RECYCLE

THOSE BUILDING BLOCKS SO THEY

DON'T WASTE ENERGY TO DO IT

AGAIN.

AGAIN THE ENZYMES TO DO THAT ARE

CALLED LYSOSOMAL ENZYMES.

SO WE KNOW THAT LYSOSOMAL

ENZYMES HOW DO THEY GET INSIDE

THE LYSOSOME.

THEY GET IN THERE BY A VERY

UNIQUE MECHANISM.

SO LYSOSOMAL ENZYMES ARE

ACTUALLY MADE IN THE END PLASTIC

RESICK LUMP -- EN ENDO PLASTIC

LYSOSOME AND THE GOLGI.

THEY ARE SECRETED OUTSIDE OF THE

CELL SO THEY MOVE INTO THE

EXTRACELLULAR SPACE AND THEN

COME BACK INTO THE CELL WHEN

THEY ARE RECOGNIZED BY THIS

RECEPTOR, THIS LYSOSOMAL ENZYME

RECEPTOR CALLED THE -- AND

TRANSPORTED TO THE LYSOSOME.

SO IT TURNS OUT THAT THE SIGNAL

FOR THIS IS ON, IS PUT ON THESE

PROTEINS OVER HERE THERE'S A

SPECIAL SIGNAL THAT HELPS THESE

LYSOSOMAL PROTEINS THAT ARE

OUTSIDE OF THE CELL, COME BACK

INTO THE CELL AND GO TO THEIR

RIGHT COMPARTMENT.

AND THAT SIGNAL IS ACTUALLY THIS

PHOSPHATE LINKED TO A -- SO THE

BIG BLUE OVAL IS A LYSOSOMAL

PROTEIN.

AND THE SUGARS ON HERE, THIS IS

A MONOSACCHARIDE, A SUGAR LINKED

TOGETHER IN THIS VERY SPECIFIC

OLD GOLOGO SACCHARIDE AND THE
OTHER

ARE NANO.

THIS STRUCTURE ITSELF IS THE

BEGINNING OF THE PRE CURSOR OF

A -- WHICH MEANS IT'S LINKED

TO -- AND LLO SACCHARIDE MEANS.

SUGARS.

THIS IS A WELL-KNOWN STRUCTURE

AND PUT ON THESE LYSOSOMES.

WHAT HAPPENS ON LYSOSOMAL

ENZYMES IS THESE ENZYMES WITH

TRANSFRAIFTRANSFERASE --
PREEXHAUSTS IT SO

THIS IS.

THIS ENJIMM ENSEAM IS ENZYME IS
CODED FOR 
--

THAT'S THE FIRST STEP THAT PUTS

THIS GLYCO NET PHOSPHATE AND

CODED BY ANOTHER GENE THAT

ACTUALLY DENNIS HAS SEEN CHANGES

ININ IN INDIVIDUALS WHO STUTTER.

THIS IS THE SECOND STEP.

THIS IS RELEASED OUT AND THE

PHOSPHATE IS HERE LEFT ON THE

NANO.

AND SO THIS SIGNAL, THIS

STRUCTURE THAT'S PUT ON THESE

LYSOSOMAL PROTEINS IS RECOGNIZED

BY THE NANO 6 PHOSPHATE RECEPTOR

AND BROUGHT BACK INTO THE

LYSOSOME.

BUT THE QUESTION IS, SO IF THERE

ARE CHANGES IN THIS, IN THESE

GENES THAT WOULD CAUSE THOSE

ENZYMES NOT TO FUNCTION, WHAT

WOULD HAPPEN TO A CELL?

SO IF YOU BLOCK IT HERE BECAUSE

THESE LYSOSOMAL PROTEINS DON'T

HAVE THE SIGNAL TO BE RECOGNIZED

BY THIS NANO 6 PHOSPHATE

RECEPTOR, YOU HAVE AN EMPTY

LYSOSOME.

DO YOU HAVE A LYSOSOME THAT WHEN

ALL OF THOSE LIPIDS AND GLIEP

CO-PROTEINS GO INSIDE THE

LYSOSOME, NOTHING CAN BREAK THEM

DOWN.

RIGHT?

BECAUSE THEY DON'T HAVE THE

PROTEINS THAT THEY NEED TO BREAK

THEM DOWN INTO THEIR BUILDING

BLOCKS AND RECYCLE TO NORMAL.

SO IT'S THESE THREE GENES CARRY

MUTATIONS THEY MAKE

NON-FUNCTIONAL PROTEINS.

THE LYSOSOMAL PROTEINS WILL NOT

HAVE THE CORRECT SIGNAL TO GET

BACK INTO THE LYSOSOMES AND THE

LYSOSOMES WON'T FUNCTION

DIRECTLY.

CORRECTLY.

WHAT HAPPENS TO A PERSON WHEN

THEY DON'T HAVE FUNCTIONAL

LYSOSOMAL ENZYMES?

SO THIS IS AN IMAGE THAT -- GAVE

ME HERE FROM -- PATIENTS.

AND THIS IS A CELL.

HERE'S THE NUCLEUS AND AS YOU

CAN SEE, THE CELL IS ENGORGED

WITH GLYCO LIPIDS.

THESE CELLS ARE FROM -- DISEASE

BECAUSE THEY DON'T MAKE,

INDIVIDUALS WITH THE DISEASE,

DON'T MAKE THE ENZYME CORRECTLY

THAT BREAKS DOWN THE GLYCO

LIPIDS -- SO THEY BASICALLY

STORE GLUCO IN -- HERE'S AN

ELECTRON M MY MY MY MY
CROSSCOPY.

IT TURNS OUT THERE ARE ABOUT 40

DIFFERENT LYSOSOMAL DISEASES

THAT YOU CAN IMAGINE.

ANY ENZYME INVOLVED IN BREAKING

DOWN ANY ONE OF THOSE LIKE A

LIPID OR LIKE A PROTEIN IF

THEY'RE NOT FUNCTIONAL THEY

WOULD LEAD TO STORAGE SO THEY

WOULD STORE DIFFERENT MATERIALS.

THERE ARE 40 DIFFERENT ONES ALL

RESULT IN THE ACCUMULATION OF

INCOMPLETELY DIGESTED SUBSTRATES

WITHIN LYSOSOME WITH CELLULAR

IMPAIRMENT AND CONSEQUENCE

PATHOLOGY.

TYPICALLY WHEN WE SEE AN

INDIVIDUAL AND WE ARE THINKING,

WE'RE CONCERNED ABOUT THE

POSSIBILITY OF THE STORAGE OF

DISEASE WE THINK OF THREE

DIFFERENT ORGAN SYSTEMS.

WE THINK OF CONNECTIVE TISSUES

AND BONES AND PATHOLOGY AND

STORAGE IN CONNECTIVE TISSUE OR

BONE.

YOU THINK OF STORAGE IN NERVOUS

TISSUE AND THE RESULTING

PATHOLOGY OF THAT.

WE THINK OF STORAGE IN

PARENCHYMA ORGANS WHICH ARE --

SOFFITS ORGANS THAT CAN BECOME

ENLARGED AND THAT'S WHAT YOU'RE

SEEING IN THIS MAN.

HE HAS A VERY LARGE LIVER AND

SPLEEN FROM MATERIAL THAT DIDN'T

GO ANYWHERE AND BASICALLY MADE

THE ORGAN BIGGER.

WHAT'S CRITICAL TO KNOW ABOUT

THE STORAGE DISEASE IS NOT ALL

ORGANS ARE AFFECTED IN ALL

STORAGE DISEASES MAKING IT OF

COURSE COMPLICATED AND THE

REASON WHY WE HAVE THE WEB,

THANK GOODNESS.

SO IT TURNS OUT THAT SOME

LYSOSOMAL DISEASE HAS SOME

INVOLVEMENT WITH THE TISSUE

INVOLVEMENT AND THEIR LIVER AND

SPLEENS ARE ENLARGED AND THEIR

BRAINS AND NERVOUS SYSTEMS ARE

OKAY.

SOME LYSOSOMAL STORAGE DISEASES

HAVE JUST LIVER AND SPLEEN AND

SOME JUST HAVE NEUROLOGIC ISSUES

AND SOME HAVE PSYCHIATRIC

INVOLVEMENT.

SO THAT THE SYMPTOMS THAT YOU

CAN SEE FROM A LYSOSOMIC STORAGE

DISORDER ARE WIDELY VARIED AND A

CLINICIAN NEEDS TO PUT THAT INTO

THE DIFFERENTIAL DIAGNOSIS WHEN

THEY SEE A CHILD WITH A LOT OF,

OR AN ADULT, WITH A LOT OF

DIFFERENT SYMPTOMS AND WE'LL

TALK ABOUT THOSE RIGHT NOW.

IT TURNS OUT THAT THERE'S LOTS

OF DIFFERENT FLAVORS OF

LYSOSOMAL STORAGE DISEASES

DEPENDING ON WHAT THEY

STOREMENTED THEY STORE A

PARTICULAR SUBSTRATE BECAUSE

THEY CAN'T BREAK IT DOWN.

THEY STORE -- POLYSACCHARIDES,

OLD GOLOGO SACCHRIDES -- SUGAR
LINKED

TO LIPIDS.

LIPIDS ARE STORED, IF YOU CAN'T

BRAKE DOWN GLYCOGEN, IT'S THE

PATHWAY FOR GLYCOGEN DEGRADATION

IS IMPAIRED YOU HAVE A GLYCOGEN

STORAGE DISORDER.

THERE ARE LYSOSOMAL DISORDERS

WHERE YOU CAN BREAK THEM DOWN

BUT CAN'T GET THEM OUT.

SO YOU STORE THESE SMALL

MOLECULES IN THE LYSOSOME AND

THAT CAUSES PATHOLOGY.

THESE ARE ALL DIFFERENT KINDS OF

STORAGE DISORDERS.

THAT'S THE BIG PICTURE.

BUT REMEMBER, WE'RE TALKING

ABOUT A VERY SPECIFIC KIND OF

LIVES SOMAL STORAGE DISORDER

WHICH IS THE INABILITY TO GET A

LOT OF DIFFERENT LYSOSOMAL

ENZYMES BACK INTO THE LYSOSOME.

OKAY.

SO THESE COULD MANIFEST A LOT OF

DIFFERENT WAYS BUZ BECAUSE WE
DON'T

KNOW WHICH ENZYMES WILL TAKE

PRIORITY BUT WE DO HAVE

HISTORICALLY, WE KNOW ABOUT TWO

DIFFERENT DISORDERS.

AS DENNIS POINTED OUT WHICH IS

NEUCLO LIPDOZENS TYPDOSES OR
ML3.

WE KNOW THAT HISTORICALLY

AFFECTED INDIVIDUALS HAD

MUTATIONS IN GNTAB WHICH CODES

FOR SUBUNITS OF THE PHOSPHO

TRANSFERASE.

AND WHEN DENNIS CALLED ME AND

SAID I HAVE STUTTERING LINKED TO

GNTAB I'M THINKING ABOUT WHAT

THAT MEANS FOR OTHER SYMPTOMS IN

THE INDIVIDUALS THAT IN THE

STUDIES.

I WOULD LIKE YOU TO THINK ABOUT

LYSOSOMAL STORAGE DISEASES AND I

SAID ARE THEY WELL AND HE SAID

YES AND I SAID REALLY?

BECAUSE I WAS, I'M A PEDIATRIC

GENETICIST AND I WAS USED TO

SEEING INDIVIDUALS WHO ARE

REALLY QUITE ILL.

NOW RECOGNIZE THAT THESE ARE

REST CESSIVE DISORDERS SO THESE

HAVE CHANGES IN BOTH ALLELES.

THE ONE FROM THE MOM AND THE ONE

FROM THE DAD.

AND AS DENNIS SAID, ACTUALLY

THIS I THINK BRINGS TO LIFE A

COMPLEXITY OF THE WORK THAT

DENNIS IS DOING.

BECAUSE HOW EXACTLY THIS WORKS

MOLECULARLY IS NOT GOING TO BE

AS SIMPLE AS A RECESSIVE

DISORDER WHERE YOU HAVE ONE

INCORRECTLY OPERATING GENE FROM

THE MOMS, ONE INCORRECTLY

OPERATING GENE FROM THE DAD

UNLESS YOU HAVE NO ACTIVITY,

THERE'S A SUBTLETY HERE THAT I

THINK IS GOING TO BE THE BASIS

OF DENNIS' LIFE WORK, NEVER AND

EVER, RIGHT?

BUT HISTORICALLY, WE KNOW THAT

INDIVIDUALS WHO DO NOT HAVE TWO

FUNCTIONAL GNTAB GENES HAVE A

DEFECT IN TARGETING ENZYMES TO

THEIR LIEFTIO LYSOSOMES.

THIS IS ACTUALLY ONE OF THE VERY

FEW METABOLIC DISORDERS WHERE

THE CHILDREN HAVE DISMORPHOLOGY

OR SAFETY IN INFUN IS A.

MOST CHILDREN WITH METABOLIC

DISORDERS LOOK ATYPICAL.

THIS ONE IS SLOWLY PROGRESSIVE

AS IT STARTS IN INFANCY WITH A

FATAL OUTCOME IN EARLY CHIDE

HOOD.

USUALLY THE CHILDREN PASS AWAY

BETWEEN THREE AND FIVE YEARS OF

AGE.

THEY HAVE SHORT STATURE.

THEY HAVE JOINT CONTRACTURES,

THESE NOBBY KNEES, JOINTS AND

BONES ARE FULL OF MATERIAL.

THEY HAD LARGE HANDS.

THEY LOOK KIND OF SWOLLEN.

THEY CAN HAVE COARSE FEATURES

AND THE WORD COARSE FEATURES IS

THE WORDS CLINICIANS USE TO

DESCRIBE KIND OF PUFFY AROUND

THE EYES, A BROAD NOSE, KIND OF

FULL LIST LIPS, PUFFY CHECKS.

THEY HAVE COARSE FACIAL

FEATURES.

THEY COULD HAVE CARDIAC SYMPTOMS

BECAUSE THEIR HEART STORE

MATERIAL AND ACTUALLY THESE

CHILDREN MASS AWAY BECAUSE THEY

HAVE STORAGE IN THEIR

RESPIRATORY TRACT WHICH

BASICALLY CLOSES THE AIRWAYS

DOWN, NARROWS THE AIRWAY DOWN

AND THE CHILDREN HAVE

SIGNIFICANT RESPIRATORY

COMPROMISE.

THE DIAGNOSIS IS MADE BECAUSE

THERE'S AN INCREASE PLASMA

ACTIVITY OF MULTIPLE LYSOSOMAL

ENZYMES.

IN OTHER WORDS, THOSE ENZYMES

STAYED OUTSIDE OF THE CELL SO

THEY ARE FLOATING AROUND IN THE

PLASMA SPACE.

AND ALSO YOU CAN LOOK FOR THE

SUBSTRATES THAT BROKE OUT OF

CELLS BECAUSE THEY COULDN'T BE

BROKEN DOWN AND ARE FLOATING

THROUGH THE PLASMA.

YOU CAN SEE THOSE AS WELL.

THE SECOND DISORDER IS REALLY A

MILDER FORM OF PROBLEMS WHICH

THE SAME GENES, GNTAB.

THIS IS LICK OW GLYCO LIPDOSES
3.

THIS IS PUT BY THE PEOPLE IN

GREEN WOOD AND IN NORTHERN

EUROPE.

THIS IS, THESE KIDS HAVE LOAN E

CHANGES WHICH YOU CAN SEE BY THE

POSTURE OWES TWO SIBLINGS.

THEIR KNEES BOOK BENT BECAUSE

THEY CAN'T EXTEND THEM.

THESE CAN'T EXTEND THEIR ARM

BECAUSE THEY HAVE FREEZING OF

THE SHOULDER WITH THE

ENGORGEMENT WITH STORAGE.

AND YOU CAN SEE THEY HAVE THAT

SOUNDNESS THAROUNDNESS AND
PUFFINESS.

THEY GET RESTRICTIVE LUNG

DISEASE.

THEY ALSO CAN BE DIAGNOSED.

SO I JUST WANTED TO GO BACK OVER

AGAIN WHEN DENNIS SAID I'M

THINKING ABOUT LIVE LYSOSOMAL
STORAGE

DISEASES I FLASHED WHAT WOULD IT

BE I WOULD BE LOOKING FOR IN AN

INDIVIDUAL WHO COULD POTENTIALLY

HAVE SOME SIGNS, ALBEIT SUBTLE

OF A LYSOSOMAL STORAGE DISORDER.

SO YOU LOOK FOR CELLULAR

STORAGE.

WE ACTUALLY COULD LOOK AT AN EYE

EXAM BECAUSE INDIVIDUALS OF

LYSOSOMAL STORAGE CAN HAVE

CHERRY RED SPOTS ON THEIR MACULA

WHICH IS STORAGE ON THE BACK OF

THEIR EYE WHICH YOU CAN SEE BY

LOOKING AT THE BACK OF THEIR

EYES.

THEY CAN HAVE CON CORNEAL

INVOLVEMENT AND SOME HAVE A

HISSINESS AT THE SURFACE OF THE

EYE.

THIS IS A VERY INTERESTING

STORY.

THIS IS THE CORNEA OF A MOTHER

OF A YOUNG MAN WHO HAS FABRAY

DISEASE.

SHE'S A CARRIER.

SHE DOESN'T HAVE ANY SYMPTOMS OF

FABRAY DISEASE.

BUT SHE DOES HAVE THIS CORNEA.

YOU WOULD HAVE EXPECTED SHE

WOULDN'T HAVE ANY SYMPTOMS IF

SHE'S THE CARRIER OF THE

DISEASE.

BUT IT'S A REMINDER AND PROBABLY

ONE, WAS ONE OF THE VERY EARLY

EXAMPLES WHERE GENETICISTS TOOK

A STEP BACK AND SAID WE ALL

LEARN THAT CARRIERS DON'T HAVE

SYMPTOMS.

AND HERE'S AN EXAMPLE WHERE A

CARRIER HAD A CLEAR CLINICAL

FINDING THAT WAS RELATED TO THE

GENETICKIGENETIC CHANGE.

WE CONTINUE TO LOOK FOR IN

GENETICS AND SAY IS THERE

ANYTHING IN THIS CARRIER THAT

MIGHT TEACH US SOMETHING.

OBVIOUSLY THE OFFSPRING ARE

AFFECTED.

PEOPLE HAVE HEPATO LIVER.

THIS IS A PARTICULARLY ENLARGED

SCREEN.

ALSO THINK ABOUT
ANGIOCARECARETOMA.

THEY CAN HAVE SKELETAL STORAGE

AND YOU CAN SEE THESE ARE LACEY

BONES, THEY STORE WITHIN THE

BONES, THE BONES BECOME MORE

FRAGILE AND THEY CAN HAVE PAIN

CRISES BUT ALSO THEY GET THE

BONES ENLARGE AND THEY CALL HAVE

AN EARLY MEYER FLAP ANOMALY.

SO YOU LOOK FOR -- MULTIPLEX,

CHANGES ALL OVER THE BODY.

THESE ARE PARTICULARLY NICE

EXAMPLE OF IT.

THE DIAGNOSIS AS WE JUST TALKED

ABOUT, IT CAN BE MADE BY LOOKING

FOR SPILLOVER IN WHAT'S STORED

IN THE CELLS OR LOOKING FOR THE

ENZYME IN THE CASE OF ENZYMES

THAT ARE IN THE WRONG PLACE.

SO WE KNEW THAT WE HAD TO LOOK

FOR CLINICAL AND LAB FEATURES IN

INDIVIDUALS WITH MUTATIONS IN

GNTAB AND -- AND SO THAT IS

WHERE I BRING DR. FRIEDMAN IN

WHO IS A CLINICAL CENTER'S

INTERNAL MEDICINE AND MUCH

BETTER LOOKING FOR THINGS THAN I

AM.

>> CAN YOU HEAR ME?

I'M PENNY FRIEDMAN AND I WAS

ASKED BY DENNIS AND DONNA TO

TAKE A LOOK AT SOME INDIVIDUALS

WHO DENNIS HAD ASCERTAINED WHO

HAD STUTTERING.

AND THEY WERE PEOPLE IN THE

UNITED STATES WHO WERE PARTS

PUNT --PARTICIPANTS IN HIS
STUDIES.

WHAT THEY WANTED FROM ME WAS AN

ASSESSMENT AS TO WHETHER OR NOT

THESE PEOPLE WHO ALREADY HAD

IDENTIFIED MUTATIONS IN THE

PARTICULAR GENES OF INTEREST

THAT WAS KNOWN ABOUT THEM BEFORE

I EVER SAW THEM.

AND IT WAS ALSO KNOWN THAT THEY

HAD STUTTERING AS CHILDREN AND

HAD BEEN ABLE TO OVERCOME THEIR

STUTTERING TO VARIOUS DEGREES.

BUT WHAT WASN'T KNOWN WAS

WHETHER OR NOT THEIR PHYSICAL

CHARACTERISTICS OR THEIR

COGNITIVE CHARACTERISTICS OR

THEIR BEHAVIORAL CHARACTERISTICS

ECHOED SOME OF THE ABNORMALITIES

THAT DR. KRASNEWHICH HAS TOLD

YOU ABOUT.

SO I WAS ASKED TO TAKE A LOOK AT

THESE FOUR INDIVIDUALS.

THEY WERE UNRELATED FROM

DIFFERENT FAMILIES, ALL WITH

STUTTERING.

AND USUALLY I'M AN INTERNIST.

I'M A PEDIATRICIAN FOR ADULTS,

AND MY JOB IS BASICALLY TO DO A

GREAT MANY THINGS.

AN INTERNIST PLAYS A LOT OF

DIFFERENT ROLES.

SOMETIMES I'M JUST A MECHANIC,

AND I TORT O SORT OF ANALYZE THE
HUMAN

MACHINE AND TRY TO FIND A WAY TO

FIX SOMETHING.

BUT IN THIS PARTICULAR CASE, I

WAS ASKED TO BE A DETECTIVE.

SO I HAD TO APPROACH THESE

PATIENTS WITH AN OPEN MIND AND

CHANNEL MY INNER DETECTIVE WHICH

IS SOMETHING I LOVE TO DO ANYWAY

AND SEE WHAT I COULD FIND OUT.

SO EACH PATIENT BECOMES A LITTLE

MYSTERY.

AND I WAS, MY PURPOSE WAS TO

IDENTIFY THE CHICK
CHARACTERISTIC OF

EACH AFFECTED INDIVIDUAL, THAT

MEANS PEACMEAN PEACH STUTTERING
INDIVIDUAL

AND LOOK FOR EVIDENCE OF ANY

OTHER UNUSUAL MEDICAL PROBLEM OR

QUALITY THAT MIGHT BE RELATED TO

THE MUTATIONS THAT WE'VE BEEN

TALKING ABOUT.

AND I WON'T SAY ALL THE LETTERS.

SO MY PURPOSE WAS TO TRY AND

FIGURE OUT WHETHER OR NOT A

PATIENT'S INDIVIDUAL

ABNORMALITIES COMPRISED A

SYNDROME, IN OTHER WORDS, CAME

TOGETHER IN A GROUP LIKE THE

PATIENTS THAT DONNA HAS

DESCRIBED TO YOU WHERE THEY HAVE

CONNECTIVE TISSUE DISORDERS.

THEY HAVE BONY DISORDERS, THEY

HAVE NERVOUS SYSTEM DISORDER AND

THEY MAYBE HAVE ENLARGED SPLEENS

AND LIFERS AS WELL.

SO COULD I FIND THESE PEOPLE HAD

A WHOLE COLLECTION OF ABNORMALLY

OR DID THEY HAVE OTHER

UNCONNECTED MEDICAL PROBLEMS

THAT MIGHT BE RELATED TO THE

FACT THAT THEY HAD MUTATIONS IN

THESE SPECIFIC GENES.

I ALSO WANTED TO SEE WHETHER OR

NOT THERE ARE ABNORMALITY SINGLY

OR COLLECTIVELY RESEMBLE THESE

DISEASES THAT DR. KRASNEWHICH

HAS IDENTIFIED FOR YOU.

SO FOR ANY INVESTIGATION, YOU

HAVE METHODS.

AND MY METHODS ARE THE TYPICAL

PHYSICIAN METHOD.

I INTERVIEW PEOPLE AND I ASK

QUESTIONS.

SOMETIMES THEY'RE VERY POINTED

QUESTIONS, SOMETIMES THEY'RE

QUITE GENERAL AND I SOMETIMES

JUST LISTEN WHAT PATIENTS SAY TO

ME.

I ALSO DO A PHYSICAL EXAM AND

THAT'S WHEN I MEASURE THINGS I

LOOK AT THEIR FACE AND SEE

WHETHER IT'S TYPICAL OR

ATYPICAL.

I OBSERVE TO THE VERY BEST OF MY

ABILITY EVERYBODY ABOUT THEM AND

THEN WE DID SOME LABORATORY

EVALUATION WHICH WAS JUST BASIC

TESTING BUT ALSO A LITTLE

TESTING OF THE SUGARS IN THEIR

BLOOD TO SEE WHETHER, AND THEIR

URINE, TO SEE WHETHER OR NOT

THEY MIGHT HAVE ABNORMALITIES

AGAIN BY A CHEMICAL ABNORMALITY

THAT ARE CHARACTERISTIC OF THE

PATIENTS WITH ML2 OR 3.

THEN WE DID OTHER DIAGNOSTIC

STUDIES DONE BONE X-RAYS OR BONE

SURVEY, A SORT OF GENERAL SET OF

X-RAYS TO LOOK AT A LOT OF

DIFFERENT SPOTS AND THE

SKELETON.

WE DID AN ECHOCARDIOGRAM WHICH

IS AN ULTRA SOUND OF THE HEART

AND AN EKG WHICH WAS AN

ELECTRICAL TRACING OF THE

ELECTRICAL ACTIVITY IN THE HEART

IF WE FELT ON THE BASIS OF MY

INVESTIGATION THERE WAS

SOMETHING ELSE UNUSUAL ABOUT

THEM, WE COULD DO OTHER STUDIES

AS WELL.

SO THERE WERE FOUR AFFECTED

INDIVIDUALS, ALL OF THEM WERE AS

I SAID AMERICAN, FROM DIFFERENT

FAMILIES, FROM DIFFERENT PARTS

OF THE COUNTRY, ONE WAS A 63

YEAR OLD WOMAN, ONE WAS A

19-YEAR-OLD MAN, A 72-YEAR-OLD

MAN AND A 58-YEAR-OLD MAN AND

THEY HAD QUIE DIFFERENT LEVELS

OF DISABILITY FROM THEIR

STUTTERING AND THE OTHERS, THE

OTHERS IDENTIFIED THAT THEY HAD

ALL HAD CHILDHOOD ONSET OF

STUTTERING, JUST AS DENNIS

DESCRIBED THE ONSET OF

STUTTERING.

THEY ALL HAD PRETTY THOROUGH

CARDIAC EVALUATIONS AND THEIR

HEARTS WERE ENTIRELY NORMAL.

THEY HAD PHYSICAL EXAMS THA

LOOKED AT THE SIZE OF THEIR

SPLEEN, THE SIZE OF THEIR LIVER,

THE SHAPE OF THEIR BONES, THE

CONSTRUCTION AND SHAPE OF THEIR

FACE, THEIR SKIN.

WE LOOKED AT EVERYTHING, PRETTY

MUCH.

AND WE DID NOT FIND ANY EVIDENCE

OF THE PHYSICAL PATHOLOGY

CHARACTERISTIC OF I CELL DISEASE

OR ML3.

AND OUR LABORATORY RESULTS AGAIN

FOUND NO EVIDENCE OF BIOCHEMICAL

PATHOLOGY CHARACTERISTIC OF

EITHER ML2, iCELL DECEMBER OR OR
ML3.

WHEN WE LOOKED AT THEIR BASIC

BLOOD COUNT IT WAS NORMAL, WHEN

WE LOOKED AT THEIR BASIC BLOOD

CHEMISTRIES IT WAS NORMAL AND

THEIR UR URINE ANALYSIS WAS
NORMAL.

THEIR BONES WERE NORMAL.

WHEN WE LOOKED AT ALL OF THE

STUDIES THAT WE DID, WE DID NOT

FIND ANY UNION INDEMNIFYING

FACTORS WHICH MIGHT HAVE BEEN --

UNIFYING FACTORS WHICH MIGHT

HAVE BEEN SAY THEY HAD BONES,

THE UPPER BONES OF THEIR LEGS,

THE FEMURS THAT HAD BEEN CHANGED

TO LOOK LIKE THE FLASK WHICH

DR. KRASNEWHICH IDENTIFIED.

NIF SOAFERL SEVERAL OF THESE
PATIENTS HAD

HAD A FEMUR THAT LOOKED LIKE

THAT, THAT WOULD HAVE SPARKED

OUR INTEREST AND MAKE US WONDER

WHETHER OR NOT THESE WERE PEOPLE

WHO HAD A VERY SUBTLE FORM OF

THE MUCO LIPIDOSIS.

THAT'S OFTEN CALLED A FORMED

CALLS A FRUSTRATED FORM OF THE

DISEASE.

WE DIDN'T FIND ANYTHING LIKE

THAT.

EVERYBODY WAS NORMAL OR TYPICAL

EXCEPT FOR THEIR HISTORY OF

STUTTERING.

SO IN TERMS OF THE FOUR PEOPLE

THAT WERE EXAMINED WHO DID HAVE

THESE MUTATIONS THAT DENNIS HAD

FIRST IDENTIFIED IN THE LARGE

HINDERANCE THAT HE STUDIED  AS
HE

SHOWED YOU ONE FROM PAKISTAN.

TO THE EXTENT WE WERE ABLE TO

STUDY THESE FOUR INDIVIDUALS,

THERE WAS NO EVIDENCE OF iCELL

DISEASE OR MUCO LIPIDOSIS THREE

OR ANY OTHER CLINICALLY

SOMETHINGANT DISORDER LIKELY TO

BE ASSOCIATED WITH THE MUTATIONS

FOUND TO BE SORTING WITH THE

TRADE OF STUTTERING.

AND SOMETIMES THAT'S EXACTLY

WHAT MEDICINE DOES FOR YOU.

SOMETIMES IT JUST DOCUMENTS

NORMALITY.

AND AN INDIVIDUAL, RATHER THAN

FINDING OUT THAT THEY HAVE A

SURPRISING ABNORMALITY, IN THIS

CASE ALL OF THESE INDIVIDUALS

WERE REALLY PEOPLE THAT YOU

WOULD NEVER THINK HAD ANYTHING

ELSE WRONG WITH THEM OTHER THAN

THEIR STUTTERING.

OKAY.

>> SO WHERE DID THIS LEAVE US AT

THIS POINT?

WELL, REALLY SINCE WE COULDN'T

FIND EVIDENCE OF THE DISEASES

THAT ARE CLASSICALLY ASSOCIATED

WITH MUTATIONS IN THESE GENES,

COULD WE GET ANY MORE EVIDENCE

OTHER THAN JUST A GENETIC

EVIDENCE THAT IN FACT MUTATIONS

IN THESE GENES WERE REALLY

CAUSING STUTTERING IN THESE

PEOPLE, RIGHT.

SO FORTUNATELY, BECAUSE OF THE

VERY LONG HISTORY IN MEDICAL

JETS ANGENETICS AND BIOCHEMISTRY
IN

STUDYING THESE DISORDERS, THERE

IS A LOT OF INFRASTRUCTURE

AVAILABLE TO ASK QUESTIONS ABOUT

THE ENZYMES INVOLVED.

SO I JUST WOULD LIKE TO NOTE

THAT MUCOLIPIDOSIS IS TYPICALLY

ASSOCIATED WITH TRUNCATING

MUTATIONS.

MUTATIONS THAT ARE A DELETION

AND REMOVE THE WHOLE GENE OR

THEY PRODUCE A STOP CODE ON SO

THE GENE IS CUT OFF AT THE

POSITION OF THAT STOP CODE.

MUCOLIPIDOSIS TYPE 3 HAS

CLASSILY VERY VERY VERY LOW

ACTIVITIES OF THESE ENZYMES.

TYPICALLY ZERO TO 3%.

ESSENTIALLY NO BIO CHEMICAL

ACTIVITY DETECTABLE IN A TEST

TUBE OFF THESE ENZYMES IN THESE

PATIENTS.

MUCOLIPIDOSIS TYPE 3 SOMETIMES

DISPLAYS A LITTLE BIT OF

ACTIVITY.

SOMETIMES FOR INSTANCE THE STOP

CODE IS NEAR THE FAIL END O TAIL
END OF TH
E

GENE SO IT LOSES A MODEST PART

OF THE PROTEIN AND MAINTAINS A

LITTLE BIT OF ENZYMATIC

ACTIVITY.

SO WE WENT AND LOOKED AT THESE

MUTATIONS AS BEST WE COULD IN A

SELECTION OF PATIENTS, TO SEE IF

WHAT KIND OF BIO CHEMICAL

ACTIVITIES THEY HAD.

AND I SHOULD JUST TELL YOU OF

THE SHORT ANSWER IS HERE.

THAT AS YOU SEE, THERE'S NOT A

LOT OF PATIENTS IN THIS SAMPLE.

THIS IS A GRAND TOTAL OF ONE SO

THERE'S NO ERROR.

THESE ARE FOUR MUTATIONS OR FOUR

PATIENTS WITH DIFFERENT

MUTATIONS THAT WE LOOKED AT IN

THIS GENE.

AND WHAT YOU CAN SEE IS EVEN

THOUGH THERE'S A LOT OF

VARIATION, HERE'S ONE MUTATION

HERE.

SHOWED ROUGHLY HALF OF NORMAL

ACTIVITY YEAR.

THE MU TITION WAS IN THE 68-YEAR

OLD WOMAN THAT WAS EVALUATED

HERE.

ACTIVITY OF THE ENZYMES THAT

THEY ENCODE, OKAY.

SO THAT GETS US A LITTLE BIT

FARTHER.

BUT THE BIG QUESTION HERE I

THINK STILL REMAINS UNANSWERED

WHICH IS WHAT'S THE

NEUROPATHOLOGY HERE.

WHY DO MUTATIONS IN THESE GENES

CAUSE STUTTERING IN THE ABSENCE

OF ANY OTHER SYMPTOMS.

AND THE SHORT ANSWER IS AT THE

MOMENT, WE DON'T KNOW.

HOWEVER WE HAVE A WORKING POLTS

AND IT GOES -- HYPOTHESES AND IT

GOES AS FOLLOWS.

THERE IS A SPECIFIC GROUP OF

NEURONS IN THE BRAIN THAT ARE

SNEAK TO SPEECH PRODUCTION AND

UNIQUELY SENSITIVE TO THIS

RELATIVELY MODEST METABOLIC

DEFICIT.

WHY DO WE THINK THESE NEURONS

ARE UNIQUE TO SPEECH REDUCTION

IS BECAUSE THEY HAVE NO OTHER

NEUROLOGICAL SYMPTOMS.

IT'S THE ONLY NEUROLOGICAL

DEFICIT THESE PEOPLE DISPLAY.

SO OUR GOAL, YOU KNOW, NOT THAT

WE'RE MODEST HERE IN OUR

SCIENTIFIC GOALS.

WE WANT TO IDENTIFY THESE CELLS.

DISCOVER WHAT THEY DO, DETERMINE

WHAT THEY'RE CONNECTED TO AND

UNDERSTAND HOW THIS IN HERITED

DEFICIT UNIQUELY AFFECTS THEM.

AS SOMEONE MENTIONED A

SUBSTANTIAL PROJECT.

SO I JUST WANTED TO GIVE YOU A

QUICK UPDATE ON WHERE WE HAVE

GOTTEN SINCE THEN.

WE'VE MADE SOME PROGRESS IN

ADDITION TO STUDYING THE

ENZYMATIC DEFECTS THAT ARE

PRODUCED BY THESE MUTATIONS.

WE HAVE THIS SORT OF WORKING

IDEA FOR HOW THE TISSUE

SPECIFICITY COULD BE PRODUCED IN

THIS DISORDER AND THAT IS OFTEN

INHERITED DEFICIT IN A GENE

PRODUCT WILL BE PREFERENTIALLY

AT THE HIGHEST LEVEL.

SO CELLS IS A VERY INTUITIVE

NOTION.

CELLS THAT NEED A LOT OF

SOMETHING ARE THE FIRST ONE THAT

HAVE A PROBLEM WHEN THERE'S A

MUTATION IN THAT.

RIGHT?

OKAY.

SO THE GOAL HERE IS TO DO A VERY

CAREFUL DETAILED SEARCH THROUGH

DIFFERENT REGIONS OF THE HUMAN

BRAIN TO SEE IF WE CAN FIND

PLACES THAT EXPRESS THESE GENES

AT PARTICULARLY HIGH LEVEL.

WE HAVE A LITTLE BIT OF

PRELIMINARY DATA HERE.

THIS DATA I'M ABOUT TO SHOW YOU

NEEDS TO BE TAKEN WITH A GRAIN

OF SAT BU SALT BUT IT SHOWS YOU
WHAT

CAN BE DONE.

I'M SORRY, THERE ARE ACTUALLY 20

DIFFERENT REGIONS OF THE HUMAN

BRAIN THAT ARE TESTED FOR RNA

EXPRESSION OF THE GNPTAB GENES.

A COME OF HIGH LEVEL EXPRESSIONS

PARTICULARLY OF GNTAB AND GNTTG

HERE IN THE DARKER BLUE.

NOW EXCEPT FOR THE SO-CALLED

POST CENTRAL GYRUS WHICH IS A

REGION UP HERE, THERE ARE

SEVERAL NOTABLE PLACES LIKE HERE

IN THE CEREBELLA CONSOLE AND THE

CARCEREBELLUM OVERALL, LEFT AND

RIGHT.

HERE, THIS IS THE CEREBRAL,

CEREBELLUM M MENINGES.

SO THESE ARE HIGH LEVELS OF

EXPRESSION IN THE CEREBELLUM

WHICH IS THE PORTION OF THE

BRAIN, THE BASE OF THE BRAIN AND

IS KNOWN TO BE INVOLVED IN MOTOR

CONTROL, MINE MOTO FINE MOTOR
CONTROL.

WHAT THE CEREBELLUM DOES HAS

BEEN IMPROVEN OVER THE LAST

DECADE OR SO AND IT'S NOW KNOWN

TO BE INVOLVED IN OTHER

FUPTIONIONS OF THE BRAIN.

BUT IT'S CLASSICALLY CONSIDERED

PART OF THE BRAIN THAT ELLS

MOTOR FUNCTION -- CONTROLS MOTOR

FUNCTION.

PEOPLE WHO STUTTER, THEY DON'T

HAVE ANY PROBLEMS WITH WHAT

SPEECH LANGUAGE PATHOLOGISTS

CALL PREMOTOR PROCESSES.

THEY KNOW THE WORDS.

THEY HAVE NO PROBLEM PUTTING

TOGETHER WHAT THEY WANT TO SAY

WITH THE WORDS USED TO SAY IT.

THEY DON'T HAVE PROBLEMS WITH

GRAMMAR.

THE BOY WENT TO THE STORE, THE

STORE WENT TO THE BOY MANY THEY
--

BOY, THEY DON'T HAVE THOSE

PROBLEMS.

THEY DON'T KNOW WHAT THEY WISH

TO SAY, THEY JUST CAN'T SAY IT.

IT'S AS IF THEY HAD SOME SORT OF

VERY SPECIFIC MOTOR DEFICIT THAT

MAKES IT VERY DIFFICULT FOR

THEM, PARTICULARLY INITIATING

WORDS OR SPEECH SOUND.

SOMETIMES THEY GET GOING, IT

COULD BE BETTER.

BUT IF IT'S CLEAR THAT IF THERE

WAS A SIGNIFICANT MOTOR

COMPONENT IN THIS DISORDER, IT

WOULDN'T BE A SURPRISE TO

ANYONE.

OKAY.

SO NOW I WOULD LIKE TO JUST

MENTION ONE OTHER QUICK THING,

WHICH IS THAT WHAT IS IT ABOUT

PEOPLE, WHAT IS IT ABOUT THESE

MUTATIONS.

WHY DO THESE PEOPLE, SOME

MUTATIONS IN THIS GENE SEEM TO

CAUSE MUCOLIPIDOSIS AND OTHER

MUTATIONS SEEM TO CAUSE

STUTTERING.

WHAT'S GOING ON HERE.

THERE ARE THREE FACTS ON THIS.

MOST OF ALL MOST CASES OF

MUCOLIPIDOSIS ARE ASSOCIATED

WITH TRUNCATING MUTATIONS AS I

SAID.

THE SECOND THING I HAVEN'T 20E8D

YOU YET IS ALMOST ALL THE

MUTATIONS ASSOCIATED WITH

STUTTERING ARE MISOIL SENSE --

MIS-SENSE MUTATIONS.

THEY'RE TRANSLATED INTO RNA AND

PROTEINS WITH A SINGLE AMINO

ACID THAT'S INCORRECT AT ONE

SPOT.

WHAT I ALSO HAVEN'T TOLD YOU YET

IS THAT THESE ENZYMES ARE

MULTISUBUNIT.

SO THE FIRST STEP IN THAT

LYSOSOMAL TARGETING PATHWAY IS

CACATALOGED BY HAVING TWO AL
FAWZ,

TWO BETA AND TWO GAMMA SUBUNITS.

OKAY.

SO WHAT WE THINK IS THAT THE

DIFFERENCE, THE THING THAT IS

SPECIAL ABOUT STUTTERING

MUTATION IS THAT THEY INFACT ARE

TRANSLATED INTO PROTEIN AND

INCORPORATED INTO THIS

MULTISUBUNIT ENZYME

SUBUNIT ENZYME STRUCTURE.

WHAT ARE THE PARENTS.

THEY ARE ALL OBLIGATE CARRIERS.

ALTHOUGH THE STUDY HASN'T BEEN

PUBLISHED, I HAVE A PERSONAL

COMMUNICATION FROM AN EXPERT IN

THIS FIELD WHO IS ACTUALLY THE

DISCOVERER OF THE iCELL

DISEASE.

HE'S THE FIRST PERSON WHO

NOTICED THE INCLUSIONS OF CELLS

IN THESE PATIENTS WHO LOOKED PAT

A LOT OF PARENTS WHO ARE

CARRIERS AND FOUND NO INCREASED

EVIDENCE OF SPEECH PROBLEM IN

THIS GROUP.

SO WHAT'S GOING ON HERE?

WELL, WE HAVE ANOTHER HYPOTHESES

AND IT GOES LIKE THIS.

TRUNCATING MUTATIONS IS IN NO

STABLE MESSAGE RNA.

THE ONLY MESSENGER RNA IN A

OBLIGATE CARRIER PARENT WILL

DERIVE FROM THE NORMAL COPY OF

THE GENE.

THIS PERHAPS REDUCED AMOUNT OF

NORMAL MESSENGER RNA WE THINK

MIGHT MAKE SUFFICIENT ENZYMES TO

RUNNEDDER THESE INDIVIDUALS

MEDICALLY.

SO IN OTHER WORDS THEY MAY ONLY

HAVE ONE FUNCTIONAL COPY OF THE

GENE BUT WHAT THEY DO HAVE IS

NORMAL AND THAT MAKES ENOUGH

ENZYMES TO PRECENT SYMPTOMS.

A HYPOTHESES, OKAY.

IN THIS SENSE MUTATIONS ON THE

OTHER HAND MANIFEST PROTEINS

WHICH ASSEMBLE INTO MULTISUBUNIT

ENZYMES THAT DISPLAY AS I SHOWED

YOU IN THE BIO CHEMICAL DATA

MILD DEFICITS, MAYBE 50%.

THESE ONLY AFFECT A SPECIFIC

CLASS OF NEURONS IN THE BRAIN

THAT ARE ALSO HIGHLY SENSITIVE

TO SUCH A DEFICIT.

SO THAT IS AGAIN A HYPOTHESES.

NOW, JUST TO GIVE YOU AN IDEA.

THE OTHER QUESTION IS, HOW MUCH

OF STUTTERING MUTATIONS EXPLAIN,

IT'S LESS THAN 10%.

WE ONLY HAVE SORT OF A PIECE OF

STUTTERING AS A DISORDER AT THIS

POINT.

SO OUR GOAL IS TO TRY AND FIND

MORE GENES THAT MIGHT EXPLAIN

MORE OF THIS DISORDER.

AND MAYBE GIVE US OTHER AVENUES

OR OTHER WINDOWS   INTO THE

NEUROPATHOLOGY OF THE DISORDER.

I SHOULD TELL YOU THAT, IF YOU

COULD RAISE YOUR HAND, HE'S

FOUND VERY STRONG LINKAGE

EVIDENCE FOR TWO ADDITIONAL

PLACES.

THERE'S A GENE ON THE LONG ARM

OF CHROMOSOME 3 THAT CLEARLY

CONTAINS A STUTTERING GENE AND

LIKEWISE A DIFFERENT GENE ON

ANOTHER CHROMOSOME THAT CONTAINS

ANOTHER STUTTERING GENE.

WE'RE HOT ON THE TRAIL OF THESE

TWO GENES AND WE THINK THEY ARE

LIKELY TO BE ABLE TO EXPLAIN

MORE OF STUTTERING TO US.

OKAY.

THEN FINALLY THE WILD ELSE THING

IN MOUSE MODELS.

A KNOCKOUT MOUSE A GNTAB WAS IN

A ZIP HER TYPE OF MUCOLIPIDOSIS.

THESE MICE ARE BONE, THEY ARE

VERY SICK PLIES THEY DON'T LIVE

VERY LONG AND THEY HAVE

DISORDERS, THEY HAVE SYMPTOMS,

MANY PHENOTYPIC SYMPTOMS THAT

ARE SIMILAR TO HUMAN

MUCOLIPIDOSIS.

THEY ARE PROBLEMATIC TO YOU.

SO THE GOAL HERE IS TO CREATE

KNOCK-IN MICE CARRYING

HUMAN MUTATIONS THAT WAS FOUND

AS STUTTERING IN THE MICE AND

LOOK AT THE VOCALIZATION OF THE

MICE.

WHAT WE'RE TALKING ABOUT HERE IS

STUTTERING MICE, RIGHT.

SO THE QUESTION A LOT OF PEOPLE

SAY I HAD NO IDEA MICE WERE SO

CONVERSATIONAL.

AND F, THE FAC FACT THE FACT IS
MICE HAVE

EXTREMELY RARE COMMUNICATION AND

I MUST TELL YOU IT'S EXTREMELY

PURELY CHARACTERIZED AT THIS

TIME PARTLY BECAUSE ALL OF THE

INTERESTING ASPECTS OF MOUSE

VOCAL COMMUNICATION ARE

ULTRASONIC.

THERE ARE PEOPLE NOW WORKING ON

THIS.

AND SO WHAT I'LL DO IS I'LL GIVE

YOU AN EXAMPLE OF A LITTLE MOUSE

SPEECH HERE.

WHAT YOU'RE GOING TO HEAR IS A

MOUSE VOCALIZATION.

THIS IS A VOCALIZATION FOR THIS

BY AN AWE MUFL ADULT MALE MOUSE
IN THE

PRESENCE OF AN ADULT FEMALE.

THIS IS LIKE THE BARN, THIS IS

LIKE A DATE.

SO THIS AS ISA AS I SAY IS
ULTRASONIC.

IT IS LOWERED IN PITCH SO WE CAN

HEAR IT BUT IT ISN'T EXPANDED IN

TIME FREQUENCY.

THE TIMING IS REAL TIME BUT THE

PITCH IS LOWER.

THIS IS WHAT MALE MICE SOUND

LIKE.

OKAY.

IT HAS MANY FEATURES OF A SONG.

IF YOU WEREN'T TOLD THIS WAS A

TRANSFORMED SIGNAL FROM A MALE

MICE, MALE MOUSE YOU MIGHT THINK

IT WAS FROM A BIRD, RIGHT?

IT'S VERY PREDICTABLE.

SO I SHOULD JUST TELL YOU THAT

WE HAVE NOW SUCCESSFULLY MADE A

KNOCK-IN.

THIS IS A MOUSE THAT CONTAIN TWO

COPIES OF THE MUTATION, THE

HUMAN MUTATION THAT'S PRESENT IN

THAT VERY LARGE PAKISTANI

STUTTERING FAMILY THAT I SHOWED

YOU.

AND YOU CAN SORT OF MAYBE SEE A

LITTLE HINT IDENTIFYING TATTOO

ON HIS TAIL HERE.

HOPEFULLY YOU CAN SEE THERE'S

NOTHING ELSE THAT LOOKS UNUSUAL

ABOUT THIS MOUSE AND I CAN TELL

YOU LIKE THE HUMANS WHO CARRY

THIS MUTATION, IT SEEMS TO BE

OTHERWISE PHYSICALLY AND

BEHAVIORALLY NORMAL, OKAY.

WE'RE JUST BEGINNING TO GET VOC

EL -- VOCAL RECORDING.

SO THE CONCLUSION OF MY PART

BEFORE IT GOES BACK TO DONNA IS

ALTHOUGH WE CAN EXPLAIN A SMALL

FRACTION OF STUTTERING WITH THE

MUTATIONS FOUND TO DATE, WE CAN

USE EVEN THIS LIMITED

INFORMATION TO STUDY THE

PATHOPHYSIOLOGY OF STUTTERING IN

A WAY THAT WAS NOT POSSIBLE.

OKAY.

SO, BACK TO THE BIG PICTURE.

>> SO THE LAST THREE SLIDES, I

WANTED TO TALK ABOUT THE JET

LESSONS THAT WE -- JEELT LESSONS

WE LEARN -- GENETIC LESSONS WE

LEARNED FROM THIS.

IT WASN'T REALLY THE STUTTERING

BUT HOW WE THINK ABOUT THIS AND

THE TERRIFIC JOB OF HOW WE THINK

ABOUT JETS.

JETS -- GENETICS.

I THINK THAT'S WHERE THE FUTURE

OF GENETICS IS.

SO WE KNOW FIRST LESSON ARE

SINGLE GENE DISORDERS.

YOU'VE SEEN A TERRIFIC EXAMPLE.

AN UNEXPECTED PHENOTYPE CAUSED

BY CHANGES IN A WELL-STUDIED

GENE.

WE KNOW THAT, WE KNOW THAT

CARRIERS OF GENE MUTATIONS MAY

NOT ALWAYS BE ASYMPTOMATIC.

NOW THIS CASE THERE'S A LITTLE

BIT OF GLORY IN THAT BUT THERE'S

A REALLY GOOD EXAMPLE ACTUALLY

IN THAT, THAT'S BEEN WELL

DOCUMENTED.

SO REMEMBER IN THE PAST WE ALL

THOUGHT THAT CARRIERS OF

RECESSIVE DISORDERS HAD NO

SYMPTOM AT ALL.

IT TURNS OUT THE CARRIERS OF

INDIVIDUALS WHO HAVE CHANGES IN

THE -- HAVE AN INCREASE OF THE

PAPARKPARPARKINSON'S.

WE'RE WORKING HARD TO UNDERSTAND

WHY SOMEONE WHO HAS 50% ACTIVITY

OF THAT GENE AND REALLY ENOUGH

TO COVER HAS INCREASE THE RISK

OF A NEUROLOGIC ISSUE.

PATHERE'S A JET TERM FOR THE

EXPANNIVENESS AND THE TERM IS

PHENOTYPIC -- IT'S UNEXPECTED

CAUSE.

PHENOTYPE IS HOW SOMEONE LOOKS

AT A CLINICAL PRESENTATION OF A

JEGENETIC DISORDERS.

OTHER IS CHANGES IN THE GENE CAN

CAUSE DIFFERENT DISORDERS.

-- OCCURS IN INFANTS.

IT'S A CONGENITAL PROBLEM.

THEY HAVE INCORRECT IN NURSE

VISION OF THE COLON AND -- IN

NERVATION OF THE COLON AND THEY

CAN'T STOOL, THEY CAN'T POOP

BECAUSE THEY HAVE NO WAY OF SORT

OF ORDERING THAT AND IT IS

SIGNIFICANT MEDICAL ISSUES AND

HAVE TO HAVE SURGERY AND VERY

EARLY IN LIFE.

THAT'S WHY ON THE -- IS A CANCER

SYNDROME.

COME ON.

YOU KNOW.

HOW DO YOU PULL THOSE TWO

TOGETHER.

THE SECOND EXAMPLE, ACTUALLY

THERE ARE MANY EXAMPLES BUT THE

SECOND EXAMPLE IS THE LAMIN A

GENE WHICH MOWATIONS IN THE

LAMIN A GENE CAN CAUSE MUSCULAR

DISTROPHY, A DEGENERATIVE

DISORDER AND -- WHICH IS

PREMATURE AGING.

COMPLETELY YOU WOULD NEVER HAVE

ANTICIPATED THAT THESE TWO

WILDLY VARIABLE PHENOTYPES WERE

CAUSED BY CHANGES IN THE SAME

GENE.

AND I THINK THAT SOME PEOPLE

DON'T KNOW WHY, BUT IT'S AN AREA

AT THE FOREFRONT OF RESEARCH.

IS IT BECAUSE THERE ARE MODIFIER

GENES OR TRANSLATIONAL

PROCESSING.

I THINKENNIS GAVE A VERY GOOD

EXAMPLE ON CREATING A DIFFERENT

PRODUCT THAN NO MUTATIONS AND

WHAT IT DOES TO THE P PATHOLOGY.

I THINK WE NEED TO THINK ABOUT

THE EXAMPLE OF PHENOTYPIC

HETEROGENEITY AND I THINK THIS

IS A GOOD ONE.

I THINK THE OTHER LESSON THAT

WE'VE LEARNED IS THAT MANY

DISEASES HAVE MULTIPLE GENETIC

ETIOLOGIES.

SO THIS IS STUTTERING, THESE

INDIVIDUALS COULD NOT BE

IDENTIFIED AS DIFFERENT

STUTTERERS THAN EACH OTHER.

HOWEVER, INDIVIDUALS IN THE

POPULATION HAVE CHANGES IN THREE

DIFFERENT GENES.

SO IT TURNS OUT THAT WHEN I

PRESENTED THIS, IT'S PRETTY --

IN OTHER WORDS THEY HAVE CHANGES

IN GENES THAT ARE SEQUENTIAL IN

PROCESS TO EACH OTHER.

SO YOU CAN IMAGINE THAT IF YOU

HAVE A VERY LONG REACTION THAT

HAS 30 STEPS IN IT, ALL OF WHICH

PRODUCE AN INCORRECT PRODUCT,

MUTATIONS IN ANY ONE OF THOSE

STEPS ALONG THE WAY WOULD CREATE

THE SAME PHENOTYPE.

NOW THAT TURNS OUT YOU'RE

SMARTER THAN PEOPLE WERE 20

ARS AGO BECAUSE WE WEREN'T

THINKING OF THAT.

WE THOUGHT THAT EVERY PHENOTYPE

CAN ONE GENE ASSOCIATED WITH IT.

AND NOW PEOPLE ARE RECOGNIZING

THAT EVERY PHENOTYPE HAS MANY

GENES ASSOCIATED WITH IT AND

IT'S CALLED LOCUS HEATE
HETEROGENEITY.

IN SOME CASES IT'S NOT SO EASY

AND BASICALLY YOU HAVE A GENE IN

A PATHWAY THAT HAS TO DO WITH

INTERMEDIARY METABOLISM AND A

PATHWAY THAT HAD TO DO WITH LIPO

METABOLISM.

AND THOSE GENES DON'T INTERACT

BY ANY KNOWN BIOLOGICAL CHEMICAL

PATHWAY THAT ANYBODY'S PROVED SO

FAR.

BUT YOU HAVE THE HUMAN

REPRESENTATION THAT YOU KNOW

THERE IS SOME COMMONALITY TO

THEM BECAUSE THEY PRODUCE THE

SAME PHENOTYPE.

SO PEOPLE ARE WORKING HARD TO

CONNECT THOSE NETWORKS TOGETHER.

SO THAT'S

COME TOGETHER.

THIUNDERSTOOD THERE'S ONE
PHENOTYPE

AND MANY GENES AND THAT'S CALLED

LOCUS HETEROGENEITY AND YOU CAN

SEE THAT IN THESE DISORDERS.

IT BRINGS TO MIN MIND COMMON

DISEASES, COMMON PRESENTATIONS

HAVE MANY ETIOLOGIES AND IT WAS

TESTED OUT TO HELP US UNDERSTAND

THE BASICS OF MECHANISM AND

OBVIOUSLY HOW TO TREAT THEM.

I THINK THE LAST LESSON THAT WE

LEARNED FROM THIS IS THAT

INTERDISCIPLINARY COLLABORATIONS

OF CLINICIANS AND CELL

BIOLOGISTS AND EACH PATHOLOGIST

AND BIO KES CHEMIST NEEDS TO
THINK

OUTSIDE OF THE BOX WHEN WE LOOK

AT CLINICAL PROBLEMS SO WE

UNDERSTAND THE BASIS OF CLINICAL

DISORDERS AND ALSO ELUCIDATE

THERAPEUTIC OPTIONS.

SO WITH THAT, I'LL PRESENT OUR

ACKNOWLEDGMENT.

DENNIS, IF YOU WANT TO COME UP

AND DO THIS.

AND THEN WE'LL TAKE QUESTIONS IF

THERE ARE ANY BUT YOU'D HAVE TO

SPEAK INTO A MIC.

WE HAVE A HAS NO HAND HELD
BECAUSE IT'S

BEING PRESENTED IN REAL TIME.

>> I WANT TO MENTION THIS IS A

VERY LARGE UNDERTAKING THAT

COULD NOT HAVE BEEN DONE WITHOUT

REALLY SPECTACULAR EFFORTS BY A

LARGE NUMBER OF PEOPLE AT A

LARGE NUMBER OF ORGANIZATIONS.

AND I THINK MY ONE LAST ADDITION

IS SORT OF A PLUG FOR THE NIH

AND A REMINDER TO ALL OF US WHO

WORK HERE IS THAT I THINK IT

PROBABLY WOULD HAVE BEEN

IMPOSSIBLE FOR US TO DO THIS

KIND OF PROJECT ALMOST ANYWHERE

ELSE.

THERE'S REALLY NO OTHER

INSTITUTION IN THE WORLD THAT I

COULD THINK OF, AND I'VE BEEN TO

A NUMBER OF THEM, WHERE GETTING

THE KIND OF GENETIC RESULTS WE

GOT CAN THEN JUST LEAD TO A

SINGLE PHONE CALL THAT BROUGHT

THE ENTIRE CLINICAL, THE WEIGHT

AND THE MIGHT OF THE NIH

CLINICAL CENTER TO BE BROUGHT

UPON REALLY QUITE AN UNUSUAL

GENETIC TYPING.

SO I THINK THAT THE FACT IT

COULD BE DONE AT A PLACE LIKE

THIS WITH THE RESOURCES OF THE

CLINICAL CENTER IS REALLY A

TRIBUTE TO THE ORGANIZATION AND

THE STRUCTURE OF THE NIH

INTRAMURAL PROGRAM.

SO WITH THAT, I WILL JUST THINK

EVERYONE FOR THEIR ATTENTION AND

I THINK WE WILL BE HAPPY TO TAKE

QUESTIONS, IF THERE ARE ANY.

PLEASE, THIS IS BEING BROADCAST,

I UNDERSTAND.

SO IF YOU HAVE QUESTIONS, PLEASE

STEP A MICROPHONE.

>> I'M MICHAEL -- WITH THE

NATIONAL CENTER FOR

REHABILITATION RESEARCH.

CLINICIANS HAVE BEEN WORKING

WITH STUTTERERS FOR YEARS.

YOU HAVEN'T BROUGHT UP THE

FACTOR OF HEARING DURING THE

SPEECH PROCESS.

AND I'M WONDERING IF YOU'RE

CONSIDERING THAT BECAUSE WE CAN

INDUCE STUTTERING IN A CLINICAL

SETTING BY USING NTERRUPTIVE

FACTORS.

AND SO THERE'S SOME CONNECTION

BETWEEN THE INDUCEMENT SPEECH

AND THE PERSON'S SELF REGULATION

OF THE SPEECH.

>> RIGHT.

SO THANK YOU FOR THAT.

THAT'S A VERY GOOD QUESTION.

I SHOULD ALSO JUST ADD TO KIND

OF ADD MORE OF YOUR QUESTION, A

NUMBER OF THERAPY-ASSISTED

DEVICES INTERRUPT THE SPEAKERS'

PERCEPTION OF THEIR OWN SPEECH.

BY VARIOUS MECHANISMS.

AND SOME OF THESE HAVE VERY

SIGNIFICANT EFFECTS ON THE

FLUENCY OF AFFECTED INDIVIDUALS.

SO THE SHORT ANSWER IS THAT

EVERYONE IN OUR STUDY HAS NORMAL

HEARING.

AND IT DOESN'T SEEM TO BE A

FACTOR IN THE PEOPLE WE'VE

IDENTIFIED TO DATE.

>> HI, JUST A QUICK QUESTION.

WITH A PACK OF THE GROUP OF --

FAMILIES, WERE YOU ABLE TO GO

BACK OR MAYBE THIS IS SOMETHING

[INDISCERNIBLE] ON THE FAMILY TO

SEE IF THEY HAVE ANY POSSIBLE OF

THOSE DISORDERS YOU WERE LOOKING

INTO IN THE FOUR PATIENTS.

>> RIGHT.

SO SO WE HAVE TESTED PEOPLE THAT

HAVE MUTATIONS MAYBE ONE OR TWO

OF THE FOUR PATIENTS HAVE THE

SAME MUTATIONS IN FAMILY WE HAVE

FOUND IN PAKISTAN.

BUT THAT BIG FAMILY WE HAVE NOT

BROUGHT THOSE PEOPLE BACK IN THE

UNITED STATES FOR LARGE SCALE

INVESTIGATIONS.

>> SO THE PAKISTANI HAVE THE

SAME EXACT MUATION.

>> THE SAME NUCLEOTIDE AND THE

SAME CODON IN THE SAME GENE.

THESE MUTATIONS WE SEE OVER AND

OVER AGAIN.

>> SO DO YOU THINK POSSIBLY

THERE'S SOME SORT OF SLIGHT

VARIANCE BUT ONE LEADS TO

VERTING AND ONE LEADS TO --

>> THERE'S NO EVIDENCE THAT

SLICING IS INVOLVED.

THESE THINGS ARE NOW ON A --

THEY'RE BASICALLY IN THE MIDDLE

OF --

>> WHAT ABOUT LIKE HISTONE DEAWE

DEACETYLASE OR GENOME TYPE.

>> OUR LINKAGE STUDIES ARE

GENOME-WIDE.

THEY SCAN FOR THE LOCATION OF

THE GENE THAT CAUSES THE

DISORDER ACROSS THE WHOLE LENGTH

OF ALL CHROMOSOMES.

AND WE DON'T, FOR INSTANCE IN

THAT BIG FAMILY I SHOWED THERE'S

NO EVIDENCE ELSEWHERE THAT

FAMILY.

NOW THERE ARE OTHER STUTTERING

FAMILIES WHERE WE CAN FIND

EVIDENCE FOR LINKAGE IN MORE

THAN ONE PLACE IN A BIG FAMILY.

AND THAT TELLS US THERE'S MORE

THAN BUN GEN ONE GENE AT WORK IN
THOSE

FAMILIES.

>> THANK YOU.

>> SURE.

>> I HAVE A QUESTION ABOUT THE

MICE YOU MADE.

THIS IS A QUESTION ABOUT THE

KNOCK-IN AND KNOCK-OUT MICE.

I WAS WONDERING SINCE YOU DENIED

OR SHOWED THOSE TWO GENES ARE

HIGHLY YO UPREGULATED IN SOME
PART

OF THE BRAIN, THE DEFECTS FOR

EXAMPLE -- OBVIOUSLY YOU SAY

THERTHEY ARE NORMAL IN TERMS OF

THEIR BEHAVIOR AND THEIR MOTOR

FUNCTIONS.

BUT HAVE YOU LOOKED.

>> NO, NOT YET.

THE KNOCK-OUTS ARE A MESS.

IT WAS THE SAME PERSON WHO DID

OUR BIO CHEMICAL ENZYME IN THE

ACKNOWLEDGMENT THERE.

>> THANK YOU.

>> NO OTHER QUESTIONS?

THEN, THANK YOU ALL.