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NORD Guides for Physicians

The Physician’s Guide to

Gaucher Disease

Visit website at:nordphysicianguides.org/Gaucher-Disease

For more information about NORD’s programs and services, contact:National Organization for Rare Disorders (NORD)PO Box 1968Danbury, CT 06813-1968Phone: (203) 744-0100Toll free: (800) 999-NORDFax: (203) 798-2291Website: www.rarediseases.org Email: orphan@rarediseases.orgNORD’s Rare Disease Database and Organizational Database may be accessed at www.rarediseases.org.Contents ©2013 National Organization for Rare Disorders®

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Introduction

WelcometotheNORDPhysicianGuidetoGaucherdisease.TheNORDOnlinePhysicianGuidesarewrittenforphysiciansbyphysicianswithexpertiseonspecificraredisorders.ThisguidewaswrittenbyRoscoeO.Brady,MD,NationalInstituteofNeurologicalDisordersandStroke(NINDS),NationalInstitutesofHealth(NIH)(seeacknowledgementsforadditionalinformation).

NORDisanonprofitorganizationrepresentingallpatientsandfamiliesaffected by rare diseases. The information NORD provides to medical professionals is intended to facilitate timely diagnosis and treatment for patients.

Gaucherdiseaseisalipidstoragediseasecausedbyanenzymedeficiencythatresultsinexcessglycolipidglucocerebrosidethroughoutthebodyespecially in the spleen, liver and bone marrow, and is characterized by a wide range of severity.

The author and NORD appreciate your interest in this topic. There are opportunities for follow-up questions and/or discussion in the Clinician Comments section of the online guide.

What is Gaucher Disease?Gaucherdiseaseisarare,inheritedmetabolicdisorderinwhichdeficiencyof the enzyme glucocerebrosidase results in the accumulation of harmful quantitiesofcertainlipids,specificallytheglycolipidglucocerebroside,throughout the body especially within the spleen, liver, and bone marrow. ThesymptomsandphysicalfindingsassociatedwithGaucherdiseasevarygreatlyfromcasetocase.Someindividualsdevelopfewornosymptomsand others may have serious complications. Common manifestations of Gaucherdiseaseincludehepatosplenomegaly,anemia,thrombocytopenia,andskeletalabnormalities.ThreeclinicalpresentationsofGaucherdisease

2

havebeenidentifiedthataredistinguishedbytheabsenceof,orthepresenceandextentof,neurologicalinvolvement.AllthreeformsofGaucherdiseaseareinheritedasautosomalrecessivetraits.

Gaucherdiseaseiscategorizedasalysosomalstoragedisorder.Lysosomesarethemajordigestiveunitsincellscontainingenzymesthatbreakdowncarbohydrates, lipids (fatty materials) and proteins that arise from membranesandothercomponentsofcellsundergoingturnover.InGaucherdisease,glycolipidsaccumulateinthebodybecauseofthelackof the enzyme, glucocerebrosidase, leading to the various symptoms and physicalfindingsassociatedwithalysosomalstoragedisease.Gaucherdisease is the most common type of lysosomal storage disorder.

Symptoms and SignsTherearethreedistinctformsofGaucherdiseaseclassifiedbytheabsence(type1)orpresenceandextent(type2ortype3)ofneurologicalcomplications.ThemajorityofaffectedindividualshaveGaucherdiseasetype1.Approximately5%ofpatientshavetype2andtype3Gaucherdisease. Type 2 patients have severe brain damage and die early in life. Type 3 patients live longer and have involuntary horizontal eye movement and often muscle contractions.

OneoftheearliestmanifestationsofGaucherdiseaseisenlargementofthespleen.Itmaybesmallanddetectablejustbelowtheribcageorhugeextendingdowntheleftsideoftheabdomenandpalpablefromlefttoright across the lower pelvis. The liver also becomes enlarged but not to themagnitudeexhibitedbythespleen.Theskeletonmayalsobeinvolved.The long bones, pelvis and vertebrae become under-mineralized resulting inseveredeformationandeasyfracturing.Aconsiderablepercentageofpatientsexperiencepainfulbonecrises.Majormanifestationsoccurin the circulation including severe thrombocytopenia with easy bruising and hemorrhage and moderate to severe anemia. The lungs can become involved, and pronounced dyspnea occurs in a small number of patients. Respiratorygasexchangeiscompromised,anddiffusepulmonaryinfiltrationisevidentradiographically.Thelymphnodesmaybeenlarged,andinfiltrationofpharyngealtonsilsandPeyer’spatchesintheintestinearecommoninchildren.Pericardialinvolvementhasoccasionallybeennoted.ThekidneysareinvolvedinsomepatientswithGaucherdisease,butfrank

3

renal failure is uncommon. There is a well-recognized increase in certain hematologicalmalignanciesincludingB-cellorplasmacellmalignancies,multiplemyeloma,chroniclymphocyticleukemia,acutemyeloidleukemia,acutelymphoblasticleukemia,largeB-celllymphoma,Hodgkinlymphoma,as well as non-hematologic malignancies

1

.PatientsthatsurvivetoadulthoodhaveasignificantlyincreasedchanceofParkinsonism

(2)

.

Gaucherdiseasetype2,alsoknownasacuteneuronopathicGaucherdisease, occurs in newborns and infants and is characterized by neurological complications due to the abnormal accumulation of glucocerebroside in the brain.Splenomegalyisoftenthefirstsignandmaybecomeapparentbeforesixmonthsofage.Hepatomegalyisnotalwayspresent.Affectedinfantsmaylosepreviouslyacquiredmotorskillsandexhibithypotonia,spasticity,strabismus,rapidheadthrustingandseizures.Inaddition,affectedinfantsmayexperiencedysphagia,resultinginfeedingdifficulties,retroflexionofthehead,failuretothrive,andstridorduetolaryngealspasm.Anemiaandthrombocytopeniamayalsooccur.Gaucherdiseasetype2oftenprogresses to life-threatening complications such as respiratory distress or aspirationpneumonia.Severelyaffectednewbornsmayshowcollodionskinorichthyosiformchangesandhydrops,withdeathinthefirstfewweeksoflife.Otherchildrenwithtype2Gaucherdiseasehavegreatlyreducedlifespans,withdeathusuallyoccurringbetween1and3yearsoflife.Ithasbeenestimatedthatabout10suchinfantsarebornintheU.S.eachyear.

Gaucherdiseasetype3,alsoknownaschronicneuronopathicGaucherdisease,occursduringthefirstdecadeoflife.Type3patientshaveavaryingdegree of early hepatosplenomegaly that may initially be moderate and in somemaybecomeextensive.Inadditiontothebloodandboneabnormalitiesdiscussed above, affected individuals develop neurological complications thatdevelopandprogressslowerthaninGaucherdiseasetype2.Associatedneurologicalcomplicationsincludementaldeterioration,ataxia,andmyoclonicseizures.Someindividualswithtype3Gaucherdiseasemayhavehorizontalgazepalsy.PatientswithType3Gaucherdiseasecanalsohave a vertical gaze palsy that usually occurs later than the horizontal gaze paresis.Asignificantproportionofpatientsalsodevelopinterstitiallungdisease. There can be wide variability in presentation and clinical course amongpatientswithtype3Gaucherdisease.Someaffectedpatientsmaylive into their teens and early 20’s, while others have lived for much longer (30’sand40’s).Itisanticipatedthatthelifespanmaybefurtherextended

4

by effective treatment such as enzyme replacement therapy (vide infra).

CausesGaucherdiseaseisaautosomalrecessivegeneticdisordercausedbymutations in a gene on human chromosome 1 that codes for an enzyme thatisimportantforlipidmetabolism.Bothparentsmustcarryamutationof the gene in order to produce a child that is affected with the disorder. Suchparentsarecalledcarriers(heterozygotes).Whentwoheterozygotesmarry, there is a 1 in 4 chance with each pregnancy that the child will have thedisorder.Thereis50-50chancethatthechildwillbeaheterozygotecarryingamutationfromoneofitsparents.Gaucherheterozygotesaregenerallyasymptomatic.Thereisa25%chancewitheachpregnancythat the offspring will be affected (have two mutations) or be completely unaffected (no mutations).

ThecauseofallthreeformsofGaucherdiseaseistheaccumulationofafattymaterialcalledglucocerebroside(alsoknownasglucosylceramide)throughoutthebodyandbloodstreamofpatients.Glucocerebrosideisalipidconsistingofthreecomponents.Thefirstoftheseisalongchainalcoholcalledsphingosine(Fig1).Alongchainfattyacidislinkedtothenitrogen atom (N) on carbon atom 2 of sphingosine creating a structure knownasceramide(Fig.2).Amoleculeofglucoseislinkedtotheoxygenatomoncarbon1ofthesphingosinemoietyofceramideformingglucocerebroside (Fig 3). Organs and cells in the body contain an enzyme called glucocerebrosidase that catalyzes the hydrolytic cleavage of glucose from glucocerebroside

(3)

(Fig. 4). The activity of this enzyme is reduced in patientswithGaucherdiseaseandisthemetabolicdefectinthisdisorder(4,5)

. The reduction of glucocerebrosidase activity causes the accumulation oftoxicamountsofglucocerebrosideinorgans,tissuesandthebloodofpatientswithGaucherdisease.Theprincipalsourceofaccumulatingglucocerebroside in the spleen, liver and bone marrow are rapidly turning overcellssuchaswhitebloodcells(Fig.5).GlucocerebrosidealsoarisesfromthebiodegradationofgangliosideGM3inplatelets(Fig.6)andfrom globoside, the principal sphingolipid in red blood cells (Fig. 7). The accumulation of glucosylsphingosine (Fig 8) in the brain is a major cause of the pathological changes that occur in the central nervous system of patientswithtypes2and3Gaucherdisease

(6)

.

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Figure1Sphingosine

Figure2.Ceramide.Alongchainfattyacidislinkedtothenitrogenatomoncarbonatom2

of sphingosine.

Figure3.Glucocerebroside.Amoleculeofglucoseislinkedtotheoxygenatomoncarbon

atom 1 of the sphingosine moiety of ceramide.

Figure4.Siteofactionofglucocerebrosidase,theenzymethatcatalyzesthehydrolyticcleavageof

glucose from glucocerebroside.

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Figure5.Structureoftheprincipalsphingolipidofwhitebloodcells.

Figure6.Majorsphingolipidofbloodplatelets.

Figure7.Majorsphingolipidofredbloodcells.

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PrognosisWiththeexceptionofpatientswithType2Gaucherdiseasewithseverecentral nervous system involvement and death in infancy, the rapidity and extentoftheseverityofthesignsandsymptomsinpatientswithGaucherdiseaseisremarkablyvariable.ThelifespanofpatientswithType3GaucherdiseasehasbeenmentionedpreviouslyinthesectiononSymptomsandSigns.TheprognosisinpatientswithType1Gaucherdiseaseisquitevariable.Manypatientsdevelophepatosplenomegalyasearlyasfouryearsof age while in others, this manifestation may not become apparent until themidorlatethirties.Generally,theearliertheonsetofprominentsignsthat often include anemia and thrombocytopenia, the more rapidly the pathological manifestations of the disorder proceed.

Affected PopulationsAllformsofGaucherdiseaseaffectmalesandfemalesinequalnumbers.Gaucherdiseasetype1isthemostcommontype,accountingformorethan90percentofcases.IndividualswithGaucherdiseasetype1usuallyexhibitsymptomsduringadolescence,buttheageofonsetrangesfromchildhoodtoadulthood.TheageofonsetforGaucherdiseasetype2isduringearlyinfancy.TheageofonsetofGaucherdiseasetype3varies,butthe disorder generally begins during childhood or adolescence.

Thereareapproximately6,000individualswithGaucherdiseaseintheU.S.Gaucherdiseaseisthemostcommongeneticdisorderofpersonsof

Figure8.Glucosylsphingosine.Ahighlycytotoxicsubstancethatalsoaccumulatesin

organsandtissuesofpatientswithGaucherdiseasebuttoamuchlesserextentthan

glucocerebroside.

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AshkenazicJewishancestry,wheretheincidencemaybeashighas1in600births.ThereisnoethnicprevalenceassociatedwithGaucherdiseasetypes2or3.However,thereisasubtypeofGaucherdiseasetype3thatoccurswithgreaterfrequencyintheNorrbottenregionofSweden(NorrbottnianGaucherdisease).TheestimatedprevalenceintheSwedishNorrbottenpopulationis1in50,000.

DiagnosisGaucherdiseaseshouldbeconsideredinpersonswithenlargementofthespleenandliver.Additionalmajorsignsincludeanemia,easybruising,episodes of bone pain and fractures of the femur and pelvis. The diagnosis canbereadilyconfirmedbymeasuringtheactivityofglucocerebrosidasein white blood cells

(7)

orculturesofskinfibroblasts(8)

.Afluorogenicmimic of glucocerebroside was employed as substrate in the investigation withskinfibroblasts.ThissubstrateiswidelyusedforthediagnosisofGaucherdiseaseatthepresenttime.ThediagnosismaybeconfirmedbyDNAanalysisformutationsinthecausalgenes.TheidentificationofheterozygouscarriersofGaucherdisease

(9)

and the prenatal diagnosis of Gaucherdiseasebygeneticanalysisareestablishedprocedures

(10)

.

TreatmentEnzyme replacement therapy (ERT) has proven highly effective for patients with type1Gaucherdisease.AnemiaandlowplateletcountshaveimprovedwithERT,enlargementoftheliverandspleenhavebeengreatlyreduced,andskeletalfindingshaveimproved

(11-15)

. These systemic manifestations also improve in individualswithtype3GaucherdiseasewhoreceiveERT

(16,17)

.However,ERThasnot been effective in reducing or reversing neurological signs associated with types2and3Gaucherdisease.

ERTisthestandardofcareforpatientswithGaucherdisease.Manypatientshavebeensuccessfullytreatedwithpurifiedhumanplacentalglucocerebrosidase(11)

. The sugar side chains of the enzyme were shortened so that it is primarily takenupbymacrophages.Theuseofthisproducthasbeensupersededbytheadministrationofrecombinantglucocerebrosidase.Thefirstpreparationwasproduced in Chinese hamster ovary cells

(12)

. This preparation is called Cerezyme (imiglucerase).ItismarketedbyGenzyme,aSanofiCompany.

Atthepresenttimetherearetwoadditionalsourcesofglucocerebrosidase.OneofthemcalledVPRIV(velaglucerasealfa)isproducedfroma

9

fibrosarcomacelllinebyShirePharmaceuticals.TheothercalledtaliglucerasealfaisfromcarrotrootcellsproducedbyProtalixBiotherapeutics,anIsraelicompanyanddistributedbyPfizer,Inc.underthetradenameELELYSO™(UPLYSO™).

Administrationoftheenzymecausesreductioninthesizeofthespleenandliverandimprovementoftheskeleton,anemiaandthrombocytopenia.Severelyillpatientswithtype1Gaucherdiseasearegenerallystartedwithadoseof60Units(U)ofenzymeperkgofbodyweighteveryotherweek.Aspatientsimprove,thedosemaybereducedto30Uperkgofbodyweight,andinmanycasesto20Uperkgofbodyweighteveryotherweek.Thefrequencyofadministrationofenzymehasbeenextendedtoevery3weeksin a number of patients who have been maintained in good condition with thisregimen.LongtermbenefitofERTinpatientswithtype1Gaucherhasbeen clearly documented

(13-15)

.HepatosplenomegalyandhematologicalmanifestationscanbeimprovedbyERTinpatientswithtype3Gaucherdisease but neurological and other complications of the condition have not responded to this therapy

(16,17)

.

AnotherapproachtothetreatmentofpatientswithGaucherdiseaseistotrytoblocktheformationofglucocerebrosidewithcompoundsthatinhibittheadditionofglucosetoceramide(Fig.2).AproductofthistypecalledMiglustat(Zavesca)ismarketedbyActelion.ItisapprovedbytheU.S.FoodandDrugAdministrationforthetreatmentofpatientswithGaucherdisease “for whom enzyme replacement therapy is not an option”.

Investigative TherapiesOraldeliveryofplantGlucocerebrosidase(prGCD)ERTasacarrotcellsuspension,(expressed)isunderdevelopment.Additionally,anumber of investigations are directed toward reducing the formation of glucocerebroside

(18-20)

.Molecularchaperonetherapythatpreventsintracellular mis-folding and subsequent destruction of mutant forms of glucocerebrosidase is also under active investigation

(21)

.Blockingtheactivity of histone deacetylases may be a promising strategy to restore reduced mutant glucocerebrosidase activity

(22)

. Future investigations may includetheuseofviralvectorstoincreasetheexpressionofthegeneforglucocerebrosidase

(23)

.

Information on current clinical trials is posted at www.clinicaltrials.gov.

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NORD does not endorse or recommend any particular studies.

References1

.LoSM,SteinP,MullalyS,BarM,JainD,PastoresGM,MistryPK.ExpandingthespectrumoftheassociationbetweenType1Gaucherdiseaseandcancers:Aseriesofpatientswithupto3sequential cancers of multiple types. Correlation with genotype and phenotype. Am J Hematol 2010;85:340-345.

2

.SidranskyEetal.MulticenteranalysisofglucocerebrosidasemutationsinParkinson’sdisease.N Engl J Med2009;361:1651-1661.

3

.BradyRO,KanferJ,ShapiroD.Themetabolismofglucocerebrosides.I.Purificationandproperties of a glucocerebroside-cleaving enzyme from spleen tissue. J Biol Chem1965;240:39-42.

4.

BradyRO,KanferJN,Shapiro,D.Metabolismofglucocerebrosides.II.EvidenceofanenzymaticdeficiencyinGaucher’sdisease.Biochem Biophys Res Commun1965;18:221-225.

5

.BradyRO,KanferJN,BradleyRM,ShapiroD.Demonstrationofadeficiencyofglucocerebroside-cleavingenzymeinGaucher’sdisease. J Clin Invest1966;45:1112-1115.

6

.NilssonO,SvennerholmL.Accumulationofglucosylceramideandglucosylsphingosine(psychosine)incerebrumandcerebellumininfantileandjuvenileGaucherdisease.J Neurochem 1982; 39: 709-718.

7

.KampineJP,BradyRO,KanferJN,FeldM,ShapiroD.ThediagnosisofGaucher’sdiseaseandNiemann-Pickdiseaseusingsmallsamplesofvenousblood.Science1967;155(3758):86-8.

8

.BeutlerE,KuhlW,TrinidadF,TeplitzR,NadlerH.DetectionofGaucher’sdiseaseanditscarrierstatefromfibroblastcultures.Lancet1970;2(7668):369.

9

.BradyRO,JohnsonWG,UhlendorfBW.Identificationofheterozygouscarriersoflipidstorage diseases. Am J Med1971;51:423-431.

10.

SchneiderEL,EllisWG,BradyRO,McCullochJR,EpsteinCJ.InfantileTypeII)Gaucher’sdisease: in utero diagnosis and fetal pathology. J Pediatr 1972; 81: 1134-1139.

11.

BartonNW,BradyRO,DambrosiaJM,DiBisceglieAM,DoppeltSH,et al. Replacement therapyforinheritedenzymedeficiency—macrophage-targetedglucocerebrosidaseforGaucher’sdisease.N Engl J Med1991;324:1464-1470.

12.

GrabowskiGA,BartonNW,PastoresG,DambrosiaJM,BanerjeeTK,McKeeMA,ParkerC,SchiffmannR,HillSC,BradyRO.EnzymetherapyinGaucherdiseaseType1:Comparativeefficacyofmannose-terminatedglucocerebrosidasefromnaturalandrecombinantsources.Ann Int Med1995;122:33-39.

13.

WeinrebNJ,CharrowJ,AnderssonHC,KaplanP,KolodnyEH,MistryP,PastoresG,RosenbloomBE,ScottCR,WappnerRS,ZimranA.Effectivenessofenzymereplacementtherapyin1028patientswithtype1Gaucherdiseaseafter2to5yearsoftreatment:areportfromtheGaucherRegistry.Am J Med 2002; 113: 112-119.

14.

WeinrebNJ,GoldblattJ,VillalobosJ,CharrowJ,ColeJA,KerstenetzkyM,VomDahlS,HollakC.Long-termclinicaloutcomesintype1Gaucherdiseasefollowing10yearsofimiglucerase treatment. J Inherit Metab Dis2012doi:10.1007/s10545-012-9528-4

11

15.

Deegan,PB,CoxTM.ImigluceraseinthetreatmentofGaucherdisease:ahistoryandperspective. Drug Design, Development and Therapy2012;6:81-106.

16.

MengelE,ArnoffJ,ReinkeJ,BeckM.LongtermfollowupoftheMainzcohortofGaucherdisease type 3 patients. Mol Genet Metabol2013;108:S65-S66.

17.

BurrowTkWitteD,BaileyL,PradaC,SunY,CohenM,Wu,GrabowskiG.AbnormalpathologyfindingsinapatientwithGaucherdiseasetype3treatedwithenzymereplacementtherapy. Mol Genet Metab2013;108:S27.

18.

PlattFM,JeyakumarM.Substratereductiontherapy.Acta Paediatr Supp 2008; 97: 88-93.

19.

LukinaE,WatmanN,ArreguinEA,DragoskyM,IastrebnerM et al.Improvementinhematological,visceral,andskeletalmanifestationsofGaucherdiseasetype1withoraleliglustattartrate(GENZ-112638)treatment:2-yearresultsofaphase2study.Blood 2011; 116:4095-4098.

20.

LarsenSD,WilsonWW,AbeA,ShuLM,GeorgeCHetal.Property-baseddesignofaglucosylceramide synthase inhibitor that reduces glucosylceramide in the brain. J Lipid Res 2012;53:282-291.

21.

Bendikov-BarI,MairG,FilocamoM,HorowitzM.Ambroxolasapharmacologicalchaperonefor mutant glucocerbrosidase. Blood Cells Mol Dis2013;50(2):141-5.

22.

LuJ,YangC,ChenM,YeDY,LonserRR,BradyRO,ZhuangZ.HistonedeacetylaseinhibitorspreventthedegradationandrestoretheactivityofglucocerebrosidaseinGaucherdisease.Proc Natl Acad Sci USA2011;108:21200-21205.

23.

SardiAP,ClarkeJ,VialC,ChanM,TamsettTJet al.AugmentingCNSglucocerebrosidaseactivityasatherapeuticstrategyforparkinsonismandotherGaucher-relatedsynucleinopathies. Proc Natl Acad SciUSA2013;110(9):3537-42.

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ResourcesSupport for patients with Gaucher disease is provided by:

National Gaucher Foundation2227IdlewoodRoad,Suite6,Tucker,GA30084Telephone800-504-3189or770-934-2890FAX770-934-2911E-mail: ngf@gaucherdisease.orgWeb: www.gaucherdisease.org

Support primarily devoted toward children including those with Type 3 Gaucher disease is provided by:

Children’s Gaucher Research Fund8110 Warren CourtGraniteBay,CA95746Telephone9167973700FAX9167973707E-mail: research@childrensgaucher.orgWeb: www.childrensgaucher.org

National Organization for Rare Disorders (NORD)POBox196855KenosiaAvenueDanbury,CT06813-1968Telephone: (203) 744-0100 or (800) 999-NORDE-mail: orphan@rarediseases.orgWeb: www.rarediseases.org

Clinical Centers and Medical Experts

ThefollowinglinkistoapageontheNationalGaucherFoundationwebsitethat lists physicians and treatment centers.http://www.gaucherdisease.org/gaucher_treatment_locations.php

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Acknowledgements

NORDisgratefultoRoscoeO.Brady,MD,National InstituteofNeurologicalDisordersandStroke(NINDS),NationalInstitutesofHealth(NIH),forwritingthisguide.

Dr.Brady’saccomplishmentsincludetheidentificationofthe metabolic defects in hereditary lipid storage disorders includingGaucherdisease,Niemann-Pickdisease,Fabrydisease,andTay-Sachsdisease.

AbriefhistoryofDr.Brady’spioneeringroleinpromotingbetterunderstandingofGaucherdiseasemaybefoundat the following location on the website of the National

InstitutesofHealth(NIH):http://history.nih.gov/exhibits/gaucher/docs/page_05.html

RoscoeBradywasborninPhiladelphia,PA.HeattendedthePennsylvaniaStateUniversityandobtainedhisM.D.degreefromHarvardMedicalSchoolin1947.HeinternedattheHospitaloftheUniversityofPennsylvania.From1948to1952hewasapost-doctoralfellowintheDepartmentofPhysiologicalChemistryattheUniversityofPennsylvaniaSchoolofMedicineandfellowinclinicalmedicineintheDepartmentofMedicine.Aftertwoandone-halfyearsonactivedutyintheU.S.NavalMedicalCorps,hejoinedtheNationalInstitutesofHealthin1954.HewasChiefoftheDevelopmentalandMetabolicNeurologyBranchintheNationalInstituteofNeurologicalDisordersandStrokefrom1972to2006.Dr.BradyreceivedtheLaskerFoundationAwardin1982;theKovalenkoMedalfromtheNationalAcademyofSciencesUSAin1991;theAlpertFoundationPrizefromHarvardMedicalSchoolin1992andtheNationalMedalofTechnologyandInnovationin2008.HeisamemberoftheNationalAcademyofSciences,USAandtheInstituteofMedicineoftheNationalAcademyofSciences.Dr.BradyandhiscolleaguesidentifiedtheenzymaticdefectsinGaucherdisease,Niemann-Pickdisease,FabrydiseaseandthespecificmetabolicabnormalityinTay-Sachsdisease.Heandhisassociatesdevelopeddiagnostic,carrierdetectionandprenataltestsfortheseconditions.HedevelopedeffectiveenzymereplacementtherapyforpatientswithGaucherdiseaseandFabrydisease.Heiscurrentlyinvestigatingsubstrate depletion, molecular chaperone therapy and gene therapy for patients with metabolic storage disorders.

This guide was made possible through the Collaborations, Coalitions and SponsorshipProgramofPfizer.

Content Copyright © 2013 NORD – National Organization for Rare Disorders, Inc.Allrightsreserved.

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Patient Support and Resources National Organization for Rare Disorders (NORD) 55KenosiaAvenue POBox1968 Danbury,CT06813-1968 Phone:(203)744-0100 Toll free: (800) 999-NORD Fax:(203)798-2291

www.rarediseases.org orphan@rarediseases.org

NORD is grateful to Roscoe O. Brady, MD, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), for writing this guide.

This NORD Physician Guide was made possible by an educational grant from Pfizer.

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#2 The Pediatrician’s Guide to Ornithine Transcarbamylase Deficiency...and other Urea Cycle Disorders

#3 The Physician’s Guide to

Primary Lateral Sclerosis

#4 The Physician’s Guide to

Pompe Disease

#5 The Physician’s Guide to

Multiple System Atrophy

#6 The Physician’s Guide to

Hereditary Ataxia

#7 The Physician’s Guide to Giant Hypertrophic Gastritis and Menetrier’s Disease

#8 The Physician’s Guide to Amyloidosis

#9 The Physician’s Guide to

Medullary Thyroid Cancer

#10 The Physician’s Guide to

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The Homocystinurias

#12 The Physician’s Guide to Treacher Collins Syndrome

#13 The Physician’s Guide to Urea Cycle Disorders

#14 The Physician’s Guide to Myelofibrosis

#15 The Physician’s Guide to Lipodystrophy Disorders

#16 The Physician’s Guide to Pompe Disease

#17 The Physician’s Guide to Gaucher Disease

These booklets are available free of charge. To obtain copies, call or write to NORD or download the text from www.NORDPhysicianGuides.org.

For information on rare disorders and the voluntary health organi-zations that help people affected by them, visit NORD’s web site at www.rarediseases.org or call (800) 999-NORD or (203) 744-0100.

NORD helps patients and families affected by rare disorders by providing:

• Physician-reviewedinformation in understandable language

• Referralstosupportgroupsand other sources of help

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• Grantsandfellowshipsto encourage research on rare diseases

• Advocacyforhealth-related causes that affect the rare- disease community

• Publicationsforphysiciansand other medical professionals

Contact NORD at orphan@rarediseases.org.National Organization for Rare Disorders (NORD)POBox1968Danbury,CT06813-1968

Phone:(203)744-0100Toll free: (800) 999-NORDFax:(203)798-2291

This booklet was made possible through an educational grant from Pfizer.