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  • The

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    NORD Guides for Physicians

    The Physicians Guide to

    Gaucher Disease

    Visit website at:nordphysicianguides.org/Gaucher-Disease

  • For more information about NORDs 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.orgNORDs Rare Disease Database and Organizational Database may be accessed at www.rarediseases.org.Contents 2013 National Organization for Rare Disorders

  • 1Introduction

    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

  • 2havebeenidentifiedthataredistinguishedbytheabsenceof,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,andinfiltrationofpharyngealtonsilsandPeyerspatchesintheintestinearecommoninchildren.Pericardialinvolvementhasoccasionallybeennoted.ThekidneysareinvolvedinsomepatientswithGaucherdisease,butfrank

  • 3renal 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 20s, while others have lived for much longer (30sand40s).Itisanticipatedthatthelifespanmaybefurtherextended

  • 4by 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).

  • 5Figure1Sphingosine

    Figure2.Ceramide.Alongchainfattyacidislinkedtothenitrogenatomoncarbonatom2of sphingosine.

    Figure3.Glucocerebroside.Amoleculeofglucoseislinkedtotheoxygenatomoncarbonatom 1 of the sphingosine moiety of ceramide.

    Figure4.Siteofactionofglucocerebrosidase,theenzymethatcatalyzesthehydrolyticcleavageofglucose from glucocerebroside.

  • 6Figure5.Structureoftheprincipalsphingolipidofwhitebloodcells.

    Figure6.Majorsphingolipidofbloodplatelets.

    Figure7.Majorsphingolipidofredbloodcells.

  • 7PrognosisWiththeexceptionofpatientswithType2Gaucherdiseasewithseverecentral nervous system involvement and death in infancy, the rapidity and extentoftheseverityofthesi