A guide to ASMD Niemann-Pick disease types A and B

A guide to ASMD Niemann-Pick disease types A and B Understanding acid sphingomyelinase defi cient Niemann-Pick disease types A and B and their potential treatment
Jacqueline Imrie SRN RSCN MSc Clinical Nurse Specialist Niemann-Pick diseases
A guide to ASMD Niemann-Pick disease types A and B
Understanding acid sphingomyelinase deficient Niemann-Pick disease types A and B and their potential treatment
Jacqueline Imrie SRN RSCN MSc
Clinical Nurse Specialist Niemann-Pick diseases
Contents
Introduction3 Ascientist’sperspective4 Acidsphingomyelinasedeficientdiseaseinsummary5 ThehistoryofNiemann-Pickdisease6 ThegeneticsofASMD7 Diagnosis 10 Pathophysiology 11 Epidemiology 17 Potentialtherapies 17 Specialistcentres 19 Acalltoaction 20 Socialandpsychologicalimpact 21 Thefamilyperspective 22 Support 24 Conclusion 25 Resources 26 References 28 Glossaryofterms 31
Publishedby: Niemann-PickDiseaseGroup(UK) 11GreenwoodClose Fatfield Washington NE388LR
w wwwniemannpickorguk t 01914150693 e niemann-pick@zetnetcouk
ISBN9780956674708
©Niemann-PickDiseaseGroup(UK)2010
Thispublicationhasbeenmadeavailablethrough aneducationalgrantfromGenzyme
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Introduction
AcidsphingomyelinasedeficientNiemann-Pickdisease(ASMD)isanextremely raredisorderresultinginpotentiallylife-limitingillnessesinchildrenandyoung adultsItcoversaspectrumofconditionsandthisbookletprovidesinformation onASMDNiemann-PickdiseasetypesAandB,whicharetwoformsofthedisease associatedwithadeficiencyinthebodyoftheenzymeacidsphingomyelinase
Thebookletbringstogetherawiderangeofinformationwhichshouldbe usefultoeveryoneinvolvedinthetreatmentofpatientswithASMDNiemann- PickdiseasetypesAandB,withparticularemphasisonclassicaltypeBSupport fortypeAisaroundmanagementoftheseveresymptomsandaseparatecare manualforNPAisavailablefromtheNiemann-PickDiseaseGroup(UK)
ThescientificevidenceassociatedwithASMDispresentedfirstfollowedby informationaboutwhatlifeislikeforfamilieswithchildrenandadultswho haveASMD
Atfirstthescientificsectionmayseemverytechnicalforlaypeopleto understandandalsounfamiliartomanydoctorsHowever,anyonewhohas anassociationwiththediseasewillgraduallylearnmoreaboutthecomplexi- tiesofASMDandunderstandthesciencerelatedtoitThesectionforfamilies providesfirst-handaccountsfromparentsandinformationabouthowtogain supportThereisalsoinformationaboutthepossiblesocialandpsychological impactofthedisease
Thisbookletisintendedtohelppatients,theirfamilies,doctorsandscientists gainabetterunderstandingofthediseaseandhowtomanageitAsyetthere isnocureforASMDbutclinicalenzymereplacementtherapytrialsareintheir earlystagesandofferhopeforfutureadvances
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A scientist’s perspective
Acidsphingomyelinasedeficientdisease(ASMD)hasbeenknownsincethe early1960sasNiemann-PickdiseasetypesAandB(NPAandNPB)However,it hasbecomeapparentoverthelastdecadethatthereisawideclinicalspectrum ofdiseasecausedbythedeficiencyofthelysosomalenzymeacidsphingo- myelinase(ASM)
Patientsatthesevereendofthespectrum(NPA)haveaveryrapidlypro- gressiveneurodegenerativediseaseusuallyresultingindeathbeforetheage offourIncontrastpatientsattheotherendofthespectrum(NPB)haveaphe- notypicallyvariabledisorderthatisusuallydiagnosedinchildhoodbecauseof hepatosplenomegalyAmajorityofNPBpatientssurvivewellintoadulthood withlittleornoneurologicalinvolvementProgressivepulmonaryinfiltrationis themajordisease-relatedcomplicationformostpatients,whilstthehaemato- logicaleffectsofhypersplenismcanalsobesevere,ascanliver-relatedillness
ASMDisinheritedinanautosomalrecessivemannerwithmorethan100 publishedmutationshavingbeenidentifiedCurrentlythereisnotherapyfor ASMDbutclinicaltrialsofenzymereplacementtherapyareongoingforthose withthetypeBphenotype
BecauseoftheseverityandcomplexityofASMDitisimportantthatpatients aremanagedatspecialistcentres(seepage19)forinbornerrorsofmetabolism whereinterdisciplinarycarecanbeoffered
ThesocialandhealthcareimpactofASMDcannotbeoverestimatedand patientorganisationsandsupportgroupsplayavitalroleWithcontinuedefforts itishopedthatfutureresearchwillleadtotreatmentsandacureInternational researchisinprogresstowardsthedevelopmentoftherapiesthatcouldplay ahugeroleinfightingthisdisease
Dr Ed Wraith HonoraryProfessorofPaediatric InheritedMetabolicDisease GeneticMedicine StMary’sHospital OxfordRoad ManchesterM139WL t 01617012137 e edwraith@cmftnhsuk
Dr Edward H Schuchman GeneticDiseaseFoundation–Francis CrickProfessorofGenetics&Genomic SciencesandDirector,International CenterfortypesAandBNiemann- PickDisease,MountSinaiSchoolof Medicine,1425MadisonAvenue, Room14–20A,NewYork, NY10029USA t 2126596711 f 2128492447 e edwardschuchman@mssmedu
Jackie Imrie, SRN, RSCN, MSc ClinicalNurseSpecialistNiemann-Pickdiseases GeneticMedicine StMary’sHospital OxfordRoad ManchesterM139WL t 01617012414 e jacquelineimrie@cmftnhsuk
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Acid sphingomyelinase defi cient disease in summary
Acidsphingomyelinasedeficientdisease(ASMD)isarareautosomalrecessive inbornerrorofmetabolismthatleadstotheaccumulationofsphingomyelin incellsandtissuesandcausestheclinicaldisorderknownasNiemann-Pick disease(NPD)typesAandB1
Meikle(1999)estimatestheincidenceinnewbornsasbeingbetween04 in100,000to06in100,0002,althoughthisislikelytovarywidelyamongdif- ferentpopulationsHistorically,twodistinctsubtypeshavebeendescribedon thebasisoftheirphenotypes(typesAandB)
Type Adisease,whichhasanAshkenaziJewishpredilection,isasevere neurodegenerativediseaseofinfancycharacterisedbyprogressivepsychomo- torretardation,failuretothrive,hepatosplenomegaly,cherry-redmacula,and deathbythreetofouryearsofage
Incontrast,type B,whichispanethnic,ischaracterisedbyhepatosplenom- egaly,thrombocytopenia,interstitiallungdiseaseanddyslipidaemiawithmost patientshavinglittleornoneurologicalinvolvement3
Recentstudiessuggestthatthereisadiseasespectrumrelatedtotheamount ofenzymeactivity,presentingasanintermediatephenotypecharacterisedby differentlevelsofneurologicalinvolvement4
ThediagnosisofNPDtypeBisusuallymadeinchildhoodafterorganome- galyisnotedanditiscommonforindividualstosurvivewellintoadulthood Treatmentis,asyet,notavailableforASMDalthoughthefirstclinicaltrials ofenzymereplacementtherapyfortypeBhavebeencompleted,following promisingresultsinanASMknockoutmousemodel5Genetherapymayalso beapotentialroutefortreatment6
ThefollowingclassificationsaretakenfromDrMargaretMcGovern’spres- entationattheNPDG(UK)conferencein2007
NPD type A
massiveorganomegaly eyefindings lungdiseaseandinfections cholesterolabnormalities rapid,progressive,neurologicdisease failuretothrive deathbytheageoffour
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Types and nomenclature
In1914aGermanpaediatricianAlbertNiemann(1880–1921)describedayoung childwithbrainandnervoussystemimpairmentandhepatosplenomegaly7
LudwigPick(1868–1944)studiedtissuesafterthedeathofchildrenwho exhibitedsimilarsymptomsandprovidedevidenceofanewdisorderdistinct fromthelipidstoragedisorderswhichhadbeendescribedpreviously
In1958,CrockerandFarberpublishedacaseseriesonpatientswithvaried presentationsofNiemann-Pickdiseasebasedonthepresenceof‘foamcells’ (lipidladenmacrophages)andincreasedtissuesphingomyelin8
Becausetheirpatientsincludedchildrenwithcharacteristicneurological symptomsaswellaschildrenshowinglittleornoneurologicalsymptoms, CrockerlatercharacterisedNiemann-Pickintofourseparatecategoriesbased onbiochemicalandclinicalcriteria9
NPD type B
ASM de cient patients surviving early childhood: more variability
eyefindingsin34percent retinalfindingswerenotareliablepredictorofthe
presenceorseverityofneurologicfindings evidenceofneurologicalinvolvementin28percent progressiveneurologicdiseaseinlessthan10percent mostcommonfindingsarehypersplenismanddyslipidaemia progressionlungdiseaseoccursinmost
Variant patients
diseasesymptomsrangedfromseveretomoderate initialdevelopmentisnormal neurologicaldifficultiesbeginningbetween
18monthsofagetosevenyears languagedelay unsteadygait cognitivedecline
intellectualquotientsrangedfrom40to68
Categories of Niemann-Pick disorders
Group A(ASMD-NPA)includedpatientswithclassicneurodegenerative diseaseleadingtodeathinearlyinfancy Group B(ASMD-NPB)includedthoseshowingorganomegalywithoutnerv- oussysteminvolvement Group C(NPC)showedslowlyprogressiveneurologicalillness9
Group D(previouslyknownasNPD)closelyresembledgroupCexceptthat itwasrestrictedtoageneticisolatefromNovaScotia9
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GroupDisnolongerregardedasaseparatesub-typeasitisbiochemicallyand clinicallyindistinguishablefromNPCImportantlythough,itwasnotedthat non-neuraltissuesinNPCandNPDpatientshadrelativelylesssphingomy- elinandmorecholesterolstoragecomparedwithNPAandNPBMorerecent researchhasshownthatthiswasahighlyrelevantobservationasitreflectsthe substantialdifferencesintheunderlyingbiochemicaldefectandpathophysiol- ogyofNPCcomparedwithNPAandNPB
In1966KanferetaldemonstratedthattheprimarybiochemicaldefectinNPA andNPB(butnotNPC)wasseveregeneralisedacidsphingomyelinasedeficiency10
Thisearlyfinding,coupledwiththeobservedaccumulationofmultiple complexglycosphingolipidsinNPC(ienotonlysphingomyelin)indicated thatNPCshouldbeconsideredasaseparateentityfromNPAandNPBIn1982 anexpertconsensusdecisionwastakeninPraguetoformallyseparateNPC fromtypesAandB11
The genetics of ASMD
Regional mapping of the human ASM gene
In1991researchersidentifiedthelocationoftheASMgenetothechromosomal region11p151top15412
Althoughanumberofothersphingomyelinasesandrelatedphospholipases havebeenidentified,thesemolecularstudiesidentifiedonlyasinglelocusfor humanASM–theSMPD1gene–indicatingtheabsenceofhomologouscoding sequencesandpseudogeneselsewhereinthegenomeInaddition,genomic SouthernblottingexperimentswereconsistentwithasingleASMgene
The molecular genetics of ASM
Intron-exon junctions in the human SMPD1 gene
Exon number
splice site Intron size (NT) 3’ acceptor splice site
1 398 1-104 AGgtgagc(D1) 464 cagA(AI)
2 773 105-362 AGgtactt(D2) 1059 cagA(A2)
3 171 362-419 AAgtgagg(D3) 228 tagG(A3)
4 77 420-446 AGgtagga(D4) 201 cagG(A4)
5 145 446-494 TGgtgagt(D5) 153 cagG(A5)
6 778 495-630
Theunderlinedresiduesrepresentdivergencesfromthe5’donoror3’accep- torsplicesiteconsensussequences;theboldAAindicatesachangefromthe invariantAGdinucleotideinthe5’donorsplicesite(D3)atthejunctionof intron2andexon31InanearlystudybySchuchmanandDesnicktherewere eighteenpublishedmutations1
Ofthese,sevenoccurredinexon2,threeinexon3,oneinexons4and5, fiveinexon6,andoneinanintronicsplicesiteTherewere11missenseand twononsensemutationsOfthethreeframeshiftmutations,onewascaused
8
byanin-frame3-basedeletionthatledtotheremovalofasingleaminoacid, whiletheothertwowerecausedbysinglebasepairalterations1
In2010,theHumanGeneMutationDatabaseattheInstituteofMedical GeneticsinCardifflisted130reportedmutations13
Mutation type Number of mutations Main references
Missense/nonsense 84
Pittis(2004)14
Simonaro(2002)15
Ricci(2004)16
Dardis(2005)17
Pavlu-Pereira(2005)18
Takahashi(1992)19
Sikora(2003)20
106 (130)
Patterns of inheritance
ASMDisinheritedinanautosomalrecessivemanner,ietwocopiesofagene mutationataparticularlocusononeofthe22pairsofautosomes(non-sex chromosomes)mustbepresentforthediseasephenotypetomanifestFormost inheritedmetabolicdiseasesthephenotypeofaparticularinheritedmutation (ieageofonsetandprofile/severityofsymptoms)usuallyrunsconsistently withinfamilies25
Ineachpregnancyofacarriercouple,thereisa25percentchancethatthey willbothpasstheirnon-functionalmutantASMDgenestoachild,whowould thenbeaffectedThereisa50percentchancethatonlyoneofthemwould passonanon-functionalgene,makingthechildaheterozygotecarrierlike theparentsThereisa25percentchancethatbothfunctionalgeneswould bepassedonandthechildwouldneitherbeacarriernoraffectedOverall, unaffectedchildrenhaveatwointhreeriskofcarryingoneabnormalASMD alleleFurthermore,eachsiblingofanaffectedindividual’sparentsisat50per centriskofbeingacarrier
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Carrier detection and genetic counselling
Biochemicaltestingcannotberelied upontoidentifyindividualswhoare heterozygousforASMDmutations (carriers),becausetestresultsaresimi- lartothoseseenincontrolsMolecular analysisoftheSMPD1genecanbe usedtoidentifycarriersifthemuta- tionshavebeenfoundinanidentified, affected,familymember
Geneticcounsellingprovidesindi- vidualsandfamiliesaffectedbyASMD withinformationonthenature,inher- itanceandimplicationsofthisgenetic disorderinordertohelpthemmake informedmedicalandpersonaldeci- sionsItisparticularlyrelevantwith regardtofamilyplanningTheoptimal timetodeterminegeneticrisk,clarify carrierstatusanddiscusstheavailability ofprenataltestingisbeforepregnancy
Genetic prenatal testing
Prenataltestingisprovidedtopreg- nantwomenwherethereisa25per centriskofASMDinthefoetusThe mostcommonwayofdoingprenatal testingisdirectenzymeassayonunculturedCVBInfamilieswherethemutations areknown,molecularanalysisoffoetalcellscanbediagnosticorconfirmatory
Genotype/phenotype correlation
In2002,ateamatMountSinaiHospitalinNewYorkcarriedoutastudyofthe demographics,distributionsandmutationsinNPBMutationanalysiswascar- riedouton228NPBpatientsOnemutation,A196P,wasidentifiedinpatients withScottishheritageintheUnitedStates,theUnitedKingdomandCanada Itwasnotedthatwhereapatientcarriedonlyonecopy,evenalongsideanull mutation,theyhadtheadultformfollowinganattenuatedcourseThreeother mutations,(L137P,R474W,R600H)werealsothoughttobeconsistentwiththe milderendoftheclinicalspectrumofthediseaseThemostcommontypeB mutationinNorthAmericaandWesternEuropeisduetoasmallthreebase deletionintheSMPD1gene,calledR608
IncontrastH421Y,whichoccurredonmorethan70percentoftypeBallelesin patientsfromSaudiArabia,wasassociatedwithanearlyonsetsevereformofNPB26
Autosomal recessive inheritance
R r
Carrier child
Carrier child
Normal child
Clinical diagnosis
TherelativerarityinfrequencyofdifferenttypesofASMDmeansthatdiagnos- ingthediseaserequiresdoctorsandphysicianstobeawareofanumberof symptomsandfactors
Type A
PatientswithtypeApresentwithhepatosplenomegaly,feedingproblemsand failuretothriveinearlyinfancy,withtheearlyorganomegalybeingapparent inthefirstfewmonthsoflife
By3–6monthsneurologicalinvolvementmaybenotedanddevelopmental delayand/orlossofdevelopmentalmilestonesshouldalertphysiciansAbout 50percentofbabieswithtypeAhavemacularcherry-redspots
Type B
IntypeBthefirstindicatorissplenomegalywhichisusuallynotedinchildhood However,becausethismaybeverysubtleinmildcasesitmaynotbedetected untiladolescenceoradulthoodInsomepatientsrespiratorydiseasewitha gradualdeclineinrespiratoryfunctionmaybethemostprominentsymptom
Thepresenceofcharacteristicfoamcellsinbonemarrowaspiratessupportsthe diagnosisbutassimilarcellsareseeninotherlysosomalstoragedisorders(LSDs) includingNPCallsuspectedcasesshouldbeconfirmedbyenzymaticstudies
Enzymatic diagnosis
ASMDisreadilydiagnosedbythemarkedlydeficientactivityofacidsphingo- myelinaseinperipheralleucocytesorculturedskinfibroblasts
Incontrast,patientswithtypeCoftenhavemildlyelevatedASMlevelsand thosewithGaucherandotherstoragedisorderspresentingwithhepatosplenom- egalyand/orneurologicalproblemswouldhavenormalornearnormallevels
Ingeneral,residualASMDactivityintypeAandtypeBrangesfromlessthan onepercenttoabouttenpercentofnormal,withtypeBpatientsgenerally havinghigherlevels,butthisisnotareliablepredictorofphenotypicseverity
Thereisalsoasignificantoverlapbetweennormalandheterozygoteenzyme activitylevelsandsoenzymaticstudiesalonearenotreliableforcarrierdetection1
Molecular diagnosis
TheR496L,L302PandfsP330mutationsaccountforabout92percentofthe mutantallelesinAshkenaziJewishtypeApatientswhichleadstorapididen- tificationofmolecularlesionsinthispopulation
Innon-JewishtypeAandtypeBpatientsthereisatendencytounique mutationswiththeexceptionofR608
Infamiliesinwhichthemutationshavebeenidentifiedfamilymembers canbeaccuratelytestedforcarrierstatusbyDNAanalysis
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Pathophysiology
Acid sphingomyelinase
Undernormalconditions,ASMismainlyfoundinlysosomes,whereitsfunction istoparticipateinmembranedegradationandturnoverWithinthisorganelle theenzymeexistsinacomplexwithotherlipidhydrolases,includingacid ceramidaseTraffickingofASMtolysosomesfollowsapathsimilartothatof mostotherlysosomalhydrolasesandisdueprimarilytothepresenceofman- nose-6phosphateresiduesonN-linkedoligosaccharidesidechainsSmall amountsofenzymearereleasedfromcellsintothecirculationbutimportantly, ASMneedszincforfullactivityandinsidethelysosometheenzymeisfully saturatedwiththiscationThesecretedformisnotfullysaturatedwithzinc butcanbeactivatedinvitrobyadditionofthecationtotheassaymixture
Sphingomyelin,thesubstrateforASM,isastructuralcomponentofmost cellmembranesandtogetherwithcholesterolisamajorconstituentofmem- braneraftstructures27
Splenomegaly
Thespleenisanorganfoundinvirtuallyallvertebrateanimalswithimportant rolesinregardtoredbloodcellsandtheimmunesystemInhumans,itis locatedintheleftupperquadrantoftheabdomenItremovesoldredblood cellsandholdsareserveofbloodincaseofhaemorrhagicshockwhilealso recyclingironItsynthesisesantibodiesandremovesantibody-coatedbacte- riaalongwithantibody-coatedbloodcellsInaddition,thespleenhasbeen foundtohosthalfofthebody’scirculatingmonocytesThesemonocytes,upon movingtoinjuredtissue,turnintomorespecialisedcellsandmacrophages whilepromotingtissuehealingFinallyitisoneofthecentresofactivityofthe reticuloendothelialsystemandcanbeconsideredanalogoustoalargelymph node,asitsabsenceleadstoapredispositiontowardcertaininfections
Inanormaladultthespleenisabout11cmlongandweighsabout150g InpatientswhohaveASMDstoragethereisamassiveenlargementofthe spleenRecently,thespleenofayoungadultwasremovedduringsurgeryand weighed25kgThishasanimpactondigestionandbreathingandcancause considerablediscomfort
Pulmonary disease in ASMD
ThesenotesaretakenfromapresentationbyDrMargaretMcGovernatthe NPDG(UK)conferencein2007
PulmonarydiseasewasaconsistentfindinginaffectedpatientsItssever- ityvarieswidelyMostsymptomaticpatientsareadultsbutseverelyaffected childrencanalsohaveclinicallysignificantpulmonarydiseaseItiscausedby storageofsphingomyelininthelung
In2004Buccolieroetalnotedthat,intheASMmousemodelofNPA,levels oftheprimarystoragematerial,sphingomyelin,wereelevatedasexpected,and levelsofotherphospholipidswerealsosignificantlyraisedinthepulmonary surfactantandinlungtissueof5–7montholdmiceTheseresultssuggested
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thatchangesinthephospholipidlevelsandcompositioninlungsurfactantmay beageneralfeatureofsphingolipidsstoragediseasesTheymayalsoinpartbe responsibleforthesusceptibilityofthesepatientstorespiratoryinfections28
TheslidesofX-raysshowexamplesofsphingomyelinstoragecausinginter- stitiallungdisease(ILD)
Lung function and respiratory symptoms
In2004Wasserstein,McGovernetalcarriedoutalongitudinalstudyintothe naturalhistoryofNPDtypeB29
Thisstudyfeatured53patientsagedbetweensevenand65Thepatients allhadchestX-rays,high-resolutionchestCTscans(HRCT)andwerethen assignedascoreforinterstitiallungdisease(ILD)Pulmonaryfunctiontests werealsoperformed
ILDwaspresentinallbutonepatientandsomepatientsalsohadpulmonary nodulesTherewasnoassociationofILDscorewithageorDLCO(diffusionlung capacityforcarbonmonoxide)whichistheextenttowhichoxygenpasses fromtheairsacsofthelungsintothebloodAllpatientsreportedshortness ofbreath,fatigueandrecurrentinfections
Thesegraphsrepresentfindingsrelatedtotheeffectofsplenectomyon lungfunction30
0
100
90
80
70
60
50
40
30
20
10
Months
% D
Years
% D
Right: Lung function over time: splenectomised vs non-splenectomised patients
NPD chest X-ray
Normal chest X-ray
medication steroidstohelpdecreaseinflammationTheresponseto
treatmentisrelatedtotheamountofinflammationpresent homeoxygentherapy
breathingsupplementaloxygenincreasestheamount ofoxygeninthebloodThismayhelpreduceshortness ofbreathandpreventothercomplications
pulmonaryrehabilitation aerobictrainingsessions
smokingcessation lungtransplantationforsevereILD
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Other therapies: lung lavage cases
Twoofmanyoftheresearchstudieswhichhavebeenpublishedillustrating conflictingopinions:
Effects on lipid profi le
Inthecross-sectionalstudyitwasfoundthatmostpatientshadatherogenic lipidprofilesandlowhigh-densitylipoprotein(HDL)wasthemostcharacteristic lipidabnormalityOfthepatientsstudied,74percenthadthispatternandit wasalsofoundthat41percenthadhightotalcholesterollevels,62percent hadhightriglycerides,46percenthadhighlow-densitylipoproteinlevel(LDL) and62percenthadhighverylow-densitylipoproteinlevelsAlloftheselevels wereage-matchedandgender-matchedinthecontrolsubjectsThemean cholesterol/HDLratiowasmorethantwiceashigh(23)astheupperrange ofnormalPatientswhohadhadasplenectomyhadameancholesterol/HDL ratioalmosttwiceashighasthosewithintactspleens
Lung lavage in a child with NPD31
15-month-oldchild normaldevelopment respiratorysymptoms leftlunglavage noimprovement succumbed
Whole lung lavage in an adult32
48-year-oldmanwithcoronaryarterydisease treatedwithsteroidswithsomeimprovement
inpulmonaryfunctiontests wholelunglavageresultedinmodestincreasesinoxygenintheblood aliveforthreeyearspost-lavagebutnolong-
termpulmonaryfollow-upreported discussedwithauthorofpaperandpatienthas
movedabroadsonofollow-upavailable
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McGovernetalconcludedthatlipidabnormalitiesarepartofthephenotype intypesAandBNPDandmaybeassociatedwithearlyatheroscleroticheart disease33
Haematological problems
BleedingisafrequentprobleminpatientswithASMDInthestudycarriedout byDrMcGovernandherteam,49percentofthepatientshadsomebleeding problems3
Mostbleedingproblems(29percent)wererelatedtoepistaxisornose bleedsIntwopatientstheserequiredrepeatedcauterisationsandthecase studyonpage23describesayoungwomanwiththisproblemOtherreported bleedingeventsincludedbleedingintothebrain,lung,tonsilanduterus
AnecdotallymostpatientswithASMDdoreportahigherincidenceofbruis- ingcomparedwiththeirpeers
350
300
250
200
150
100
50
% n
O
Platelet counts over time in four patients (Normalrange150–450)
Mean lipid values for male and female patients with types A and B NPD
Male, mean (mg/dL)/(SD)
Female, mean (mg/dL)/(SD)
TypeB 237(71) 213(52)
HDL-C TypeA 16(5) 23(12) >45 <35
TypeB 20(7) 24(11)
LDL-C TypeA 156(57) 164(54) <110 >130
TypeB 169(62) 145(49)
Triglycerides TypeA 207(79) 198(87) <125 >125
TypeB 235(96) 169(90)
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Bone problems
TheassociationofboneproblemswithNPDwasinvestigatedanddocu- mentedinastudybyDrMargaretMcGovernandherteamandpresentedat theNPDG(UK)conferencein2007
Boneproblemscanleadtoincreaseddisabilityaswellaspainanddecreased mobility,thereforeitisveryimportanttorecognisethisasaproblemandtake stepstominimiseanyrelatedproblems
Normal bone metabolism
Boneisaliving,growingtissuethatturnsoveratarateofabouttenpercent ayearItismadeupofcollagen,aproteinthatgivestheboneitsstrengthand framework,andcalciumphosphatethathardenstheframeworkThroughout lifeoldboneisconstantlybeingremovedthroughresorption(thenatural absorptionofsmallamountsofbonebythebody)andreplacedbytheforma- tionofnewboneDuringearlychildhoodandintheteenageyears,newbone isaddedfasterthanoldboneisremovedandbonesbecomelarger,heavier, anddenserBoneformationhappensfasterthanboneresorptionuntilyou reachyourpeakbonemassinyourtwentiesAfterthat,boneresorptionslowly beginstohappenfasterthanboneformation
Problems with bone density
Osteoporosis,orporousbone,isadiseasecharacterisedbylowbonemassThis meansyoumaybemorelikelytogetfracturesparticularlyofthehip,spine, andwristOsteoporosisdevelopswhenboneresorptionoccurstoorapidlyand boneformationfailstokeepup
Bone resorption and formation
OsteoclastsarelargecellsthatdissolvetheboneTheyarepresentinbone marrowandarerelatedtowhitebloodcellsItispossibletoestimateosteo- clastactivitywithcertainbloodteststhatmeasuresubstancesthatresultfrom collagenbreakdown
OsteoblastsarethecellsthatformnewboneTheyarealsopresentinbone marrowYoucanestimateosteoblastactivitybymeasuringcertainchemicals includingbone-specificalkalinephosphataseandosteocalcin
How to measure bone density: DEXA scan
ADEXAscanisaspecialkindofX-rayofthebonesItprovidesa‘Tscore’which measuresyourbonedensitycomparedwithwhatisnormallyexpectedina healthyyoungadultofyourgender
ForchildrenaZscoreisalsousedwhichshowshowfarthescorefallsabove orbelowwhatisnormallyexpectedforsomeoneofthesameage,sex,weight andethnicorracialoriginTheZscoreisalsousefulinyoungadultsbecause itcanhelpdeterminewhetherfactorsotherthanageingmightbecausing boneloss
16
Preliminary results of the bone study
ResultsofstudiesshowthatosteoporosisiscommonamongpeoplewithNPD Inonestudy,sixadultswereexaminedThreehadosteoporosis,twohadosteo- peniaandonewasratedasbeingnormalfortheirageFifteenchildrenwere alsostudied,ofwhomelevenhadosteoporosisandfourhadnormalboneden- sityfortheirageAllofthepatientswithabnormalDEXAscanresultsshowed increasedbloodmarkersofosteoclastactivity
Anunusualcasewasreportedin2002inBelgiumA55-year-oldwoman presentedwithaclinicalpictureofParkinson’sdisease,severebackpain, splenomegalyandseveredyspnoeaX-raysindicatedmultiplevertebralfrac- turesShehadmarkedlyreducedsphingomyelinactivityandwashomozygous fordeletionofcodon608(R608)Becauseofthepatient’sseverefracturesshe wasscreenedforadditionalpolymorphismsIthadpreviouslybeennotedthat polymorphismswerepossiblyassociatedwithanincreasedriskofosteoporosis andseveralfractureswerefound34
Growth
MostchildrenwithASMDhavedelayedgrowthThisisparticularlynoticeable inadolescenceandcanbetheproblemwhichcausesmostanxietyforchildren withASMD
Inonestudyacross-sectionalanalysisofgrowthwasperformedon23chil- drenandadolescentswithenzymaticallyandgenotypicallyconfirmedASMD
ThemeanZscoresforheightandweightwere–124(29thpercentile)and –075(34thpercentile)Themeanliverandspleenvolumeswere206and1346 timesthenormallevelsforweight,respectivelySkeletalagewasdelayedbyan averageof25years,andserumIGF-1levelwasatorbelowthe2ndpercentilein eightof12patientsShortstatureandlowweightweresignificantlycorrelated withlargeorganvolumes,delayedboneage,andlowIGF-1levelsIncontrast topatientswithothermutations,individualshomozygousfortheΔR608muta- tionhadnormalheightandweight,markedlylesshepatosplenomegalyand boneagedelay,andnormalIGF-1levels35
TheexperienceintheUKisthat,althoughgrowthisdelayedintheirearly teens,mostadolescentscontinuegrowingwellintoearlyadulthoodanddo attainanormalheightbytheirmid-twentiesThisinformationmaybereas- suringformanychildrenwithASMDwhoworryaboutwhethertheywillgrow toaverageheight
17
Epidemiology
Incidence and prevalence
AlthoughASMDispanethnic,itiswelldocumentedthatASMDtypeAoccurs morefrequentlyamongthoseofAshkenaziJewishoriginThecarrierfrequency inthispopulationisestimatedtobeabout1:80suggestingadiseasefrequency of1in40,000Toputthisintocontextthepanethnicfrequencyisbetween 04in100,000to06in100,000innewborns2However,itmustbenotedthat sincenopopulation-basedscreeningprogramshavebeenundertakenforthis disorder,thetruefrequencyremainsunknown
ThereisdocumentedevidenceoflipidstorageinNPDfoetuseswithtypeA havingahigherfrequencyofspontaneousabortionThismeansthatthetrue incidenceoftypeAmaybehigherthanreported
TheincidenceoftypeBintheAshkenaziJewishpopulationissignificantly lessthanthatoftypeAAmongnon-JewishASMDpatients,thetypeBform ismoreprevalentbutaccurateestimatesforfrequencyareunavailableItis thoughtthatbecausemanytypeBpatientshavemildsymptoms,thefrequency oftypeBislikelytobehigherthanthatquotedinliterature1
Potential therapies
FurtherinformationrelatingtotherapiescanbefoundinThe pathogen- esis and treatment of acid sphingomyelinase-de cient Niemann-Pick disease (Schuchman,2007)27
Haematopoietic stem cell transplantation (HSCT)
HSCTusingbonemarrowasthedonorcellsourcehasbeenperformedinseveral ASMDpatientsReductioninliverandspleensizewasnotedinatleastonecase butseveretransplantation-relatedcomplicationswereseeninthispatientand weresimilarlysevereinothersNoimpactontheneurologicalphenotypeof typeApatientshasbeenshownTransplantationintheknockoutmousemodel resultedinhighengraftmentlevelsandpositiveeffectsonthereticuloendothe- lialsystem(RES)organsbutintermediateeffectsonneurologicaldisease
AsaresultoftheseandotherstudiesitisthoughtthatHSCTmaybenefit thosepatientswithnoneurologicalinvolvementbut,giventheseveretrans- plantrelatedcomplications,thisneedscarefulconsideration
Splenectomy
AnotherapproachhasbeenapartialorfullsplenectomyThereisnodocu- mentedrationaleforthisbutitispossiblyduetopainand/ortheriskofsplenic ruptureInadditiontheincreasedenergydemandoftheenlargedspleenmay contributetotheobservedpoorgrowthandfailuretothriveOtherfactors associatedwithhypersplenismincludeanaemia,lowwhitebloodcellcount andtheriskofhaemorrhagefromthrombocytopaeniaPost-splenectomy thereseemstobeincreasedpulmonarystorageandafasterprogressionand severityofpulmonarydisease
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Pulmonary lavage
Thisisdiscussedonpage13butthegeneralopinionisthattheseprocedures onlyseemtohaveatemporaryeffectonpulmonaryfunctionOvertimeinflam- matorycellsarelikelytorepopulatetheairwaysandsymptomsbecomeas badorevenworse
Enzyme replacement therapy
Enzymereplacementtherapy(ERT)isseenasthegoldstandardforachieving widespreaddeliveryofenzymetoclinicallyaffectedorgansRecombinant humanASM(rASM)wasproducedinChinesehamsterovarycellsandextensively characterisedItwasusedtotreattheknockoutmousemodelandoverall,when administeredintravenouslyintoyoungmice,lipidstoragecouldbeprevented inRESorgansProgressiveinflammatorydiseasewasalsopreventedinthese organsEffectsoftheenzymeweredosedependantandmostprofoundinthe liverandspleen,followedbythelungDespiteshowingmarkedimprovement inRESorganstherewasnoeffectontheprogressionofneurologicaldisease
Phase1oftheERTclinicaltrialshavenowbeencompletedatMountSinai toevaluateproductsafety
Future potential therapies
Gene therapy
Genetherapyapproacheshavebeenstudiedextensivelyintrialscarriedouton knockoutmiceOneexampleistheuseofretroviralvectorswhichcontained thefull-lengthSMPD1cDNAThesewereusedtotransduceknockoutbone marrowcellsandwerethentransplantedintopartiallyirradiatedlittermates TheeffectsoftheprocedureshowedthesamelevelofimprovementasERT ontheorgansbutnoeffectonneurologicalsymptoms
ThepotentialadvantageofthisoverHSCTisthatthepatient’sownbonemar- rowmightbeusedandcouldpotentiallymaketoxicpreconditioningunnecessary
Small molecule approaches
Substratereductiontherapyhasbeenevaluatedforotherlysosomalstorage disorders(LSDs)usinginhibitorsofglycolipidsynthesisTherationaleisthat glycolipidsareprimaryorsecondarystorageproductsinmanyLSDsandpre- ventionorslowingofsynthesismayimprovethelipidstoragephenotype Preliminarystudiesintheknockoutmouseshowlittleeffectonprogression ofneurologicaldisease
Inhibitorsofsphingomyelin(SPM)synthesishavealsobeenconsideredto achievesubstratereductionTherearetwopotentiallynegativeconsequences inusingsphingomyelininhibitorsSlowingthesynthesisofSPMmightleadto increasedintracellularceramidelevelsandceramideisapro-apoptoticlipid thatisgenerallytoxictocellsAlso,SPMisanimportantstructuralcomponent ofcellmembranesandreducingitmayhaveprofoundeffectsonthestructural integrityofcells
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Molecular chaperones
Smallmoleculechaperonesthatareusuallycompetitiveinhibitorsoftheenzyme canbeusedtopreventdegradationandenhancetheresidualactivityofmutant enzymesThechaperoneisonlyeffectiveindisorderswherethemutationleads tomisfoldingoftheenzymeproteinandsothisdependsonthetypeofmuta- tionTheprincipleofthisapproachhasbeenproveninotherlysosomalstorage disordersbutnonehavebeenlicensedforuseinclinicalpractice
Co-factor zinc supplementation
ASMrequireszincforfullactivityItisthoughtthatsomemutationsinASMD patientsmightlimitzincbindingtothemutantproteinsThisapproachwas evaluatedusingcellsfromASMDpatientswhowerehomozygousforseveral commonmutationsSomeenhancementofresidualenzymeactivitywasseen butthismighthavebeenduetosomegeneraleffectofzincsupplementation asopposedtoanydirecteffectofzincontheenzyme
Specialist centres
Mount Sinai School of Medicine, New York
TheInternationalCenterforASMDtypesAandBNiemann-Pickdiseasewas establishedtoprovideinformationandsupportforpatientsdiagnosedwith thesedisorders,aswellasinterestedscientistsandphysiciansItisavoluntary, not-for-profitorganisationwhoseprimarygoalsareto:
promotemedicalresearchintothecauseand treatmentoftypesAandBNPD
providemedicalandeducationalinformationtoassistinthe correctdiagnosisandreferralofchildrenwithNPD
providesupporttofamiliesofchildrenwithNPD facilitategeneticcounsellingforparentswhoareknowncarriersofNPD encouragethesharingofresearchinformationamongscientists
AllNPDpatientsareencouragedtovisitMountSinai’sGeneralClinical ResearchCenter(GCRC)tobeevaluatedbyateamofNPDexperts Generally,thisinvolvesatwo-tothree-daystayintheGCRC,which isaspecialunitofthehospitaldesignedforsuchclinicalstudies HospitalisationandothermedicalcostsforthesevisitsarefreeforUS patients(CourtesyoftheNNPDFwebsite)
20
Contact details
DepartmentofGeneticsandGenomicSciences MountSinaiSchoolofMedicine 1425MadisonAvenue NewYork,NY10029 w wwwmssmedu/departments-and-institutes/genetics-and-genomic-sciences t 2122416500
National Commissioning Group centres in the UK
MostpatientswithASMDNPAandBareseenatoneofthesevennationally fundedspecialistcentresforlysosomalstoragediseasesMostpatientswillbe seenannuallyandassessedforlungfunction,cardiacfunction,haematological statusandboneparametersAstreatmentisnotasyetavailable,symptomatic therapywillbeusedasappropriate
National centres for lysosomal diseases in the UK
Fulladdressdetailsareintheresourcessectiononpage26
Birmingham:BirminghamChildren’sHospital(childrenonly) Cambridge:Addenbrooke’sHospital(adultsonly) London:
GreatOrmondStreetHospital(childrenonly) NationalHospitalforNeurologyandNeurosurgery(adultsonly) RoyalFreeHospital(adultsonly)
Manchester:DepartmentofGeneticMedicine, StMary’sHospital(childrenonly)
Salford:SalfordRoyalHospitalFoundation TrustHopeHospital(adultsonly)
A call to action
The Patient Association’s view
WhenachildorindividualisdiagnosedwithNiemann-PicktypesAorB(ASMD), itcanadverselyaffectthewholefamilyDuetotherarityofthecondition,the pathtothisdiagnosiscanoftenbeadifficultoneAshealthandsocialcare servicesvaryaroundthecountry,familiescanfeelbewilderedandisolateddue toconflictingadviceandalackofclearinformation
Duringthisperiodofadjustment,familiesbegintocontemplatetheirfuture, andhowthediseasemightaffecttheirlovedoneToassisttheminunderstand- ingthenatureofthedisease,theyneedasupplyofaccurateinformationwhich theycaneasilyrelateto
Atthispoint,familiesfaceaconstantroundofappointmentswiththelong listofprofessionalsthatwillnowbeinvolvedincaringfortheirlovedoneAs theconditionissorare,theywillinvariablyhavetotelltheirstorytimeand timeagain;thisinitselfcanbeextremelydifficult
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Asthediseaseprogresses,familiescanstruggletocopewiththeemotional andfinancialimplicationsoftheconditionand,asaresultofthis,thequality offamilylifecanbeseverelyaffected
IntheUK,theNiemann-PickDiseaseGroup(NPDG(UK))aimstomakea differencetothoseaffectedbyacidsphingomyelinasedeficiency(ASMD) Niemann-Pickdiseasethroughtheprovisionofcareandsupport,accurate informationandthepromotionofrelevantresearchThegroupgivesemo- tional,aswellaspracticalsupportandhasdevelopedastrongfamilysupport network,helpingtoreducefeelingsofisolationanddespair
Workingincollaborationwithpatientgroupsacrosstheworld,NPDG(UK) hopetoraiseawarenessofthedisease,itspresentation,signsandsymptoms ThroughthesharingofinformationandresourcesNPpatientassociationshave createdavaluablesourceofinformationforprofessionalsItishopedthatthis informationwillbeusedtofurtherdevelopservicesforthoseaffectedandto stimulateresearchthatwillimproveunderstandingoftheconditionandhelp withtherapydevelopment
Researchisvitallyneededtoprovidemuchneededdataaboutthiscondition TheNPDG(UK)isactiveinpromoting,andwherepossiblefunding,researchthat willimproveunderstandingandleadtothedevelopmentoffuturetherapies Clinicaltrialsarecurrentlytakingplace,bothintothecausesofthediseaseand potentialtreatmentsTheNPDG(UK)wouldliketoensurethat,inthefuture, familiesaffectedbyASMDNiemann-PicktypesAandBcouldbegiventhe hopeofatreatment–orevenacure–forthispotentiallylife-limitingcondition
Social and psychological impact
Verylittleresearchhasbeenundertakenintothesocialandpsychological impactofASMD
However,DrShellyHenderson,AssistantProfessorandDirectorofBehavior MedicineatUCDavisinCalifornia,chosethissubjectforherPhDdissertationat thePacificGraduateSchoolofPsychologyin2006andhassharedthisinforma- tionwiththeBritishandAmericanNiemann-PickdiseasegroupsThefollowing drawsontheexcellentworkshehasproducedincoveringthistopic36
Extract from Psychological aspects of patients with Niemann-Pick disease (Henderson, 2006)
AcknowledgingthatpatientswithNiemann-Pickdiseasefacenumerouspsy- chologicalstressors,Hendersonsetouttoexploretheexperiencesofpatients andfamilieslivingwithNPBStressorsincludeextensivemedicalinput,uncer- taintyarounddiagnosis,livingandcopingwithchronicillnessandgriefand bereavement17patientsovertheageof13wereinterviewed
Itwasacknowledgedthateachfamilyhastheirownuniquesetofcircum- stancesbutthatthereweresomeareasofconsensus
allparticipantsidentifiedlimitedphysicalactivity,social isolationandpeerrejectionassignificantstressors
thesestressorshadaspecificimpactduringtheagespanof10–16years parentsandadultpatientsexpressedsignificantfrustration
regardingthelackofinformationandtreatmentavailable
22
patientsdescribedrelyingonclosefamilyrelationships asawayofcopingwiththeillness
adultpatientsidentifiedearlymedicalexperiencesas havingaconsiderablepsychologicalimpact
Lookingattheseresponsesitisclearthatthereareoftendiscrepanciesinhow theadolescentfeelsandhowtheparentthinkstheyfeel,whichisnotunusual inthissortofsurvey
Severalparentsdidnotrealisehowmuchtheirdaughtershadbeenhurt whentheywereteasedaboutlookingpregnantAlthoughmostparentsrealise thattheirteenagechildhasconcernsabouttheirheightthissurveydoesshow thatitcanhaveamassiveimpactonchildrenItisanagewhenmostchildren areverysensitiveabouttheirappearance
Manyofthechildrenalsomentionedthatwhentheywereyoungerthey didfeelisolatedandoftenpushedoutofsocietyTheirillnessmeantthatthey hadtoavoidcontactsportsandcouldnottakepartinteamgamesandsolost theopportunitytolearngroupandsocialskills
The family perspective
ForparentsandrelativesofpatientswithNiemann-Picktheprogressofthe disease,itssymptomsandside-effectscanbeextremelystressfulandworrying TellingthestoryofhowtheirchildhasbeenaffectedbyASMDisoftenharrow- ingbutsharingtheseexperiencescanbeverybeneficialHere,therelatives ofpatientswithtypesAandBrelatetheirexperiencesofthediseaseandthe effectsontheirchildren
Case study 1: a girl, two and half-years-old
Iamthegrandparentofachildwho passedawayShewastwoandahalf yearsoldIdon’tevenknowwhereto begintellingyouherlifestory
Shewasbornweighing5lb8oz, justafewdaysearlyPregnancyfor momwasnormalThiswastheirfirst andonlychildFromthebeginning shenevercouldeatmuchAtthree monthsoldthedoctorsaidherliver wasenlargedandaftermonthsofmanytestsliversurgerywasperformed
OnemonthafterthatweweretoldshehadNiemann-Pickdiseasebutthey didn’tknowwhetheritwastypeAorBHerDNAwastestedandstillnotype couldbedeterminedSoallwecouldgobywasthatshewasmeetingher milestonesatthatpoint
Butatabout13monthsshestoppeddevelopingAtthispointshedidn’t gobackwards,justnothingnewShegottowalkingbyholdingontothings andshewasabletoholdacupandfeedherselfTheonlywordshecouldsay was‘Hi’Allthroughthistimeshewouldgetcoldsandherconstipationwas horribleShewouldtakeMiralaxbutthatwouldcauseherstomachpainsand badgassometimes
23
InMarchshegotpneumoniaandthatwasthestartofherdownfallTheysay ittriggeredthebuttonShewasunabletodoanythinginthecomingmonths, shecouldn’tevensitupTherewasneveratimethatshecouldgomorethan threetofourhourswithouteating,includingatnight
ByOctobershewashospitalisedwithmono[glandularfever]andwasin horrifyingpainShewasinhospitalforfiveweeksandinthattimeshealsogot RSV[respiratorysyncytialvirus,amajorcauseofrespiratoryillnessinyoung children]andC di cileinfectionShewentthroughsurgerytoinsertagas- trostomytube
AfterfiveweeksweknewitwasneartheendThehospicehelpedusget herhomeAfterthatshestoppedbeingabletodigestanyfoodandaftersix daysshepassedawayThereissomuchmoretoherlifethatIwouldloveto tellyouabout
Case study 2: a four-year-old boy
Oursonwasdiagnosedatsixmonths withNiemann-PicktypeA/BHewill turnfouryearsoldsoonHehasan unusuallylargeliverandspleeneven for Niemann-Pick disease Unfor- tunately, I don’t have any recent measurementsWehaven’tnoticed anybleedingissuesorbruising,but basedonhisplateletcounts,weknow thepotentialforproblemsexists
HehadsleepapnoeaissueswhenhewastwoyearsoldAfterremovinghis adenoidsandtonsils,henowhasonlyslightapnoeaproblemsHislungsdon’t looksogoodonanX-ray,buttheyappeartobefunctioningOK
HisbonesareveryweakandhismuscletoneispoorHestruggleswalking Aboutfiveminutesisthemaximumtimehewillstayonhisfeet
Hisheightandweightarebelownormal,butonlyslightlyHeeatsfrequently anddoesn’thaveanydigestiveproblemsHeisanextremelypickyeaterthough Wedon’thaveanyfirmevidenceofneurologicalinvolvement,buttheremay besomeminorissuesWeareanxiouslyawaitingphasetwooftheenzyme replacementtrial
Case study 3: a teenager
Thisyoungladyisinhermidteens Forthewholeofherlifeshehashada massiveabdomenandgetsteasedat schoolasotherchildrensuggestsheis pregnantForthelastfewyearsshehas beeninhospitalseveraltimesayear becauseofseverenosebleedsSheis muchshorterthanherpeersbutshe isaveryintelligentyoungladyand copesverywellwithherproblemsShe isdesperateforenzymereplacement therapytostart
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Support
The role of patient associations
ASMDcanbeadevastatingconditionthatimpactsupontheentirefamilyMedi- caltherapyaside,supportintermsofadviceandeducationforboththepatient andfamilythroughoutthecourseofASMDisvitalIfpossible,counsellingserv- icesshouldbemadeavailabletothewholefamilyPatient-centredumbrella organisationsofferinformationataninternationallevel,whilenationalpatient associationsnowofferinformationandcounsellingwithinmanycountries
Patientassociationsprovideinformationaboutspecialistservicestoprofes- sionals,patientswithASMDandthepublic,andmostprovideatleastbasic educationalmaterialManypatientassociationsalsoactivelyparticipatein fund-raisingforthesupportofmedicaltherapyandresearchinASMDAlist ofsupportorganisationsisprovidedintheResourcessection
Referral to specialist care centres
Specialistcarecentres(seepage19)canprovidecomprehensive,integrated, multidisciplinarycareforpatients,aswellasinformationandsupportforfamily members,astheyaimtoincorporatenetworksofallrelevantmedicaldisciplines withinthecoreteamTheyhaveeffectivelinkswithnationalnetworksoftesting laboratoriesandothercarecentresatthenationalandinternationallevel,and haveimportantrolesindiseaseauditingandthemaintenanceofgeographical coverageMetabolicnursespecialistsplayvitalrolesintheday-to-dayrunningof clinics,anddealwithmanyofthefamilialaspectsofworkwithpatientsandfam- ilymembersPhysicaltherapists,physiotherapists,occupationaltherapistsand diseasecounsellorsshouldalsoallbeinvolvedinsupportivecareforpatients
Aprimeconcernamongstvoluntary,patient-focused,organisationsisthe needforincreasedawarenessamonggeneralhealthpractitionersregarding thesymptoms,diagnosisandmanagementofASMDInsomecases,initial healthservicescando‘moreharmthangood’ifthereisalackofanyspecialist knowledgeorexpertiseIthasbeenestimatedthatlessthanhalfofpatients withaninheritedmetabolicdiseasearecurrentlybeinglookedafterthrough specialistcarecentres,partiallyduetoageneralreluctancetorefer,butalso throughalackoflocalresources37
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Conclusion
Parentsandrelativesoftenregardnon-neurologicalASMDNiemann-Pickdis- easeasthebesttypeofNPDtohave,ifyouhaveany,asitisusuallythetype associatedwithprolongedsurvival
Althoughmostpatientsdonothaveneurologicalproblems,therespiratory disease,haematologicalproblems,bonediseaseandpsychologicaleffects canbequitesevereItisveryimportanttomonitorthecourseofthedisease andofferinterventionstominimisecomplicationsfromrespiratory,cardiac, haematologicandbonedisease
Thedisordercanbeveryheterogeneouswhichmeansthatitisnotuniform andcanaffectpeopleindifferentways
Untilenzymereplacementtherapybecomesarealitythereisnocurative treatmentAnumberofinterventionssuchasHSCT,pulmonarylavageand splenectomycanaltertheprogressionofthediseasebutareoftenassociated withahighincidenceofunwantedside-effects
AswithmanychronicdisordersthesupportgroupcanbeveryvaluableAs wellasallowingaccesstootherfamiliesinasimilarposition,itprovidesparents andpatientswithliteraturewhichispertinenttotheirneeds
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Resources
Support organisations
Niemann-Pick Disease Group (UK) 11GreenwoodClose Fatfield Washington NE388LR w wwwniemannpickorguk t 01914150693 e niemann-pick@zetnetcouk
The National Niemann-Pick Disease Foundation (USA) (NNPDF) POBox49 401MadisonAvenue,SuiteB FortAtkinson,WI53538 w wwwnnpdforg t 1-877-287-3672(tollfree) t 1-920-563-0930(office) f 1-920-563-0931 e nnpdf@nnpdforg
Children Living with Inherited Metabolic Diseases (CLIMB) ClimbUK ClimbBuilding 176NantwichRoad Crewe CW26BG w wwwclimborguk t 08006523181 e infosvcs@climborguk(general) e famsvcs@climborguk(familyservices) e cyasvcs@climborguk(childrenandyoungpeople’sservices) e irsvcs@climborguk(informationresearch)
Other resources
Birmingham
BirminghamChildren’sHospital StChads Queensway Birmingham B46NH t 01213339999 w wwwbchnhsuk/departmentshtm
27
Cambridge
Addenbrooke’sHospital CambridgeUniversityHospitalsNHSFoundationTrust HillsRoad Cambridge CB20QQ t 01223245151 w wwwcuhorguk/addenbrookes/addenbrookes_indexhtml
London
GreatOrmondStreetHospital UCLInstituteofChildHealth 30GuilfordStreet London WC1N1EH t 02072429789 w wwwichuclacuk
TheRoyalFreeHospital PondStreet London NW32QG t 02077940500 w wwwroyalfreenhsuk
NationalHospitalforNeurologyandNeurosurgery QueenSquare London WC1N3BG t 08451555000 w wwwuclhnhsuk
Manchester
DepartmentofGeneticMedicine StMary’sHospital OxfordRoad Manchester M139WL t 01612761234 w wwwcmftnhsuk/childrens-hospitals/homeaspx
Salford
SalfordRoyalHospitalNHSFoundationTrust StottLane Salford M68HD t 01617897373 w wwwsrhtnhsuk
28
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31
Glossary of terms Acid sphingomyelinase (ASM)
Lysosomalenzymethatbreaksdownasubstance calledsphingomyelinThisenzymeisdefectiveto agreaterorlesserextentinASMD
ASMD Acidsphingomyelinasedeficientdisease(formerly knownasNiemann-PickdiseasetypesAandB)
Allele AparticularformofgeneAllelesoccurinpairs, oneoneachchromosomeinheritedfromeach parent
Autosomes Anychromosomeotherthanthesex chromosomes
Cation Theioninanelectrolytewhichcarriesapositive charge
Chaperone Aproteinthataidsinthefoldingofasecond proteinThechaperonepreventsproteinsfrom takingconformationsthatwouldbeinactive
Dyslipidaemia Abnormallipids
Heterogeneous Consistingofdiverseordissimilarparts;having non-uniformstructureorcomposition
Heterozygous Anindividualisheterozygousatalocusif(s)hehas twodifferentallelesatthatlocus
Homozygous Anindividualishomozygousatalocusif(s)hehas twoidenticalallelesatthatlocus
ILD Interstitial(occurringbetweenotherstructures) lungdisease
Ion Strictly,anyatomormoleculewhichhasa resultantelectriccharge
Knockout mouse model
Niemann-Pickmousecreatedbydestroyingthe NPgene
Lipids Oils,fats,waxesandrelatedproductsfoundin livingtissues
Lysosome Sac-likeintracellularorganellethatcontains varioushydrolyticenzymes
Macula Smallyellowareaseenonexaminationofthe retina
Mutation Changeinthegeneticmaterialofanindividual
NPA Niemann-PicktypeA
NPB Niemann-PicktypeB
Phenotype Theobservablecharacteristicsofanindividual determinedbyinteractionofgenotypeand environment
Phospholipids Compoundfatmoleculeinwhichtherearetwo fattyacidsandaphosphategroupattachedto glycerol
Platelets Disc-likecomponentsinbloodwhichplayan importantroleinclotting
Polymorphisms Theoccurrenceinapopulation(oramong populations)ofseveralphenotypicforms associatedwithallelesofonegeneorhomologues ofonechromosome
Proband Thepersonthroughwhomapedigreewas discovered
Reticuloendothelial system (RES)
Mammaliandefencesystemagainstforeign bodies,consistingofmacrophagecellslocatedin thelymphnodes,liverspleenandbonemarrow
Sphingomyelin Phospholipidcomposedofalongchain base,sphingosine,alongchainfattyacidand phosphocholine
Splenectomy Theremovalofthespleen
Splenomegaly Enlargementofthespleen
Thrombocytopenia Alowplateletcount
34