Wilson Disease PDF
Preview Wilson Disease
HANDBOOK OF CLINICAL NEUROLOGY Series Editors MICHAEL J. AMINOFF, FRANÇOIS BOLLER, AND DICK F. SWAAB VOLUME 142 ELSEVIER Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates ©2017ElsevierB.V.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical, includingphotocopying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwriting fromthepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthePublisher’spermissionspolicies andourarrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyrightLicensing Agency,canbefoundatourwebsite:www.elsevier.com/permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthan asmaybenotedherein). 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BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-444-63625-6 ForinformationonallElsevierpublications visitourwebsiteathttps://www.elsevier.com/books-and-journals Publisher:MaraConner EditorialProjectManager:KristiAnderson ProductionProjectManager:SujathaThirugnanaSambandam CoverDesigner:AlanStudholme TypesetbySPiGlobal,India HandbookofClinicalNeurology3rdSeries Availabletitles Vol.79,Thehumanhypothalamus:basicandclinicalaspects,PartI,D.F.Swaab,ed.ISBN9780444513571 Vol.80,Thehumanhypothalamus:basicandclinicalaspects,PartII,D.F.Swaab,ed.ISBN9780444514905 Vol.81,Pain,F.CerveroandT.S.Jensen,eds.ISBN9780444519016 Vol.82,Motorneuronedisordersandrelateddiseases,A.A.EisenandP.J.Shaw,eds.ISBN9780444518941 Vol.83,Parkinson’sdiseaseandrelateddisorders,PartI,W.C.KollerandE.Melamed,eds.ISBN9780444519009 Vol.84,Parkinson’sdiseaseandrelateddisorders,PartII,W.C.KollerandE.Melamed,eds.ISBN9780444528933 Vol.85,HIV/AIDSandthenervoussystem,P.PortegiesandJ.Berger,eds.ISBN9780444520104 Vol.86,Myopathies,F.L.MastagliaandD.HiltonJones,eds.ISBN9780444518996 Vol.87,Malformationsofthenervoussystem,H.B.SarnatandP.Curatolo,eds.ISBN9780444518965 Vol.88,Neuropsychologyandbehaviouralneurology,G.GoldenbergandB.C.Miller,eds.ISBN9780444518972 Vol.89,Dementias,C.DuyckaertsandI.Litvan,eds.ISBN9780444518989 Vol.90,Disordersofconsciousness,G.B.YoungandE.F.M.Wijdicks,eds.ISBN9780444518958 Vol.91,Neuromuscularjunctiondisorders,A.G.Engel,ed.ISBN9780444520081 Vol.92,Stroke–PartI:Basicandepidemiologicalaspects,M.Fisher,ed.ISBN9780444520036 Vol.93,Stroke–PartII:Clinicalmanifestationsandpathogenesis,M.Fisher,ed.ISBN9780444520043 Vol.94,Stroke–PartIII:Investigationsandmanagement,M.Fisher,ed.ISBN9780444520050 Vol.95,Historyofneurology,S.Finger,F.BollerandK.L.Tyler,eds.ISBN9780444520081 Vol.96,Bacterialinfectionsofthecentralnervoussystem,K.L.RoosandA.R.Tunkel,eds.ISBN9780444520159 Vol.97,Headache,G.NappiandM.A.Moskowitz,eds.ISBN9780444521392 Vol.98,SleepdisordersPartI,P.MontagnaandS.Chokroverty,eds.ISBN9780444520067 Vol.99,SleepdisordersPartII,P.MontagnaandS.Chokroverty,eds.ISBN9780444520074 Vol.100,Hyperkineticmovementdisorders,W.J.WeinerandE.Tolosa,eds.ISBN9780444520142 Vol.101,Musculardystrophies,A.AmatoandR.C.Griggs,eds.ISBN9780080450315 Vol.102,Neuro-ophthalmology,C.KennardandR.J.Leigh,eds.ISBN9780444529039 Vol.103,Ataxicdisorders,S.H.SubramonyandA.Durr,eds.ISBN9780444518927 Vol.104,Neuro-oncologyPartI,W.GrisoldandR.Sofietti,eds.ISBN9780444521385 Vol.105,Neuro-oncologyPartII,W.GrisoldandR.Sofietti,eds.ISBN9780444535023 Vol.106,Neurobiologyofpsychiatricdisorders,T.SchlaepferandC.B.Nemeroff,eds.ISBN9780444520029 Vol.107,EpilepsyPartI,H.StefanandW.H.Theodore,eds.ISBN9780444528988 Vol.108,EpilepsyPartII,H.StefanandW.H.Theodore,eds.ISBN9780444528995 Vol.109,Spinalcordinjury,J.VerhaagenandJ.W.McDonaldIII,eds.ISBN9780444521378 Vol.110,Neurologicalrehabilitation,M.BarnesandD.C.Good,eds.ISBN9780444529015 Vol.111,PediatricneurologyPartI,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444528919 Vol.112,PediatricneurologyPartII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444529107 Vol.113,PediatricneurologyPartIII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444595652 Vol.114,Neuroparasitologyandtropicalneurology,H.H.Garcia,H.B.TanowitzandO.H.DelBrutto,eds. ISBN9780444534903 Vol.115,Peripheralnervedisorders,G.SaidandC.Krarup,eds.ISBN9780444529022 Vol.116,Brainstimulation,A.M.LozanoandM.Hallett,eds.ISBN9780444534972 Vol.117,Autonomicnervoussystem,R.M.BuijsandD.F.Swaab,eds.ISBN9780444534910 Vol.118,Ethicalandlegalissuesinneurology,J.L.BernatandH.R.Beresford,eds.ISBN9780444535016 Vol.119,NeurologicaspectsofsystemicdiseasePartI,J.BillerandJ.M.Ferro,eds.ISBN9780702040863 Vol.120,NeurologicaspectsofsystemicdiseasePartII,J.BillerandJ.M.Ferro,eds.ISBN9780702040870 Vol.121,NeurologicaspectsofsystemicdiseasePartIII,J.BillerandJ.M.Ferro,eds.ISBN9780702040887 Vol.122,Multiplesclerosisandrelateddisorders,D.S.Goodin,ed.ISBN9780444520012 Vol.123,Neurovirology,A.C.TselisandJ.Booss,eds.ISBN9780444534880 vi AVAILABLETITLES(Continued) Vol.124,Clinicalneuroendocrinology,E.Fliers,M.KorbonitsandJ.A.Romijn,eds.ISBN9780444596024 Vol.125,Alcoholandthenervoussystem,E.V.SullivanandA.Pfefferbaum,eds.ISBN9780444626196 Vol.126,Diabetesandthenervoussystem,D.W.ZochodneandR.A.Malik,eds.ISBN9780444534804 Vol.127,TraumaticbraininjuryPartI,J.H.GrafmanandA.M.Salazar,eds.ISBN9780444528926 Vol.128,TraumaticbraininjuryPartII,J.H.GrafmanandA.M.Salazar,eds.ISBN9780444635211 Vol.129,Thehumanauditorysystem:Fundamentalorganizationandclinicaldisorders,G.G.Celesia andG.Hickok,eds.ISBN9780444626301 Vol.130,Neurologyofsexualandbladderdisorders,D.B.VodušekandF.Boller,eds.ISBN9780444632470 Vol.131,Occupationalneurology,M.LottiandM.L.Bleecker,eds.ISBN9780444626271 Vol.132,Neurocutaneoussyndromes,M.P.IslamandE.S.Roach,eds.ISBN9780444627025 Vol.133,Autoimmuneneurology,S.J.PittockandA.Vincent,eds.ISBN9780444634320 Vol.134,Gliomas,M.S.BergerandM.Weller,eds.ISBN9780128029978 Vol.135,NeuroimagingPartI,J.C.MasdeuandR.G.González,eds.ISBN9780444534859 Vol.136,NeuroimagingPartII,J.C.MasdeuandR.G.González,eds.ISBN9780444534866 Vol.137,Neuro-otology,J.M.FurmanandT.Lempert,eds.ISBN9780444634375 Vol.138,Neuroepidemiology,C.Rosano,M.A.IkramandM.Ganguli,eds.ISBN9780128029732 Vol.139,Functionalneurologicdisorders,M.Hallett,J.StoneandA.Carson,eds.ISBN9780128017722 Vol.140,CriticalcareneurologyPartI,E.F.M.WijdicksandA.H.Kramer,eds.ISBN9780444636003 Vol.141,CriticalcareneurologyPartII,E.F.M.WijdicksandA.H.Kramer,eds.ISBN9780444635990 Allvolumesinthe3rdSeriesoftheHandbookofClinicalNeurologyarepublishedelectronically,onScienceDirect: http://www.sciencedirect.com/science/handbooks/00729752. Foreword ItisapleasuretopresentthisvolumeoftheHandbookofClinicalNeurology(HCN),whichisdedicatedtoWilson disease.Thereareplentyofeponymsinmedicineandparticularlyinneurology,butveryfewHCNvolumesincludea person’s name in their title and this is only the third in the present series, after Parkinson and Huntington. Kinnier Wilson (1878–1937) fully deserves this honor. In 1912, he published in Brain what had been his MD thesis: “Progressivelenticulardegeneration:afamilialnervoussystemdiseaseassociatedwithcirrhosisoftheliver.”Asis almostalways thecase, similarconditionsassociatingliverandbrain diseasehadbeen described previously,going asfarbackasMorgagniand,morerecently,byWestphalandStrumpell.However,theWilsonmonographincluded the main clinical and pathologic features of the disease, and it opened the way to a new chapter in the history of neurology,namelythatofextrapyramidalsystemdisorders,atermWilsonintroduced. Thevolumeopenswithachapterdescribingindetailthehistoryofthediseasewrittenbyoneofitsprotagonists, JohnM.Walshe,whoin1956proposedtheuseofpenicillamine,oneofthefirstdisease-modifyingdrugsinneurology. Thevolumeincludeschaptersdealingwiththeepidemiologyandgeneticsofthedisease.Itfocusesonthetwomain organsaffected,thebrainandtheliver,withdetaileddescriptionsofthepathologyandpathogenesisofthedisease, includinganimalmodels,aswellasitsdiagnosisandthevariousavailableformsofmanagementandtreatment.Novel perspectivesarediscussedinachapterthatintroducesanewchelatingagent,tetrathiomolybdate,aswellasnonchelat- ingdrugscurrentlyunderclinicalinvestigation.Asisappropriateforsucharareyethighlycomplexhereditarydisease, thevolumeconcludeswithachapteronthegroupsthatadvocateforandsupportpatientswithWilsondisease. Wehavebeenfortunatetohaveasvolumeeditorstwodistinguishedscholarsandclinicians,AnnaCzłonkowska, ProfessorattheSecondDepartmentofNeurology,InstituteofPsychiatryandNeurologyinWarsaw,andMichaelL. Schilsky, Associate Professor of Medicine and Surgeryand Medical Director of AdultLiver Transplantation atthe Yale-New Haven Transplantation Center. Both have been on the forefront of research on Wilson disease for many years.Theyhaveassembledatrulyinternationalgroupofauthorswithacknowledgedexpertiseandtogethertheyhave producedthisauthoritative,comprehensive,andup-to-datevolume.ItsavailabilityelectronicallyonElsevier’sScience Directsiteaswellasinprintformatshouldensureitsreadyaccessibilityandfacilitatesearchesforspecificinformation. Wearegratefultothemandtoallthecontributorsfortheireffortsincreatingsuchaninvaluableresource.Asseries editors we read and commented on each of the chapters with great interest. We are therefore confident that both cliniciansandresearchersinmanydifferentmedicaldisciplineswillfindmuchinthisvolumetoappealtothem. Andlast,butnotleast,wethankElsevier,ourpublisher–andinparticularMichaelParkinsoninScotland,andMara ConnerandKristiAndersoninSanDiego–fortheirunfailingandexpertassistanceinthedevelopmentandproduction ofthisvolume. MichaelJ.Aminoff Franc¸oisBoller DickF.Swaab Preface ThereisalmostnoothertreatabledisorderwithaswideaclinicalspectrumforpresentationasWilsondisease.From childtoseptuagenarianatdiagnosis,patientsmaybeasymptomaticorpresentwithadvancedcirrhosisorliverfailure, withamovementdisorderrangingfrommildtremororbradykinesiatoseveredystonia,orwithanaffectivedisorderor psychosis.Althoughthisisavolumeinaseriesfocusedonneurologicandneuropsychiatricdisorders,itwasinescap- ablethatwecrossbetweendisciplinesandconsiderthefullspectrumofthedisease,theunderlyinghepaticdiseasethat accompaniesthedisorder,thediverseneurologicpresentations,andthefascinatinghistoryofthediscoveryofitsbasis andtreatment. RecentadvancesinmoleculargeneticstestingalloweasierandfasterdiagnosisofWilsondisease,forwhichtreat- mentmayprevent,stop,orevenreversetissueinjury.Alsointroducedmorerecentlyareimagingtechniquesthathelp estimatethestageofthediseaseatthetimeofdiagnosisandwhicharehelpfulformonitoringtheprogressoftreatment. Withabetterunderstandingofthediseasepathogenesis,therearenewopportunitiesforsaferandevenmoreeffective therapy. TheaimofthistextwastoprovideathoroughexaminationofWilsondiseaseinaneasy-to-digestformat.Toaccom- plishthis,weengagedagroupofinternationalexpertsfromEuropeandNorthAmericaandaskedfortheirhelpin coveringawiderangeofrelevanttopicsimportantforallcaregiversofpatientswithWilsondisease,whetherpediatric oradultphysicians,neurologists,psychiatrists,orhepatologists. Thetextbeginswithahistoricperspective,andthenprovidesoverviewsofdiseasepathogenesisanditsunderlying geneticbasis,theeffectsofthediseaseonboththecentralnervoussystemandliver,itsdiagnosis,andtherangeof clinicaldiseaseandtreatments.Unusually,wehaveincluded theviewpointofalaypatient organizationonwhatis importantfromapatientandadvocacyperspective. Wethankallourcontributorsfortheirtimeandhelpinputtingtogetherthisvolume.Anumberofrevisionswere necessarytomakethehandbookmorecohesive,andweappreciatetheirpatienceandforbearance,whichmadethis possible. WewouldlikeparticularlytoacknowledgeJohnM.Walsheforhishistoricperspectiveandhiscontributionstothe field, and Mary L. Graper for her advocacy for all patients with Wilson disease. We especially thank all of our coworkers,withwhomwehaveworkedovertheyearstoassisthundredsofpatients,broadenourpersonalexperience, andshareitwithothers.Wearealsogratefulforthecooperationofourpatientsandtheirfamilieswhoputtheirtrustin usandfromwhomwecontinuetolearn. AnnaCzłonkowskaandMichaelL.Schilsky Contributors A.Ahmad FirstFacultyofMedicineandGeneralUniversity SectionofTransplantationandImmunology, HospitalinPrague,Prague,CzechRepublicandInstitute DepartmentofSurgery,YaleUniversitySchoolof ofNeuroradiology,UniversityMedicineGoettingen, Medicine,NewHaven,CT,USA Goettingen,Germany A.Ala K.Dziez(cid:1)yc DepartmentofClinicalandExperimentalMedicine, SecondDepartmentofNeurology,InstituteofPsychiatry FacultyofHealthandMedicalSciences,Universityof andNeurology,Warsaw,Poland SurreyandDepartmentofGastroenterologyand Hepatology,RoyalSurreyCountyHospitalNHS P.Ferenci FoundationTrust,Guildford,Surrey,UK DepartmentofInternalMedicine3,Gastroenterology andHepatology,MedicalUniversityofVienna,Vienna, O.Bandmann Austria SheffieldInstituteforTranslationalNeuroscience (SITraN),UniversityofSheffield,Sheffield,UK M.L.Graper WilsonDiseaseAssociation,Milwaukee,WI,USA S.Boga DepartmentofGastroenterology,SisliEtfalEducation S.H.Hahn andResearchHospital,Istanbul,Turkey DivisionofGeneticMedicine,DepartmentofPediatrics, UniversityofWashingtonSchoolofMedicine,Seattle R.Brůha Children’sHospital,Seattle,WA,USA FourthDepartmentofInternalMedicine,Charles UniversityinPrague,FirstFacultyofMedicineandGeneral D.Huster UniversityHospitalinPrague,Prague,CzechRepublic DepartmentofGastroenterologyandOncology, DeaconessHospitalLeipzig,Leipzig,Germany G.Chabik SecondDepartmentofNeurology,InstituteofPsychiatry T.Litwin andNeurology,Warsaw,Poland SecondDepartmentofNeurology,InstituteofPsychiatry andNeurology,Warsaw,Poland I.J.Chang DivisionofMedicalGenetics,DepartmentofMedicine, C.Lo UniversityofWashingtonSchoolofMedicine,Seattle, SheffieldInstituteforTranslationalNeuroscience WA,USA (SITraN),UniversityofSheffield,Sheffield,UK A.Członkowska V.Medici SecondDepartmentofNeurology,InstituteofPsychiatryand DivisionofGastroenterologyandHepatology, NeurologyandDepartmentofExperimentalandClinical DepartmentofInternalMedicine,Universityof Pharmacology,MedicalUniversityofWarsaw,Poland CaliforniaDavis,Sacramento,CA,USA P.Dušek J.Mikol DepartmentofNeurologyandCenterofClinical PathologyDepartment,ParisDiderotUniversity,Paris, Neuroscience,CharlesUniversityinPrague, France xii CONTRIBUTORS J.Pfeiffenberger P.Socha DepartmentofGastroenterologyandHepatology, DepartmentsofGastroenterology,Hepatology, UniversityHospitalofHeidelberg,Heidelberg, NutritionalDisordersandPediatrics,TheChildren’s Germany MemorialHealthInstitute,Warsaw,Poland A.Poujois W.Stremmel FrenchNationalReferenceCentreforWilsonDisease, DepartmentofGastroenterologyandHepatology, NeurologyDepartment,LariboisièreHospital,Paris, UniversityHospitalofHeidelberg,Heidelberg, France Germany M.Pronicki E.Torrazza-Perez DepartmentofPathology,TheChildren’sMemorial DivisionofGastroenterologyandHepatology, HealthInstitute,Warsaw,Poland DepartmentofInternalMedicine,UniversityofNew Mexico,Albuquerque,USA E.A.Roberts DepartmentsofPaediatrics,MedicineandPharmacology J.M.Walshe andToxicology,UniversityofToronto,Toronto,Canada FormerlyofAddenbrookesHospital,Cambridgeandthe MiddlesexHospital,London,UK C.Rupp DepartmentofInternalMedicine,UniversityHospital K.-H.Weiss Heidelberg,Heidelberg,Germany DepartmentofGastroenterologyandHepatology, UniversityHospitalofHeidelberg,Heidelberg,Germany I.F.Scheiber DepartmentofParasitology,FacultyofScience,Charles F.Woimant University,Prague,CzechRepublic FrenchNationalReferenceCentreforWilsonDisease, NeurologyDepartment,LariboisièreHospital,Paris, M.L.Schilsky France SectionofDigestiveDiseasesandTransplantationand Immunology,DepartmentofMedicineandSurgery,Yale P.Zimbrean UniversitySchoolofMedicine,NewHaven,CT,USA DepartmentsofPsychiatryandSurgery(Transplant), YaleUniversity,NewHaven,CT,USA J.Seniów SecondDepartmentofNeurology,InstituteofPsychiatry andNeurology,Warsaw,Poland HandbookofClinicalNeurology,Vol.142(3rdseries) WilsonDisease A.CzłonkowskaandM.L.Schilsky,Editors http://dx.doi.org/10.1016/B978-0-444-63625-6.00001-X ©2017ElsevierB.V.Allrightsreserved Chapter1 History of Wilson disease: a personal account JOHNM.WALSHE* FormerlyofAddenbrookesHospital,CambridgeandtheMiddlesexHospital,London,UK Abstract Thischapterfocusesonthehistoricaspectsofthedevelopmentofmuchofourcurrentknowledgeofthe diagnosisandtreatmentofWilsondisease.Includedaredescriptionsoftheclinicalsignsofneurologicand hepaticdisease,thenaturalhistoryofdiseaseprogression,studiesofdiseasepathogenesisandaunique perspectiveonthedevelopmentofdiagnostictestingandpharmacologicaltherapy. “Begin at the beginning,” the King said very gravely, theylaterbecameassociated(Kayser,1902).Itissurpris- “thengoonuntiltheend,thenstop.” ing,inviewoftheverydetailednatureofhisdescriptions Alice’sAdventuresThroughtheLookingGlass, of his patients, that Wilson did not observe the corneal LewisCarroll ringsandindeedherefusedtoadmitoftheirrelationship tohisdiseasefor10years after hisoriginal publication This admirable advice for any story teller is honored (Wilson,1922).Theseringswereformanyyearsthought moreofteninthebreachthantheobservance.Thediffi- topathognomonicofWilsondiseasebutitisnowknown cultyremains,whereisthebeginninganddoesthestory that they can be found in other forms of liver disease, haveanydefinitiveend?Withthehistoryofdiseasethe suchasprimarybiliarycirrhosisandchroniccholestasis probability is that there is, in all likelihood, no end. (Flemingetal.,1975). Knowledgeandtheorieswillcontinuetodevelopalmost Only 1 year after Wilson’s original publication in indefinitely. Well then, is there a beginning? Probably, Brain,theAustrianpathologist,Rumpel,reported find- butexactlywherethatis,isnotalwaysobvious.Inthis ing an excess of copper in the liver of a patient dying case,itmightseemself-evidentthatthestorybeginswith of Wilson disease, an observation whose importance Wilson’s original article in Brain in 1912, when he was completely missed (Rumpel, 1913). He also sug- describedfourcasesofwhathecalled“progressivelen- gestedthattherewasexcessofsilverintheeyes. ticular degeneration: a familial nervous disease associ- Another important observation which passed unno- ated with cirrhosis of the liver.” (Fig. 1.1) In addition ticedwasbyBramwell, whosehousephysician Wilson he found four cases in the literature which fitted his had once been (Bramwell, 1916). Bramwell described description,oneofwhichwasdatedbackto1890.Fur- a family in which four siblings died, between the ages thermore, there is a case report in Frerichs’ book of of 9 and 14 years, of rapid-onset liver failure and sug- 1860thatwasalmostcertainlyacaseofWilsondisease. gested that this might be related to Wilson disease. It Indeed, going back even further, Morgagni, in 1761, wouldbeinterestingtoseeifanydescendantsofthisfam- described several cases of liver disease associated with ily still exist so that they could be tested to see if they nervoussymptomswhichmaypossiblyhavebeencases carry,insingledose,themutationforWilsondisease. ofWilsondisease. Thenextimportantadditiontoknowledgecamewhen Itisinterestingthatoneofthedefiningphysicalsigns Hall (1921) showed that this disease was inherited in a of Wilson disease, the Kayser–Fleischer corneal rings, recessivemode,laterconfirmedinmoredetailbyBearn hadbeendescribed10yearsbeforethediseasetowhich (1960), who studied 30 families he saw in New York *Correspondence to: J.M. Walshe, MD, ScD, FRCP, 58 High Street Hemingford Grey, Huntingdon PE 28 9BN, UK. E-mail:[email protected] 2 J.M.WALSHE copperexcretedintheurine.Thisimportantobservation wasfollowedupin1951byCumingshimselfinLondon andbyDennyBrownandPorter(1951)inBoston.Both teamsshowedthatcoursesofBALresultedinsignificant improvement in their patients’ neurologic symptoms. However it soon became apparent that patients needed repeated courses of the drug and subsequent courses were less effective than the initial one. In addition the injectionswerepainfulandassociatedwithawidevari- ety of toxic reactions. This was clearly not an ideal treatment. Fig. 1.1. Dr. John Walshe (right) with Dr. James Kinner The picture changed when, in 1956, I reported that Wilson,sonofneurologistSamuelAlexanderKinnerWilson, penicillaminepromotedamuchlargerexcretionofcop- whose1912publicationonhepatolenticulardegenerationwas perintheurinethaneitherBALortheothermedicalche- being celebrated at the Centennial Symposium on Wilson’s lating agent ethylenediamine tetraacetic acid (EDTA) diseaseinLondon,October5–6,2012. (Walshe, 1956, 1960). Penicillamine is a breakdown product of penicillin and is excreted in the urine of all whoseancestrycouldbetracedbacktoEasternEuropeor patients treated with penicillin, an observation I had SouthernItaly. madesomeyearsearlierwhenstudyingchangesinamino ItmustbenotedthatinWilson’soriginalpublication acidmetabolisminpatientswithliverdamage(Walshe, ofonly4patients,hedescribedalmostallofthesignsand 1956).ThisideacametomewhenworkingintheLiver symptomswhichwenowknowarecharacteristicofthis Unit under Dr. Charles Davidson, at the Boston City disease (Wilson, 1912). He carried out his own patho- Hospital.HavingseenoneofProfessorDennyBrown’s logicstudiesandeventraveledtoSwitzerlandtocollect Wilsondiseasepatientswhowasnotprosperingontreat- thebrainofapatientdyingofhisdisease.Wilsondidnot ment with BAL, it occurred to me that penicillamine, believethattheliverpathologywasasignificantfactorin with its –SH and –NH groups, might have the right 3 thenaturalhistoryofthedisease,althoughoneofhisown chemical structure to chelate copper and promote its patientsactuallydiedofbleedingesophagealvarices. excretion in the urine. Dr. Davidson was able to obtain Over the next 30 years there were only minor forme2gramsofpenicillaminefromProfessorSheehan advances in the understanding of the disease, whose at the Massachusetts Institute of Technology. Having course remained remorseless and invariably fatal. In taken 1 gram myself to prove its safety, I administered 1922SiemerlingandOloffdescribed theassociationof the second gram to Professor Denny Brown’s patient sunflower cataracts with Kayser–Fleischer rings and and recorded the very satisfactory cupresis so induced. notedthesimilaritytolesionscausedbyintraoculardam- With this simple procedure the start of penicillamine agewithintraocularcopperfragments.Vogt(1929)and therapywaslaunched. Haurowitz(1930)reportedfindingexcesscopperinthe Inthosefar-offdaystherewerenoethicalcommittees brainandliverofWilsondiseasepatients–anobserva- to be approached for permission; life was a lot easier tionwhichwasnotfollowedup. whentryingoutnewideas.By1960Iwasabletopublish In 1945 Sir Rudolph Peters and his team in thefirstaccountofapatientwithWilsondiseaseimprov- Oxfordwereabletoreporttheirearlierworkinthedevel- ingsignificantlyasaresultofthisnewtherapy(Walshe, opment of the antiarsenical drug, dimercaprol (British 1960). This was confirmed by similar studies by anti-Lewisite,BAL).ThiswasdevelopedduringtheSec- ScheinbergandSternlieb,alsoin1960. ond World War to combat anticipated attack by Hitler Whilst these important advances in the treatment of with the arsenical gas Lewisite. The importance of this this disease were progressing, so also was our under- became apparent in 1948 when Cumings showed that standing of its pathogenesis. In 1948 Holmberg and Wilsondiseasewasindeedduetoaccumulationofexcess Laurell described the finding of a copper-carrying pro- copperinthebrainandliverofallpatientsdyingofthis tein in the plasma which they named ceruloplasmin. In disease and postulated that treatment with BAL might 1952,workingindependentlyinNewYork,bothBearn halttheprogressoftheillness(Cumings,1951).Bycoin- and Kunkel and Scheinberg and Gitlin showed that cidence, at the same time, Mandelbrote et al. (1948) patientswithWilsondiseaseallhadloworabsentcon- reported their findings on the effect of BAL on copper centrations of this protein (Bearn and Kunkel,1952; excretiononawidespectrumofpatientswithneurologic Scheinberg and Gitlin, 1952). Shortly after this diseases;oneofthesepatientshadWilsondiseaseandin Cartwright and his team (1954) in Salt Lake City pub- this particular patient there was a great increase in the lished an important article on copper metabolism in
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