Syndrome ofthe month Wolfram (DIDMOAD) …

1 83tMedGenet1997;34:838-841 SyndromeofthemonthWolfram (DIDMOAD) syndro meTGBarrett,SEBundeyAbstractWolframsyndr ome(MIM222300)istheassociationofjuvenile onsetdiabetesmel-litusandopticatrophy,al soknownasDIDMOAD(DiabetesInsipidus,Diabe tesMellitus,OpticAtrophy,andDeafness).Pa tientspresentwithdiabetesmellitusfollowe dbyopticatrophyinthefirstdecade,craniald iabetesinsipidusandsensorineuraldeafness intheseconddec-ade,dilatedrenaloutflowtr actsearlyinthethirddecade, , , , ,butthereisevidenceforlocushet-erogeneit y, ,availablediagnosticcriteriaarejuvenileH ospital,Ladywoodonsetdiabetesmellitusand opticatrophy,Middleway,Ladywood,butthere isawidedifferentialdiagnosisBirminghamB1 68ET, (7 MedGenet1997;34:838-841)DepartnentofClin icalKeywords:Wolframsyndrome; diabetes ;op ticatrophy;Genetics,B'rirmighamdeafnessW omen'sHospitalNHST rust,Edgbaston,BirminghamB152TG,UKIn1938 ,WolframandWagener'reportedfourSEBundeys ibswithdiabetesmellitusandopticatrophy.

2 Theoldesthaddiabetesmellitusfrom8years,C orrespondenceto:opticatrophyfrom11years, ,ndwnexaminedat18yearsvisualacuitywasred ucedTable1 UKStudyof45 Wolframpatients:complicationsoccurringby differentagesAgeattained(y)1020304045 Complications(n=43)(n=36)(n=27)(n=8)(n=4 )Diabetesmellitus32(74%)36(100%)Opticatr ophy17(40%)36(100%)Diabetesinsipidus7(16 %)20(56%)23(85%)8(100%)4(100%)Deafness7( 16%)15(42%)18(67%)5(62%)2(50%)Renal3(7%) 13(36%)15(56%)5(62%)4(100%)Neurological1 (2%)2(6%)11(41%)5(62%)4(100%) , ;hisvisionhadbeendocumentedasnormalat6ye ars,butonexaminationat8yearshehadopticat rophyandvisualacuitywas6 ;hehaddevelopedneurologicalsymptomsandha dbeendiag-nosedasatypicalFriedreich' ,twoofthefouraffectedsibswerealmostcompl etelyblindandhaddeveloped"cord"(neurogen ic)bladders; ,'therehavebeenover200casereports,adding diabetesinsipidus,renalout-flowtract, ;however, ' (under20years)diabetesmellitusandopticat rophy, , (range3weeks-16years)andisnon-autoimmune ,insulindeficient, (6weeks-19years),with838 on June 30, 2021 by guest.

3 Protected by Med Genet: first published as on 1 October 1997. Downloaded from Wolfram (DIDMOAD) syndrome0010203040 Age(y) ,OA=opticatrophy,DI=diabetesinsipidus,D= deafness,Renal=renaltractabnormalities,A taxia=neurologicalabnormalities(onepatie ntpresentedat5years). ; (3months-40years) ,"andmagneticresonanceimaging(MRI)showed lossofsignalfromthehypothalamusandposter iorpituitary"(fig2).Symptomaticsensorine uraldeafnessdevelopsintwothirdsofpatient satamedianageof16years(5-39years) (10-44years),withurinaryfrequency,incont inence, ,"amarkedreductioninnervefibrestainingin abladderwallbiopsysuggestsaprimaryneuro- degenerativecauseforthiscomplication.'3 Neurologicalfeaturespresentatamedianageo f30years(5-44years), ,reducedlimbreflexes,horizontalnystagmus ,dysarthria,centralapnoeas,lossoftastean dsmell, ,severepsychiatricsymptomsofdepression,p sychosis,andorganicbrainsyndromewererepo rtedinupto25%ofpatients.

4 ' 'brainstypicallyshowgeneralisedbrainatro phy,especiallyinthecerebellum,medulla,an dpons(fig2). ,successfulpreg-nanciesofhealthy,unaffec tedchildrenhavebeenreported.'5 Gastrointestinaldysmotilityiscommon, (25-49years); '"'9; ,posteriorpituitary,opticnervesandchiasm ,vestibularnuclei,pons,medullaryreticula ractivatingsystem,substantianigra,superi orandinferiorolives, , ; , ,Leber'shereditaryopticatrophy, ;itisbetterregardedasaseparatesyndrome(t hiamineresponsiveanae-miasyndrome) 'sataxia,Refsumdisease,Alstromsyndrome,L awrence-Moonsyndrome,Kearn-Sayresyndrome ,anddeaf-nessanddiabetesinthe"3243" ,whicharenegativeunlikemanypatientswitht ype1diabetesmellitus,electro-839MI on June 30, 2021 by guest. Protected by Med Genet: first published as on 1 October 1997. Downloaded from Barrett,Bundeyphysiologyincludingvisuale vokedpotentialsandelectroretinogramstoco nfirmopticnervepathology, ; , , , (deafness,opticatrophy,diabetesmellitus, andataxia) , 'Severalstudieshavebeencriticisedongroun dsofcasedefinitionormethodology; (mtDNA) ,whereasintheparentsandunaffectedsisteri trangedbetween2%and8% ; , , ;thereisa25% , (HOX7) , (fig3).

5 Onefamilywithanatypicalphenotype(congeni tal,non-progressiveopticatrophy) (withtypicalpheno-types) , , ;13 ,RynearsonEH,BaileyAA, ;25 , ;5 ,BortolussiR,LittleJ,AndermannF,FraserFC , ,opticatrophy,sensorynervedeafness, ;89 ,WijdeveldPGAB, ,opticatrophy,hearingloss,diabetesinsipi dus,atoniaoftheurinarytractandbladder,an dotherabnormalities(Wolframsyndrome).Act aPaediatrScand1977;suppl264 ,PierelliF,RispoliE,SaponaraM,VingoloE, 'ssyndrome:aclinical, ;9 ,SwiftM,DumontRH, ;18 ,BundeySE, :UKnationwidestudyofWolfram(DID-MOAD) ;346 ,CruysbergJRM, ;7 ,CharltonJ,WalfordS, ( Wolfram ) ;71 ,HortonJC, ;42 on June 30, 2021 by guest. Protected by Med Genet: first published as on 1 October 1997. Downloaded from Wolfram (DIDMOAD) syndrome12 PageMMcB,AsmalAC, :thesyndromeofdiabetesinsipidus, diabetes mellitus , ;179 ,StaffWG,MorrisJA, ;62 ,SadlerDR, ;336 ,McNichollJM,O' ;86 ,SlagerUT, ,diabetesinsipidus, ;131 ,LaronM, ;132 ,BurdenAC,HearnshawJR, ;29 ' ;48 ,PoultonK,WhitwellH,CurtisE,BrownIAR, ;15 ,PoultonK, ; ;18 ,CasademontJ,SaizA, ;58 , ,diabetesinsipidus, ;14 ,SwiftRG, ;8 ,BarrettTG,CurtisD, ;59 on June 30, 2021 by guest.

6 Protected by Med Genet: first published as on 1 October 1997. Downloaded from