DepartmentofNeuroOphthalmologyNAJAGTPFDBNeurogeneticsUnitCEWMSDepartmentofNeuropathologyRP OriginalContribution serologyIntravenousedrophoniumhadnoeffectonhisImagingStudiesCTofthebraina ID: 941577
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PupillaryDysfunctioninanAtypicalCaseofMitochondrialMyopathyWithTubularAggregatesNadeemAli,MA,MRCOphth,FRCSEd(Ophth),CatherineE.Woodward,BSc,MarySweeney,BSc,RahulPhadke,MD,FRCPath,JaniceL.Holton,PhD,MRCPath,JamesAcheson,MRCP,FCRS(Glas),FRCOphth,GordonT.Plant,MD,FRCP,FRCOphth,FionD.Bremner,PhD,FRCOphth DepartmentofNeuro-Ophthalmology(NA,JA,GTP,FDB);Neu-rogeneticsUnit(CEW,MS);DepartmentofNeuropathology(RP, OriginalContribution serology.IntravenousedrophoniumhadnoeffectonhisImagingStudiesCTofthebrainandorbitsandMRIofthethymuswereElectromyographyrevealednormalnerveconduction,re-petitivestimulation,andsingle-Þberstudies.Musclesam-plingshowedabundantspikypolyphasicunitsrecordednotonlyfromtheorbicularisoculibutalsominimallyfromtheextensordigitorumcommunis,tibialisanterior,andrectusfemoris.TheseÞndingsweresuggestiveofamildmyopathicprocessratherthanneuromuscularjunctiondysfunction.MuscleBiopsyTricepsmusclebiopsyrevealedthepresenceof3raggedredÞbersandmorethan10cytochromeoxidaseÐnegativeÞbers.Mitochondrialrespiratorychainenzymeactivityassayswerenormal.Electronmicroscopyshowedsubsarcolemmalac-cumulationsofscatteredabnormalmitochondria,manyofwhichcontainedtype1paracrystallineinclusions.Tubularaggregates(TAs)werenotedinseveralÞbers,someofwhichcontainedabnormalmitochondria(Fig.2).NoTAswereseenatthelightmicroscopiclevel.GeneticAnalysisMitochondrialgeneticanalysisconÞrmedasinglelargedeletioninmitochondrialDNAdetectedbylong-rangepolymerasechainreactionfollowedbySouthernblotting.SequencingconÞrmedthepresenceofthecommondeletionof4,977basepairs,withbreakpointsintheßankingrepeatsbetweennucleotides8,470and8,482andnucleotides13,447and13,459.ThepatientwasthereforediagnosedwithCPEO.PupillaryFunctionBasedontheclinicalimpressionofhyporeactivepupils,infraredvideopupillometrywasperformedandcomparedwithournormativedatabaseofmeasurementsfrom315healthycontrolsubjects(3)(Fig.3;Table1).Slit-lampexaminationshowednoabnormalityofpupilshapeandnoirisdamageorsectorpalsy.TherestingpupildiametersweresigniÞcantlylargerthanexpectedforhisage(outsidethe95%upperlimitofthenormalrange)bothindarknessandinlight.Theamplitudesoftheresponsesofbothpupilstoatransientlightstimuluswereattenuated(below95%lowerlimitofthenormalrange).Thepupillarymiosistotheviewingofaneartargetwasalsoattenuated(althoughitcouldonlybereliablyrecordedfromtherighteye),andtherewasnolight-neardissociation.Startleresponses(mydriasisfollowingasuddennoise)werepresentbutsluggishinbotheyes.Pharmacologicaltestingdemonstratedanormalmydri-aticresponsetotopical4%cocainedropsandnocholinergicsupersensitivityto0.1%pilocarpinedrops.PupillometrythusconÞrmedthatbothpupilswereabnormallylargewithsluggishresponsestolight,andnearstimuli,andsudden FIG.1.Ourpatientdisplaysalefthypertropiaandexo-tropiainprimarygazeandnoptosis. FIG.2.Electronmicroscopyoftricepsmusclebiopsy..Subsarcolemmalaccumulationsofabnormalmitochondria(M)..Abnormalmitochondria(m),andtubularaggregates(TA)inthesameÞber. OriginalContributionAlietal:JNeuro-Ophthalmol2010;30:153-156 noise.Withoutevidenceofdamagetothesympatheticorparasympatheticinnervation,myopathicdysfunctionwasCPEOdescribesaspectrumofconditionscharacterizedbybilateralptosisandglobalrestrictionofeyemovements(4).Itrepresentsthecommonestocularmanifestationofthemitochondrialmyopathies(5)andcanoccurinisolationorinassociationwithnonocularfeatures(6).However,thereareseveralfeaturesofthepresentcasethatarenottypicalofCPEO.First,theductionaldeÞcitswerenotsymmetricalinthe2eyes.Theeyesweremarkedlymisaligned,whereasinCPEO,theyareusuallyaligned.Althoughasymmetricophthalmoplegiahasbeenrarelydescribed(4,7),itsextent,whenaccuratelymeasured,isusuallysmall.Onestudyfoundthatin68%ofmusclepairs,thedegreeofasymmetrywaslessthan5;asymmetrygreaterthan18occurredinlessthan2%ofmusclepairs(8).Second,ourpatientlackedptosis.Bilateralptosisisal-mostalwaysfoundinCPEOandisthepresentingcom-plaintinupto90%ofcases(4).CasesofCPEOwithoutptosishaveonlyrarelybeendescribed(9).Third,involvementoftheirismusculaturehasnotbeenreportedinCPEO.Inthepresentcase,pupillometryconÞrmedtheclinicalimpressionoflargesluggishpupils.Theclinicalsigns,pupillometricmeasurements,andphar-macologicaltestsindicatedintactinnervationofthesphincteranddilatorirismusclesbutpoorcontractilityduetoanintrinsicmyopathicprocess.Giventhegeneticandhistologicalevidencesupportingadiagnosisofmitochon-drialcytopathy,itseemsreasonabletoconcludethatinthisunusualcase,thesmoothmusclesoftheirismayhavebeenaffectedbythissinglelargemitochondrialDNAdeletion.Thelargerestingdiametersofthesepupilssuggestagreater FIG.3.Pupilresponsestoatransientlightstimulusinourpatient()andinahealthycontrolsubjectaged63years(Incomparisonwiththehealthycontrolsubject,thepupilsofourpatienthavelargerrestingdiametersandshowattenuatedresponsestolightstimulus. TABLE1.Pupillometricmeasurementsinourpatient.MeasurementRightpupilLeftpupilNormalrange(3)Darkdiameter(mm)7.807.014.00Ð7.25*Lightdiameter(mm)6.585.531.80Ð3.82*Amplitudeoflightresponse(mm)0.750.981.79Ð3.95(R)1.61Ð3.55(L)redilatationtime(seconds)4.965.280.30Ð2.72(R)0.44Ð2.86(L)Amplitudeofnearresponse(mm)0.58PoorqualityrecordingNonedeÞnedStartleresponsePresentPresentNonedeÞnedThenormalrangesareforhealthycontrolsubjects.*=agematched;=expectedvaluesgiventheobservedrestingdiametersinthe=amplitudematchedortherangeofmeasurementsfoundinhealthycontrolsubjectswhenstimulusintensityisadjustedtoproducelightresponsesofsimilaramplitudetothoseseeninthispatient. OriginalContributionAlietal:JNeuro-Ophthalmol2010;30:153-156 impactofthisgenotypeonsphinctermuscleÞbersthanondilato
rmuscleÞbers.WewerestruckbytheapparentsimilaritybetweenthepupilÞndingsinourcaseandthoseassociatedwithmyo-tonicdystrophy(dystrophiamyotonica,DM),anotherconditionthatcanproduceophthalmoplegia.ThepupilsinpatientswithDMtype1areoftensmallorofmediumsize,withsluggishlowamplitudelightresponses.Theyshowthepresenceofastartleresponse,nolight-neardissociation,andnocholinergichypersensitivity(10).However,thepresentcasehadnootherclinicalfeaturessuggestiveofDM(familyhistory,gripmyotonia,iridescentlensopacities),andmoleculargenetictestingfortherecognizedmutationsassociatedwithDM1orDM2wasnegative,thusmakingaco-occurrenceofthese2geneticdisordersunlikely.AstrikinglyunusualfeatureofthepresentcasewastheÞndingofTAsonelectronmicroscopyofthemusclebiopsy.TAsinskeletalmuscleÞberscanoccurasanonspeciÞcÞndinginavarietyofconditionssuchasperiodicparalysis,myotonicdisorders,hyperaldosteronism,chronicuseofdrugs,andalcoholism.Inaddition,TAshavealsobeenfoundmorespeciÞcallyinexercise-inducedcramps,myasthenicsyndromes,anddominantlyorrecessivelyinheritedfamilialmyopathies(11).AbnormalpupilshavebeenreportedinsomeofthecasesoffamilialTAmyopathies(12,13).However,TAsarenotrecognizedasafeatureofmitochondrialcytopathies.ThereisonlyasinglereportofapatientwithdistalmyopathywhowasfoundtohavemultipledeletionsofmitochondrialDNAandahighdensityofTAs(14).ThefactthatpupilinvolvementisnotseenintypicalCPEO,togetherwiththeÞndingoftubularaggregatesonmusclebiopsyinourpatient,suggeststhatmitochondrialcytopathymightnotbethefullextentoftheabnormalityhere.Perhapsthispatienthasacombinationofamito-chondrialcytopathyandaninheriteddisorderofotherorigin.Additionally,thiscaseraisesthequestionastotheextentofundetectedsmoothmuscleinvolvementinmi-tochondrialcytopathy.ThepatientshowninFigure1providedwrittenconsentfortheimagetobepublished.KlineLB,BajandasFJ.Neuro-OphthalmologyReview,5thEdition.Thorofare:SLACKInc,2003.PaneA,BurdonM,MillerNR.TheNeuro-ophthalmologySurvivalGuide.Edinburgh:Mosby/Elsevier,2007.BremnerF,SmithS.PupilÞndingsinaconsecutiveseriesof150patientswithgeneralisedautonomicneuropathy.JNeurolNeurosurgPsychiatry.2006;77:1163Ð1168.BauV,ZierzS.Updateonchronicprogressiveexternalophthalmoplegia.Strabismus.2005;13:133Ð142.SchoserBG,PongratzD.Extraocularmitochondrialmyopathiesandtheirdifferentialdiagnoses.Strabismus.SchmiedelJ,JacksonS,Scha¬ferJ,ReichmannH.Mitochondrialcytopathies.JNeurol.2003;250:267Ð277.PettyRK,HardingAE,Morgan-HughesJA.Theclinicalfeaturesofmitochondrialmyopathy.Brain.1986;109:RichardsonC,SmithT,SchaeferA,TurnbullD,GrifÞthsP.OcularmotilityÞndingsinchronicprogressiveexternalophthalmoplegia.Eye.2005;19:258Ð263.MillerNR,NewmanNJ.WalshandHoytsClinical,5thedition.Baltimore:Williams&Wilkins,1998.LoewenfeldIE.ThePupil:Anatomy,Physiology,andClinical,2ndEdition.Oxford:Butterworth-Heinemann,llerHD,VielhaberS,BrunnA,Schro¬derJM.Dominantlyinheritedmyopathywithnoveltubularaggregatescontaining1Ð21tubuloÞlamentousstructures.ActaNeuropathol.2001;102:27Ð35.JacquesTS,HoltonJ,WattsPM,WillsAJ,SmithSE,HannaMG.Tubularaggregatemyopathywithabnormalpupilsandskeletaldeformities.JNeurolNeurosurgPsychiatry.2002;73:324Ð326.ShahrizailaN,LoweJ,WillsA.Familialmyopathywithtubularaggregatesassociatedwithabnormalpupils.Neurology.2004;63:1111Ð1113.GarrardP,BlakeJ,StintonV,HannaMG,ReillyMM,HoltonJL,LandonDN,HonanWP.Distalmyopathywithtubularaggregates:anewphenotypeassociatedwithmultipledeletionsinmitochondrialDNA?JNeurolNeurosurgPsychiatry.2002;73:207Ð208. OriginalContributionAlietal:JNeuro-Ophthalmol2010;30:153-156 PupillaryDysfunctioninanAtypicalCaseof MitochondrialMyopathyWithTubularAggregates NadeemAli,MA,MRCOphth,FRCSEd(Ophth),CatherineE.Woodward,BSc, MarySweeney,BSc,RahulPhadke,MD,FRCPath,JaniceL.Holton,PhD,MRCPath, JamesAcheson,MRCP,FCRS(Glas),FRCOphth,GordonT.Plant,MD,FRCP,FRCOphth, FionD.Bremner,PhD,FRCOphth Abstract: A62-year-oldmanpresentedwithdiplopia, ocularductionaldeÞcits,andsluggishpupils.Pupillom- etrydemonstratedlargehyporeactivepupilswithnoevi- denceofdamagetothesympatheticorparasympathetic innervation,indicatingamyopathyoftheirismuscula- ture.AsinglelargedeletioninmitochondrialDNAand characteristichistochemicalfeaturesonmusclebiopsy suggestedamitochondrialcytopathy.However,ultra- structuralexaminationofskeletalmuscleÞbersshowed tubularaggregates(TAs),aÞndingnotreportedinmito- chondrialcytopathy.Thecombinationofpupillaryabnor- malitiesandTAssuggeststhatmitochondrialdysfunction maynotexplainthefullextentofabnormalitiesinthis case. JournalofNeuro-Ophthalmology2010;30:153156 doi:10.1097/WNO.0b013e3181dbfdcd 2010byNorthAmericanNeuro-OphthalmologySociety T hesmoothmusclesoftheirisarereportedtobespared inchronicprogressiveexternalophthalmoplegia (CPEO),amitochondrialcytopathy(1,2).However,pu- pillaryfunctionhasneverbeenquantitativelystudiedinthis condition.Moreover,thereisnoreasonwhythesemuscles shouldbesparedfromtheeffectsofmitochondrial dysfunction. WepresentacaseinwhichocularductionaldeÞcits werecombinedwithpupildysfunctionandunusualultra- structuralmusclefeatures,raisingquestionsaboutthena- tureofthiscondition. CASEREPORT A62-year-oldIndianmanpresentedwithan8-month historyofslowlyprogressivebinocularhorizontaldiplopia. Hereportednoptosis,diurnalvariationinthediplopia, fatigability,orweaknessofhisarmsorlegs.Therehadbeen nopain,redness,lidswelling,orproptosis.Medicalhistory wasunremarkable,andhewasanonsmokerandnon- drinker.Therewasnofamilyhistoryofneurologicaldisease. Neuro-OphthalmologicalExamination Ourexaminationrevealedbest-correctedvisualacuitiesof 20/20inbotheyes,normalcolorvi
sion,andfullvisual Þelds.Thepupilswerenotedtoreactsluggishlybothtolight andtotheviewingofaneartarget.Horizontalductions weremoderatelyreducedinbotheyes.Intherighteye,there wasareductioninsupraduction,andinthelefteye,are- ductionininfraduction.Thepatientreporteddiplopiainall positionsofgaze.Inprimarygazeposition,therewasalarge alternatingexotropiawithalargelefthypertropia(Fig.1). Therewasnoptosis,andlevatorfunctionandorbicularis strengthwereclinicallynormal.Intraocularexamination revealedvisuallyinsigniÞcantposteriorcorticalcataractsand mildchangesinthemacularretinalpigmentepithelium, Þndingsthatwerethoughttobeagerelated.Theperipheral retinaappearednormal.Examinationoftheremaining cranialnerveswasunremarkable.Toneandstrengthwere normalinallmusclesgroups,withneitherfatigabilitynor myotonia. LaboratoryStudies Thepatientunderwentthefollowinginvestigations,which producednormalornegativeresults:acetylcholinereceptor antibodies,muscle-speciÞctyrosinekinase(MUSK)anti- bodies,striatedmuscleantibodies,thyroidthyroglobulin antibodies,thyroidmicrosomalantibodies,andtreponemal DepartmentofNeuro-Ophthalmology(NA,JA,GTP,FDB);Neu- rogeneticsUnit(CEW,MS);DepartmentofNeuropathology(RP, JLH),NationalHospitalforNeurologyandNeurosurgery,Queen Square,London,UnitedKingdom. TheauthorsdeclarenoÞnancialinterests. AddresscorrespondencetoNadeemAli,MA,MRCOphth,FRCSEd (Ophth),MoorÞeldsEyeHospital,CityRoad,LondonEC1V2PD; E-mail:nadeem.ali@nhs.net Alietal: JNeuro-Ophthalmol2010 ;30:153-156 153 OriginalContribution Copyright © North American Neuro-ophtha lmology Society.Unauthorized reproduc tion of this article is prohibited. serology.Intravenousedrophoniumhadnoeffectonhis ophthalmoplegia. ImagingStudies CTofthebrainandorbitsandMRIofthethymuswere normal. Electromyography Electromyographyrevealednormalnerveconduction,re- petitivestimulation,andsingle-Þberstudies.Musclesam- plingshowedabundantspikypolyphasicunitsrecordednot onlyfromtheorbicularisoculibutalsominimallyfromthe extensordigitorumcommunis,tibialisanterior,andrectus femoris.TheseÞndingsweresuggestiveofamildmyopathic processratherthanneuromuscularjunctiondysfunction. MuscleBiopsy Tricepsmusclebiopsyrevealedthepresenceof3raggedred Þbersandmorethan10cytochromeoxidaseÐnegativeÞbers. Mitochondrialrespiratorychainenzymeactivityassayswere normal.Electronmicroscopyshowedsubsarcolemmalac- cumulationsofscatteredabnormalmitochondria,manyof whichcontainedtype1paracrystallineinclusions.Tubular aggregates(TAs)werenotedinseveralÞbers,someofwhich containedabnormalmitochondria(Fig.2).NoTAswere seenatthelightmicroscopiclevel. GeneticAnalysis MitochondrialgeneticanalysisconÞrmedasinglelarge deletioninmitochondrialDNAdetectedbylong-range polymerasechainreactionfollowedbySouthernblotting. SequencingconÞrmedthepresenceofthecommondeletion of4,977basepairs,withbreakpointsintheßankingrepeats betweennucleotides8,470and8,482andnucleotides 13,447and13,459.Thepatientwasthereforediagnosed withCPEO. PupillaryFunction Basedontheclinicalimpressionofhyporeactivepupils, infraredvideopupillometrywasperformedandcompared withournormativedatabaseofmeasurementsfrom315 healthycontrolsubjects(3)(Fig.3;Table1).Slit-lamp examinationshowednoabnormalityofpupilshapeandno irisdamageorsectorpalsy.Therestingpupildiameterswere signiÞcantlylargerthanexpectedforhisage(outsidethe 95%upperlimitofthenormalrange)bothindarknessand inlight.Theamplitudesoftheresponsesofbothpupilsto atransientlightstimuluswereattenuated(below95%lower limitofthenormalrange).Thepupillarymiosistothe viewingofaneartargetwasalsoattenuated(althoughit couldonlybereliablyrecordedfromtherighteye),and therewasnolight-neardissociation.Startleresponses (mydriasisfollowingasuddennoise)werepresentbut sluggishinbotheyes. Pharmacologicaltestingdemonstratedanormalmydri- aticresponsetotopical4%cocainedropsandnocholinergic supersensitivityto0.1%pilocarpinedrops.Pupillometry thusconÞrmedthatbothpupilswereabnormallylargewith sluggishresponsestolight,andnearstimuli,andsudden FIG.1. Ourpatientdisplaysalefthypertropiaandexo- tropiainprimarygazeandnoptosis. FIG.2. Electronmicroscopyoftricepsmusclebiopsy. A .Subsarcolemmalaccumulationsofabnormalmitochondria(M). B .Abnormalmitochondria(m),andtubularaggregates(TA)inthesameÞber. OriginalContribution 154 Alietal: JNeuro-Ophthalmol2010 ;30:153-156 Copyright © North American Neuro-ophtha lmology Society.Unauthorized reproduc tion of this article is prohibited. noise.Withoutevidenceofdamagetothesympatheticor parasympatheticinnervation,myopathicdysfunctionwas suggested. DISCUSSION CPEOdescribesaspectrumofconditionscharacterizedby bilateralptosisandglobalrestrictionofeyemovements(4). Itrepresentsthecommonestocularmanifestationofthe mitochondrialmyopathies(5)andcanoccurinisolationor inassociationwithnonocularfeatures(6). However,thereareseveralfeaturesofthepresentcase thatarenottypicalofCPEO.First,theductionaldeÞcits werenotsymmetricalinthe2eyes.Theeyesweremarkedly misaligned,whereasinCPEO,theyareusuallyaligned. Althoughasymmetricophthalmoplegiahasbeenrarely described(4,7),itsextent,whenaccuratelymeasured,is usuallysmall.Onestudyfoundthatin68%ofmusclepairs, thedegreeofasymmetrywaslessthan5 ;asymmetrygreater than18 occurredinlessthan2%ofmusclepairs(8). Second,ourpatientlackedptosis.Bilateralptosisisal- mostalwaysfoundinCPEOandisthepresentingcom- plaintinupto90%ofcases(4).CasesofCPEOwithout ptosishaveonlyrarelybeendescribed(9). Third,involvementoftheirismusculaturehasnotbeen reportedinCPEO.Inthepresentcase,pupillometry conÞrmedtheclinicalimpre
ssionoflargesluggishpupils. Theclinicalsigns,pupillometricmeasurements,andphar- macologicaltestsindicatedintactinnervationofthe sphincteranddilatorirismusclesbutpoorcontractilitydue toanintrinsicmyopathicprocess.Giventhegeneticand histologicalevidencesupportingadiagnosisofmitochon- drialcytopathy,itseemsreasonabletoconcludethatinthis unusualcase,thesmoothmusclesoftheirismayhavebeen affectedbythissinglelargemitochondrialDNAdeletion. Thelargerestingdiametersofthesepupilssuggestagreater FIG.3. Pupilresponsestoatransientlightstimulusinourpatient( A )andinahealthycontrolsubjectaged63years( B ). Incomparisonwiththehealthycontrolsubject,thepupilsofourpatienthavelargerrestingdiametersandshow attenuatedresponsestolightstimulus. TABLE1. Pupillometricmeasurementsinourpatient. MeasurementRightpupilLeftpupilNormalrange(3) Darkdiameter(mm)7.807.014.00Ð7.25* Lightdiameter(mm)6.585.531.80Ð3.82* Amplitudeoflightresponse(mm)0.750.981.79Ð3.95(R) 1.61Ð3.55(L) T 3/4 redilatationtime(seconds)4.965.280.30Ð2.72(R) à 0.44Ð2.86(L) à Amplitudeofnearresponse(mm)0.58PoorqualityrecordingNonedeÞned StartleresponsePresentPresentNonedeÞned Thenormalrangesareforhealthycontrolsubjects.*=agematched; =expectedvaluesgiventheobservedrestingdiametersinthe dark; à =amplitudematchedortherangeofmeasurementsfoundinhealthycontrolsubjectswhenstimulusintensityisadjustedto producelightresponsesofsimilaramplitudetothoseseeninthispatient. OriginalContribution Alietal: JNeuro-Ophthalmol2010 ;30:153-156 155 Copyright © North American Neuro-ophtha lmology Society.Unauthorized reproduc tion of this article is prohibited. impactofthisgenotypeonsphinctermuscleÞbersthanon dilatormuscleÞbers. Wewerestruckbytheapparentsimilaritybetweenthe pupilÞndingsinourcaseandthoseassociatedwithmyo- tonicdystrophy(dystrophiamyotonica,DM),another conditionthatcanproduceophthalmoplegia.Thepupilsin patientswithDMtype1areoftensmallorofmediumsize, withsluggishlowamplitudelightresponses.Theyshowthe presenceofastartleresponse,nolight-neardissociation, andnocholinergichypersensitivity(10).However,the presentcasehadnootherclinicalfeaturessuggestiveofDM (familyhistory,gripmyotonia,iridescentlensopacities), andmoleculargenetictestingfortherecognizedmutations associatedwithDM1orDM2wasnegative,thusmaking aco-occurrenceofthese2geneticdisordersunlikely. Astrikinglyunusualfeatureofthepresentcasewasthe ÞndingofTAsonelectronmicroscopyofthemusclebiopsy. TAsinskeletalmuscleÞberscanoccurasanonspeciÞc Þndinginavarietyofconditionssuchasperiodicparalysis, myotonicdisorders,hyperaldosteronism,chronicuseof drugs,andalcoholism.Inaddition,TAshavealsobeen foundmorespeciÞcallyinexercise-inducedcramps,myasthenic syndromes,anddominantlyorrecessivelyinheritedfamilial myopathies(11).Abnormalpupilshavebeenreportedinsome ofthecasesoffamilialTAmyopathies(12,13).However,TAs arenotrecognizedasafeatureofmitochondrialcytopathies. Thereisonlyasinglereportof apatientwithdistalmyopathy whowasfoundtohavemultipled eletionsofmitochondrial DNAandahighdensityofTAs(14). Thefactthatpupilinvolvementisnotseenintypical CPEO,togetherwiththeÞndingoftubularaggregateson musclebiopsyinourpatient,suggeststhatmitochondrial cytopathymightnotbethefullextentoftheabnormality here.Perhapsthispatienthasacombinationofamito- chondrialcytopathyandaninheriteddisorderofother origin.Additionally,thiscaseraisesthequestionastothe extentofundetectedsmoothmuscleinvolvementinmi- tochondrialcytopathy. ACKNOWLEDGMENT ThepatientshowninFigure1providedwrittenconsentfor theimagetobepublished. REFERENCES 1. KlineLB, BajandasFJ. Neuro-OphthalmologyReview Manual ,5thEdition.Thorofare:SLACKInc,2003. 2. PaneA, BurdonM,MillerNR. TheNeuro-ophthalmology SurvivalGuide .Edinburgh:Mosby/Elsevier,2007. 3. BremnerF, SmithS.PupilÞndingsinaconsecutiveseries of150patientswithgeneralisedautonomicneuropathy. JNeurolNeurosurgPsychiatry.2006;77:1163Ð1168. 4. BauV, ZierzS.Updateonchronicprogressiveexternal ophthalmoplegia.Strabismus.2005;13:133Ð142. 5. SchoserBG, PongratzD.Extraocularmitochondrial myopathiesandtheirdifferentialdiagnoses.Strabismus. 2006;14:107Ð113. 6. SchmiedelJ, JacksonS,Scha ¬ferJ,ReichmannH. Mitochondrialcytopathies.JNeurol.2003;250:267Ð277. 7. PettyRK, HardingAE,Morgan-HughesJA.Theclinical featuresofmitochondrialmyopathy.Brain.1986;109: 915Ð938. 8. RichardsonC, SmithT,SchaeferA,TurnbullD,GrifÞthsP. OcularmotilityÞndingsinchronicprogressiveexternal ophthalmoplegia.Eye.2005;19:258Ð263. 9. MillerNR, NewmanNJ. WalshandHoytsClinical Neuro-ophthalmology ,5thedition.Baltimore:Williams& Wilkins,1998. 10. LoewenfeldIE. ThePupil:Anatomy,Physiology,andClinical Applications ,2ndEdition.Oxford:Butterworth-Heinemann, 1999. 11. Mu ¨ llerHD, VielhaberS,BrunnA,Schro ¬derJM.Dominantly inheritedmyopathywithnoveltubularaggregates containing1Ð21tubuloÞlamentousstructures.Acta Neuropathol.2001;102:27Ð35. 12. JacquesTS, HoltonJ,WattsPM,WillsAJ,SmithSE, HannaMG.Tubularaggregatemyopathywithabnormal pupilsandskeletaldeformities.JNeurolNeurosurg Psychiatry.2002;73:324Ð326. 13. ShahrizailaN, LoweJ,WillsA.Familialmyopathywith tubularaggregatesassociatedwithabnormalpupils. Neurology.2004;63:1111Ð1113. 14. GarrardP, BlakeJ,StintonV,HannaMG,ReillyMM, HoltonJL,LandonDN,HonanWP.Distalmyopathywith tubularaggregates:anewphenotypeassociatedwith multipledeletionsinmitochondrialDNA?JNeurol NeurosurgPsychiatry.2002;73:207Ð208. OriginalContribution 156 Alietal: JNeuro-Ophthalmol2010 ;30:153-156 Copyright © North American Neuro-ophtha lmology Society.Unauthorized reproduc tion of this article is prohibited