BritishJournal ofOphthalmology, 1992, 76, 58-60

Vitelliform macular degeneration associated withmitochondrial myopathy

Girish Modi, Jeannine M Heckman, David Saffer

AbstractA patient with mitochondrial myopathy isdescribed. Examination of his fundus revealedbilateral viteiliform degeneration of themaculae. This lesion is a focal abnormality ofthe retinal pigment epithelium and may be amanifestation of the underlying mitochondrialdisease.

Neurology Unit,Department of Medicine,Baragwanath Hospital,and the University of theWitwatersrand,Johannesburg, SouthAfricaG ModiJ M HeckmanD SafferCorrespondence to:Dr G Modi.Accepted for publication30 May 1991

The mitochondrial myopathies (MM) or cyto-pathies or encephalomyopathies, as they arevariably described, are a group of disorders withmarked clinical and biochemical heterogeneity.The brain and muscle are the principal tissuesthat are affected, but involvement of haemo-poietic, endocrine, cardiac, liver, and oculartissues is well recognised.' Diagnosis of theseconditions is based on the demonstration ofmorphological abnormalities of mitochondriaon skeletal muscle biopsies; identification ofbiochemical defects, mainly along the respira-tory chain; or as has been described recently byidentification of abnormal or mutant mitochon-drial (mt) DNA by means of restriction fragmentlength polymorphisms and DNA sequencing. '-3The basis of the heterogeneity is explained in

terms of the mitotic segregation hypothesis,whereby it is proposed that each cell contains aproportion of wild type and mutant mt DNA."When the relative proportion ofmutant mt DNAis present at a critical threshold in a selectedtissue, clinical disturbance of that tissue willresult.' This proportion of mutant mt DNA istransmitted maternally and is distributed bymitotic segregation at the time of zygote forma-tion.3'

In this paper we describe the occurrence ofvitelliform macular degeneration in a patientwith infantile mitochondrial myopathy. Thepossible significance of this association is dis-cussed.

Case reportA 20-year-old black male patient presented withsymptoms of a multisystem disorder. He was ofshort stature (height 145 cm) and had markedmental impairment. The essential findings werethose of a proximal myopathy with a cardio-pathy; ptosis without ophthalmoplegia; bilateralsensorineural deafness; distal symmetrical sen-sory neuropathy; and raised concentration ofcerebrospinal fluid protein (0 5 g/l). He had nodysmorphic features but showed evidence ofdelayed sexual maturation. Funduscopyrevealed normal optic discs but striking vitelli-form changes of the maculae (Fig 1). Biochemi-cally the main abnormalities were those of araised resting serum lactate (2-8 mmol/l;normal=0-16-1A 8 mmol/l) and a raised serumpyruvate (83 mmol/l, normal=41-67 mmol/l). Abiopsy of the left biceps brachii showed that anestimated 10% of the fibres were 'ragged red' onthe modified Gomori-trichrome stain (Fig 2a).Subsarcolemmal accumulations of mitochondriawere noted on NADH-reductase stain. Cyto-chrome oxidase and phosphorylase activity wasfound to be normal with the appropriate stainsfor these enzymes. Electron microscopy revealedelongated and oval shaped mitochondria con-taining laminated paracrystalline inclusions(Fig 2b).

DiscussionPigmentary retinopathy in association with mito-chondrial myopathies (MM) is well described.'Three patterns of retinopathy, namely, a 'saltand pepper' type, a retinitis pigmentosa type,and atrophy of the retinal pigment epithelium(RPE) have been described.7 Approximately36% of patients with mitochondrial myopathieshave involvement of the RPE, with the salt andpepper type being the commonest.7 The reasonsfor involvement of the RPE are not clear. TheRPE contains large numbers of mitochondria, inkeeping with its high energy state.7 Enlargedmitochondria and widespread loss or atrophy ofthe RPE in patients with MM have been des-cribed.7 However, the RPE mitochondria havenot been studied in a functional manner inpatients with MM, and biochemical abnormali-ties ofmuscle mitochondria described in patientswith MM have not been reported in the RPEmitochondria.7

Vitelliform macular degeneration is recog-

Figure I Photograph ofthe patient's rightfzindusshowing the typical 'eggyolk'appearance diagnostic ofvitelliform degeneration ofthe macula. The optic discand vasculature are normal.No pigmentary retinopathy ispresent.

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Vitellifonn macular degeneration associated with mitochondrial myopathy

Figure 2 A: Gomori-trichrome stain ofa section ofthe patient's muscle biopsy(biceps brachii) showingragged redfibres withsubsarcolemmalaccumulation ofmitochondria (arrows). B:Electron micrographshowing oval shapedmitochondria, withlaminated paracrystallineinclusions (arrows).(x42 000.)

nised by its characteristic 'egg yolk' appearance.IIt is typically present in Best's disease, an

autosomal dominant hereditary maculardisease.89 In this disease the classical vitellinelesion, which is encountered infrequently,occurs focally in the region of the macula, butmay occur multifocally and in extramacularsites.'0 The lesions may be present uniocularlyand occur asymmetrically.'0 Diagnosis oftenrequires the establishment of an autosomaldominant mode of inheritance as well as thedemonstration of an abnormal electro-oculo-gram (EOG).8-'0 The EOG is invariablyabnormal in all affected members and carriers,and is abnormal in both eyes in cases where thelesion is uniocular. The abnormality in the EOGindicates that the disorder affects the RPE in a

widespread manner and is not specifically a

macular response.Vitelline lesions may also occur in patients

with a normal EOG and no evidence of a

dominantly inherited maculopathy. Thesepseudovitelliform lesions occur in adults andhave been associated with perifocal retinal capil-lary leakage, RPE and neurosensory detach-ments, or non-specific pigmentary changes. Inthese instances the vitelliform lesion is postu-lated to occur as a result of an acquired maculardegeneration.'°The finding of vitelliform macular degenera-

tion in a patient with MM is therefore remark-able, and raises several possibilities regarding thereasons for the coexistence of these two un-common diseases. The first is that this is a chanceassociation of two rare disorders. The inheri-tance pattern of the MM is maternal,"5 whereasvitelliform macular degeneration, as it occurs inBest's disease, obeys nuclear Mendeliangenetics.89 It is our contention, however, thatvitelliform macular degeneration is a furtheratypical form ofRPE abnormalities that occur as

a consequence of MM - that is, in addition tothose already described by Mullie et al.7

In support ofthis contention is the observationof macular degeneration in a patient with mito-chondrial encephalomyopathy and brain infarc-tions described by Kuriyama et al." Theseauthors described their patient as having a 'welldemarcated white-yellow circular spot thatresembled an egg-yolk'. While no photograph ofthe lesion is shown, this description is typical ofvitelliform macular degeneration. We thereforeconsider that the association withMM is unlikelyto be a chance finding. The degeneration wouldthus be due to widespread mitochondrial dys-function in the RPE. This would be in keepingwith the abnormal EOG found in this disorder,which reflects the widespread involvement of theRPE. The reasons for the focal macular presenta-tion are unclear but, in terms of the MM, onemay speculate that differential distribution ofmitochondria containing mutant mitochondrialDNA in the RPE would account for both focalmacular and extramacular lesions. Furtherclinical and pathological analyses are importantto determine the nature of this association.With respect to Best's disease, the question

that arises from the discussion above is whetheror not it is a disorder of mitochondrial dysfunc-tion. The autosomal dominant nature of thecondition does not preclude it from being causedby mitochondrial disease. The concept ofnuclear factors or genes influencing mitochon-drial functions, with the resultant diseaseappearing to follow Mendelian genetics, hasbeen proposed by several authors. '` Familypedigrees of patients with MM have been shownto follow dominant or recessive modes of inheri-tance. `-5 In the case described here there was noclinical vitelliform macular degeneration in thepatient's mother or step-sister. The grand-mother has senile maculopathy, which can bedifficult to distinguish from long stahding vitelli-form degeneration.9 We were unable to examineother family members or carry out EOG examina-

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Modi, Heckman, Saffer

tions. Kuriyama et all" also do not give details offamily members in their case. Further investiga-tions of established pedigrees of Best's maculardystrophy are therefore needed.The authors thank Dr V Fabian, Department of Pathology,University ofthe Witwatersrand, Johannesburg, for her assistancewith the histology and electron microscopic findings. Our thanksalso to Mrs B Pelser and Mrs J Gagu for typing the manuscript.1 Petty RKH, Harding AE, Morgan-Hughes JA. The clinical

features of mitochondrial myopathy. Brain 1986; 109:915-38.

2 Harding AE. The mitochondrial genome - breaking the magiccircle. NEnglJMed 1989; 320: 1341-3.

3 Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A new

mitochondrial disease associated with mitochondrial DNAheteroplasmy. AmJ Hum Genet 1990; 46: 428-33.

4 Rosing HS, Hopkins LC, Wallace DC, Epstein CM, Weiden-heim K. Maternally inherited mitochondrial myopathy andmyoclonic epilepsy. Ann Neurol 1985; 17: 228-37.

5 Di Mauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo C.Mitochondrial myopathies. Ann Neurol 1985; 17: 521-38.

6 Holt IJ, Harding AE, Morgan-Hughes JA. Deletions ofmitochondrial DNA in patients with mitochondrial myo-pathies. Nature 1988; 331: 717-9;

7 Mullie MA, Harding AE, Petty RKH, et al. The retinalmanifestations of mitochondrial myopathy. Arch Ophthalmol1985; 103:1825-30.

8 Remsky H, Rix J, Klier KF. Dominant - autosomale Macula-degeneration (Best, Sorsby) mit zytischen und vitelliformenStadian (Huysmans, Zanen) KlinMonatsblAugenheilkd 1965;146: 473-97.

9 Cavender JC, Schwartz LJ, Spirey BE. Hereditary maculardystrophies. In: Duane TD, ed. Clinical ophthalmology.2nd ed. Hagerstown: Harper and Row, 1978; 3: chapter 9:1-16.

10 Noble KG. Hereditary macular dystrophies. In: Renie WA,ed. Goldberg's genetic and metabolic eye disease. 2nd ed. Little,Brown, Boston: 1986: 439-64.

11 Kuriyama M, Umezaki H, Fuduka Y, et al. Mitochondrialencephalomyopathy with lactate - pyrurate elevation andbrain infarctions. Neurology 1984; 34: 72-7.

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