Ophthalmologic manifestations of mitochondrial disorders are frequently neglected or overlooked because they are often not regarded as part of the phenotype. This review aims at summarizing and discussing the etiology, pathogenesis, diagnosis, and treatment of ophthalmologic manifestations of mitochondrial disorders. Review of publications about ophthalmologic involvement in mitochondrial disorders by search of Medline applying appropriate search terms. The eye is frequently affected by syndromic as well as nonsyndromic mitochondrial disorders. Primary and secondary ophthalmologic manifestations can be differentiated. The most frequent ophthalmologic manifestations of mitochondrial disorders include ptosis, progressive external ophthalmoplegia, optic atrophy, retinopathy, and cataract. More rarely occurring are nystagmus and abnormalities of the cornea, ciliary body, intraocular pressure, the choroidea, or the brain secondarily affecting the eyes. It is important to recognize and diagnose ophthalmologic manifestations of mitochondrial disorders as early as possible because most are accessible to symptomatic treatment with partial or complete short-term or long-term beneficial effect. Ophthalmologic manifestations of mitochondrial disorders need to be appropriately diagnosed to initiate the most effective management and guarantee optimal outcome.
MeulemansASenecaSLagaeL. A novel mitochondrial transfer RNA(Asn) mutation causing multiorgan failure. Arch Neurol. 2006;63:1194–1198.
2.
Al-EneziMAl-SalehHNasserM. Mitochondrial disorders with significant ophthalmic manifestations. Middle East Afr J Ophthalmol. 2008;15:81–86.
3.
SchmitzKLinsHBehrens-BaumannW. Bilateral spontaneous corneal perforation associated with complete external ophthalmoplegia in mitochondrial myopathy (Kearns-Sayre syndrome). Cornea. 2003;22:267–270.
4.
LeeJJTripiLMErbeRWGarimella-KroviSSpringateJE. A mitochondrial DNA deletion presenting with corneal clouding and severe Fanconi syndrome. Pediatr Nephrol. 2012;27:869–872.
5.
KasbekarSAGonzalez-MartinJAShafiqAEChandnaAWilloughbyCE. Corneal endothelial dysfunction in Pearson syndrome. Ophthalmic Genet. 2013;34:55–57.
6.
WójcikKABłasiakJKurowskaAKSzaflikJSzaflikJP. Oxidative stress in the pathogenesis of keratoconus. Klin Oczna. 2013;115:311–316.
7.
HayashiNGeraghtyMTGreenWR. Ocular histopathologic study of a patient with the T 8993-G point mutation in Leigh’s syndrome. Ophthalmology. 2000;107:1397–1402.
8.
BarboniPSaviniGPlazziG. Ocular findings in mitochondrial neurogastrointestinal encephalomyopathy: a case report. Graefes Arch Clin Exp Ophthalmol. 2004;242:878–880.
9.
BurglenLChantot-BastaraudSGarelC. Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. Orphanet J Rare Dis. 2012;7:18.
10.
RummeltVFolbergRIonasescuVYiHMooreKC. Ocular pathology of MELAS syndrome with mitochondrial DNA nucleotide 3243 point mutation. Ophthalmology. 1993;100:1757–1766.
11.
BremnerFDShallo-HoffmannJRiordan-EvaPSmithSE. Comparing pupil function with visual function in patients with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 1999;40:2528–2534.
12.
AliNWoodwardCESweeneyM. Pupillary dysfunction in an atypical case of mitochondrial myopathy with tubular aggregates. J Neuroophthalmol. 2010;30:153–156.
13.
IsashikiYNakagawaMOhbaN. Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation. Acta Ophthalmol Scand. 1998;76:6–13.
14.
BeneJNádasiEKosztolányiGMéhesKMeleghB. Congenital cataract as the first symptom of a neuromuscular disease caused by a novel single large-scale mitochondrial DNA deletion. Eur J Hum Genet. 2003;11:375–379.
15.
LachmundUMojonDS. Leber’s hereditary optic neuropathy in malnutrition: a case report. Klin Monbl Augenheilkd. 2006;223:393–396.
16.
Van HoveJLCunninghamVRiceC. Finding twinkle in the eyes of a 71-year-old lady: a case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease. Am J Med Genet A. 2009;149A:861–867.
17.
GrauTBurbullaLFEnglG. A novel heterozygous OPA3 mutation located in the mitochondrial target sequence results in altered steady-state levels and fragmented mitochondrial network. J Med Genet. 2013;50:848–858.
18.
TitahSMMeunierIBlanchetC. Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene. Eur J Ophthalmol. 2012;22:254–258.
19.
GrönlundMAHonarvarAKAnderssonS. Ophthalmological findings in children and young adults with genetically verified mitochondrial disease. Br J Ophthalmol. 2010;94:121–127.
20.
TyniTPaetauAStraussAWMiddletonBKiveläT. Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Res. 2004;56:744–750.
21.
PfefferGSirrsSWadeNKMezeiMM. Multisystem disorder in late-onset chronic progressive external ophthalmoplegia. Can J Neurol Sci. 2011;38:119–123.
22.
SieverdingLSchmaltzAAApitzJ. Encephalomyelopathy, cardiomyopathy, cataract and changes in the retinal pigment epithelium resulting from a cytochrome c oxidase deficiency. Klin Padiatr. 1988;200:381–387.
23.
MoriMMytingerJRMartinLCBartholomewDHickeyS. m.8993T>G-Associated Leigh syndrome with hypocitrullinemia on newborn screening. JIMD Rep. 2014;17:47–51.
24.
HanJLeeYMKimSMHanSYLeeJBHanSH. Ophthalmological manifestations in patients with Leigh syndrome. Br J Ophthalmol. 2015;99:528–535.
25.
RathPPJenkinsSMichaelidesM. Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence. Br J Ophthalmol. 2008;92:623–629.
GormanGSTaylorRW. Mitochondrial DNA abnormalities in ophthalmological disease. Saudi J Ophthalmol. 2011;25:395–404.
28.
GuillausseauPJMassinPDubois-LaforgeD. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med. 2001;134:721–728.
29.
MassinPVirally-MonodMVialettesB. Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. Ophthalmology. 1999;106:1821–1827.
30.
PabloLEGarcia-MartinEGazullaJ. Retinal nerve fiber hypertrophy in ataxia of Charlevoix-Saguenay patients. Mol Vis. 2011;17:1871–1876.
31.
PonjavicVAndreassonSTranebjaergLLubsHA. Full-field electroretinograms in a family with Mohr-Tranebjaerg syndrome. Acta Ophthalmol Scand. 1996;74:632–635.
32.
DhallaMSDesaiURZuckerbrodDS. Pigmentary maculopathy in a patient with Wolfram syndrome. Can J Ophthalmol. 2006;41:38–40.
33.
BarrientosACasademontJGenísD. Sporadic heteroplasmic single 5.5 kb mitochondrial DNA deletion associated with cerebellar ataxia, hypogonadotropic hypogonadism, choroidal dystrophy, and mitochondrial respiratory chain complex I deficiency. Hum Mutat. 1997;10:212–216.
La MorgiaCCaporaliLGandiniF. Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions. BMC Neurol. 2014;14:116.
36.
HeidaryGCalderwoodLCoxGF. Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature. J Neuroophthalmol. 2014;34:39–43.
37.
Mäkelä-BengsPSuomalainenAMajanderA. Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome. Pediatr Res. 1995;37:634–639.
38.
NikaliKLönnqvistT. Infantile-onset spinocerebellar ataxia. 2009 Jan 27 [updated 2015 Jan 15]. In: PagonRAAdamMPArdingerHH, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993-2015. http://www.ncbi.nlm.nih.gov/books/NBK3795/. Accessed March 14, 2015.
39.
FilianoJJGoldenthalMJMamourianACHallCCMarín-GarcíaJ. Mitochondrial DNA depletion in Leigh syndrome. Pediatr Neurol. 2002;26:239–242.
40.
MetodievMDGerberSHubertL. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014;51:834–838.
41.
ValentinoMLBarboniPRengoC. The 13042G --> A/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype. J Med Genet. 2006;43:e38.
42.
TabanMCohenBHDavid RothnerATraboulsiEI. Association of optic nerve hypoplasia with mitochondrial cytopathies. J Child Neurol. 2006;21:956–960.
43.
InagakiYMashimaYFuseNOhtakeYFujimakiTFukuchiT; Glaucoma Gene Research Group. Mitochondrial DNA mutations with Leber’s hereditary optic neuropathy in Japanese patients with open-angle glaucoma. Jpn J Ophthalmol. 2006;50:128–134.
44.
Yu-Wai-ManPStewartJDHudsonG. OPA1 increases the risk of normal but not high tension glaucoma. J Med Genet. 2010;47:120–125.
45.
BekirNAGüngörKGüranS. A DIDMOAD syndrome family with juvenile glaucoma and myopia findings. Acta Ophthalmol Scand. 2000;78:480–482.
46.
BanerjeeDBanerjeeAMookherjeeS. Mitochondrial genome analysis of primary open angle glaucoma patients. PLoS One. 2013;8: e70760.
47.
RoseLVRoseNTElderJEThorburnDRBonehA. Ophthalmologic presentation of oxidative phosphorylation diseases of childhood. Pediatr Neurol. 2008;38:395–397.
48.
NakasoKAdachiYFusayasuE. Leber’s hereditary optic neuropathy with olivocerebellar degeneration due to G11778A and T3394C mutations in the mitochondrial DNA. J Clin Neurol. 2012;8:230–234.
49.
ShinmeiYKaseMSuzukiY. Ocular motor disorders in mitochondrial encephalopathy with lactic acid and stroke-like episodes with the 3271 (T-C) point mutation in mitochondrial DNA. J Neuroophthalmol. 2007;27:22–28.
50.
JiJQDimmockDTangLY. A novel c.592-4_c.592-3delTT mutation in DGUOK gene causes exon skipping. Mitochondrion. 2010;10:188–191.
51.
Da PozzoPCardaioliEMalfattiE. A novel mutation in the mitochondrial tRNA(Pro) gene associated with late-onset ataxia, retinitis pigmentosa, deafness, leukoencephalopathy and complex I deficiency. Eur J Hum Genet. 2009;17:1092–1096.
52.
LiskovaPUlmanovaOTesinaP. Novel OPA1 missense mutation in a family with optic atrophy and severe widespread neurological disorder. Acta Ophthalmol. 2013;91:e225–e231.
53.
AnesiLde GemmisPPandolfoMHladnikU. Two novel homozygous SACS mutations in unrelated patients including the first reported case of paternal UPD as an etiologic cause of ARSACS. J Mol Neurosci. 2011;43:346–349.
54.
Grosse AldenhövelHBGallenkampUSulemanaCA. Juvenile onset diabetes mellitus, central diabetes insipidus and optic atrophy (Wolfram syndrome)—neurological findings and prognostic implications. Neuropediatrics. 1991;22:103–106.
55.
KiliçMSivriHSDursunA. A novel mutation in the DGUOK gene in a Turkish newborn with mitochondrial depletion syndrome. Turk J Pediatr. 2011;53:79–82.
56.
BekriSD’HoogheMVermeerschP. X-linked sideroblastic anemia and ataxia. 2006 Mar 01 [updated 2014 Apr 03]. In: PagonRAAdamMPArdingerHH, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993-2014. http://www.ncbi.nlm.nih.gov/books/NBK1321/. Accessed March 14, 2015.
57.
SonmezFMYayliSKulS. Pontocerebellar hypoplasia associated with nevoid hyperpigmentation and dysmorphic findings: a new subtype?Genet Couns. 2012;23:347–352.
58.
DilberEAynaciFMAhmetogluA. Pontocerebellar hypoplasia in two siblings with dysmorphic features. J Child Neurol. 2002;17:64–66.
59.
KunclRWHoffmanPN. Myopathies and disorders of neuromuscular transmission. In: MillerNRNewmanNJ, eds. Walsh and Hoyt’s Clinical Neuro-Ophthalmology. 5th ed. Baltimore, MD: Williams & Wilkins; 1999:1351–1460.
60.
RobberechtKDecockCStevensASenecaSDe BleeckerJLeroyBP. Ptosis as an associated finding in maternally inherited diabetes and deafness. Ophthalmic Genet. 2010;31:240–243.
61.
BostanAGlibertGDachyBDanB. Novel mutation in spacer region of POLG associated with ataxia neuropathy spectrum and gastroparesis. Auton Neurosci. 2012;170:70–72.
62.
FukuharaNTokiguchiSShirakawaKTsubakiT. Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): disease entity or a syndrome? Light- and electron-microscopic studies of two cases and review of literature. J Neurol Sci. 1980;47:117–133.
HanischFKornhuberMAlstonCLTaylorRWDeschauerMZierzS. SANDO syndrome in a cohort of 107 patients with CPEO and mitochondrial DNA deletions. J Neurol Neurosurg Psychiatry. 2015;86:630–634.
65.
FinstererJAhtingU. Mitochondrial depletion syndromes in children and adults. Can J Neurol Sci. 2013;40:635–644.
66.
Delgado-AlvaradoMde la RivaPJiménez-UrbietaH. Parkinsonism, cognitive deficit and behavioural disturbance caused by a novel mutation in the polymerase gamma gene. J Neurol Sci. 2015;350:93–97.
67.
TanakaKTateishiTKawamuraNOhyagiYUrataMKiraJ. A case of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis with multiple mitochondrial DNA deletions. Rinsho Shinkeigaku. 2013;53:205–211.
68.
FinstererJKovacsGGAhtingU. Adult mitochondrial DNA depletion syndrome with mild manifestations. Neurol Int. 2013;5:28–30.
69.
ZehariaAFischel-GhodsianNCasasK. Mitochondrial myopathy, sideroblastic anemia, and lactic acidosis: an autosomal recessive syndrome in Persian Jews caused by a mutation in the PUS1 gene. J Child Neurol. 2005;20:449–452.
GendronSPBastienNMalletJDRochettePJ. The 3895-bp mitochondrial DNA deletion in the human eye: a potential involvement in corneal ageing and macular degeneration. Mutagenesis. 2013;28:197–204.
72.
DaruichAMatetABorruatFX. Macular dystrophy associated with the mitochondrial DNA A3243G mutation: pericentral pigment deposits or atrophy? Report of two cases and review of the literature. BMC Ophthalmol. 2014;14:77.
73.
HeiduschkaPSchnichelsSFuhrmannN. Electrophysiological and histologic assessment of retinal ganglion cell fate in a mouse model for OPA1-associated autosomal dominant optic atrophy. Invest Ophthalmol Vis Sci. 2010;51:1424–1431.
74.
ChoiSYKimYOhSWJeongSHKimJS. Pursuit-paretic and epileptic nystagmus in MELAS. J Neuroophthalmol. 2012;32:135–138.
WeitgasserLWechselbergerGEnsatFKaplanRHladikM. Treatment of eyelid ptosis due to Kearns-Sayre syndrome using frontalis suspension. Arch Plast Surg. 2015;42:214–217.
79.
FinstererJBrunnerS. Madarosis from mitochondriopathy. Acta Ophthalmol Scand. 2005;83:628–630.
80.
Müller-VahlKRKolbeHEgenspergerRDenglerR. Mitochondriopathy, blepharospasm, and treatment with botulinum toxin. Muscle Nerve. 2000;23:647–648.
81.
Yu-Wai-ManPChinneryPF. Leber Hereditary Optic Neuropathy 2000 Oct 26 [updated 2013 Sep 19]. In: PagonRAAdamMPArdingerHH, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993-2015. http://www.ncbi.nlm.nih.gov/books/NBK1174/. Accessed March 14, 2015.
82.
WangKTakahashiYGaoZL. Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. Neurogenetics. 2009;10:337–345.
83.
Yu-Wai-ManPGriffithsPGHudsonG. Inherited optic neuropathies. J Med Genet. 2009;46:145–158.
84.
Yu-Wai-ManPGriffithsPGBurkeA. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. 2010;117:1538–1546.
85.
PayneMYangZKatzBJ. Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a missense mutation in OPA1. Am J Ophthalmol. 2004;138:749–755.
86.
O’NeillECDanesh-MeyerHVKongGX; Optic Nerve Study Group. Optic disc evaluation in optic neuropathies: the optic disc assessment project. Ophthalmology. 2011;118:964–970.
