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Mitochondrial Retinopathy

Open AccessPublished:July 10, 2021DOI:https://doi.org/10.1016/j.oret.2021.02.017

      Purpose

      To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease.

      Design

      Retrospective case series.

      Participants

      Twenty-three patients with retinopathy and mitochondrial disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness (MIDD), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and other systemic manifestations.

      Methods

      Review of case notes, retinal imaging, electrophysiologic assessment, molecular genetic testing including protein modeling, and histologic analysis of muscle biopsy.

      Main Outcome Measures

      Phenotypic characteristics of mitochondrial retinopathy.

      Results

      Genetic testing identified sporadic large-scale mitochondrial DNA deletions and variants in MT-TL1, MT-ATP6, MT-TK, MT-RNR1, or RRM2B. Based on retinal imaging, 3 phenotypes could be differentiated: type 1 with mild, focal pigmentary abnormalities; type 2 characterized by multifocal white-yellowish subretinal deposits and pigment changes limited to the posterior pole; and type 3 with widespread granular pigment alterations. Advanced type 2 and 3 retinopathy presented with chorioretinal atrophy that typically started in the peripapillary and paracentral areas with foveal sparing. Two patients exhibited a different phenotype: 1 revealed an occult retinopathy, and the patient with RRM2B-associated retinopathy showed no foveal sparing, no severe peripapillary involvement, and substantial photoreceptor atrophy before loss of the retinal pigment epithelium. Two patients with type 1 disease showed additional characteristics of mild macular telangiectasia type 2. Patients with type 1 and mild type 2 or 3 disease demonstrated good visual acuity and no symptoms associated with the retinopathy. In contrast, patients with advanced type 2 or 3 disease often reported vision problems in dim light conditions, reduced visual acuity, or both. Short-wavelength autofluorescence usually revealed a distinct pattern, and near-infrared autofluorescence may be severely reduced in type 3 disease. The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination.

      Conclusions

      Different types of mitochondrial retinopathy show characteristic features. Even in absence of visual symptoms, their recognition may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease.

      Keywords

      Abbreviations and Acronyms:

      BCVA (best-corrected visual acuity), COX (cytochrome c oxidase), AF (autofluorescence), CPEO (chronic progressive external ophthalmoplegia), KSS (Kearns-Sayre syndrome), MELAS (mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes), MIDD (maternally inherited diabetes and deafness), NIR (near infrared), RP (retinitis pigmentosa), RPE (retinal pigment epithelium), SDH (succinate dehydrogenase)
      Mitochondria are central for cellular function and survival because they mediate processes such as energy production, metabolism control, and apoptosis.
      • Schapira A.H.
      Mitochondrial diseases.
      • Koopman W.J.
      • Willems P.H.
      • Smeitink J.A.
      Monogenic mitochondrial disorders.
      • Craven L.
      • Alston C.L.
      • Taylor R.W.
      • Turnbull D.M.
      Recent advances in mitochondrial disease.
      In 1988, initial reports described an association of variants in the mitochondrial genome with monogenic disease, including Leber hereditary optic neuropathy, Kearns-Sayre syndrome, and mitochondrial myopathies.
      • Wallace D.C.
      • Singh G.
      • Lott M.T.
      • et al.
      Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy.
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      • Zeviani M.
      • Moraes C.T.
      • DiMauro S.
      • et al.
      Deletions of mitochondrial DNA in Kearns-Sayre syndrome.
      Mitochondrial disease may involve 1 or several organs with limited genotype–phenotype correlations and symptoms ranging from mild to severe.
      • Schapira A.H.
      Mitochondrial diseases.
      ,
      • Koopman W.J.
      • Willems P.H.
      • Smeitink J.A.
      Monogenic mitochondrial disorders.
      Studies on the retinal phenotype associated with a specific mitochondrial variant (m.3243A>G, MT-TL1 gene) indicate that diagnosis of associated syndromes such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD) often may be facilitated by identification of the distinct retinal features.
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      • Massin P.
      • Virally-Monod M.
      • Vialettes B.
      • et al.
      Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.
      • Müller P.L.
      • Treis T.
      • Pfau M.
      • et al.
      Progression of retinopathy secondary to maternally inherited diabetes and deafness—evaluation of predicting parameters.
      • Müller P.L.
      • Maloca P.
      • Webster A.
      • et al.
      Structural features associated with the development and progression of RORA secondary to maternally inherited diabetes and deafness.
      • Smith P.R.
      • Bain S.C.
      • Good P.A.
      • et al.
      Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the mitochondrial DNA 3243 tRNA(Leu) A to G mutation.
      • Latkany P.
      • Ciulla T.A.
      • Cacchillo P.F.
      • Malkoff M.D.
      Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation.
      • Michaelides M.
      • Jenkins S.A.
      • Bamiou D.E.
      • et al.
      Macular dystrophy associated with the A3243G mitochondrial DNA mutation. Distinct retinal and associated features, disease variability, and characterization of asymptomatic family members.
      • Rath P.P.
      • Jenkins S.
      • Michaelides M.
      • et al.
      Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence.
      • van den Ouweland J.M.
      • Lemkes H.H.
      • Ruitenbeek W.
      • et al.
      Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      A grading scheme for m.3243A>G-associated retinal manifestations and a comprehensive characterization of associated systemic features illustrated the variable disease severity across organ systems and among patients.
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      • Massin P.
      • Virally-Monod M.
      • Vialettes B.
      • et al.
      Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.
      • Müller P.L.
      • Treis T.
      • Pfau M.
      • et al.
      Progression of retinopathy secondary to maternally inherited diabetes and deafness—evaluation of predicting parameters.
      • Müller P.L.
      • Maloca P.
      • Webster A.
      • et al.
      Structural features associated with the development and progression of RORA secondary to maternally inherited diabetes and deafness.
      Less detailed information is available about retinal changes in patients with other mitochondrial diseases, and a comprehensive characterization of retinal phenotypes is lacking.
      With upcoming potential treatment options for mitochondrial disease, a detailed understanding of associated retinal neurodegeneration is required for patient identification and as potential parameters for clinical end points.
      • Viscomi C.
      Toward a therapy for mitochondrial disease.
      Here, we investigate the phenotypic spectrum of mitochondrial retinopathy and illustrate novel phenotypic features and genotype–phenotype correlations.

      Methods

      This retrospective study of patients with retinal changes and a diagnosis of mitochondrial disease adhered to the tenets of the Declaration of Helsinki. Institutional review board approval (Ethics Committee, Medical Faculty, University of Bonn) and patient informed consent were obtained.
      Best-corrected visual acuity (BCVA) and visual impairment was classified according to World Health Organization (WHO) definitions as mild (<20/40), moderate (<20/60), or severe (<6/60). Clinical assessment included standardized anterior segment and dilated fundus examination and, in selected patients, full-field electroretinography. Multimodal retinal imaging included OCT, autofluorescence (AF), and ultra-widefield imaging
      • Birtel J.
      • Gliem M.
      • Holz F.G.
      • Herrmann P.
      [Imaging and molecular genetic diagnostics for the characterization of retinal dystrophies].
      (Supplemental Methods, available at www.ophthalmologyretina.org).
      A comprehensive general medical history was obtained and a neurologic workup was performed. Muscle biopsy samples were obtained from a proximal limb muscle, and cryostat sections were analyzed histologically and histochemically, including with modified Gomori’s trichrome, cytochrome c oxidase (COX), and succinate dehydrogenase (SDH) stainings.
      • Dubowitz V.
      • Sewry C.
      • Oldfors A.
      Muscle Biopsy: A Practical Approach.
      ,
      • Pfeffer G.
      • Chinnery P.F.
      Diagnosis and treatment of mitochondrial myopathies.
      Information on genetic testing may be found in the Supplemental Methods.

      Results

      The study included 23 patients (10 women) from 22 families with an age at first presentation between 17 and 74 years (median, 50 years; interquartile range, 36–62 years; Table 1). The retinal phenotype was key to suspecting mitochondrial disease in 11 patients; 12 patients had been diagnosed with mitochondrial disease before retinal examination (Table S1, available at www.ophthalmologyretina.org).
      Table 1Patient Characteristics
      Mitochondrial RetinopathyPatient No.GenderReferral DiagnosisSymptoms Associated with RetinopathyFirst ExaminationLast ExaminationElectroretinographyResults of Genetic Testing (Reference)Heteroplasmy Level (Specimen)
      Age (yrs)BCVA (OD/OS)Refraction (OD/OS)Age (yrs)BCVA (OD/OS)ScotopicPhotopic
      Type 1
      1FPtosisNone3520/20+0.50/–0.75/75°5120/20NormalReducedSporadic single mtDNA deletion, 3.8kb (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      48% (muscle)
      20/20+1.00/–1.00/93°20/20
      2MCPEONone4920/200.00/–1.25/96°6420/20NENESporadic single mtDNA deletion, m.11037_14597del (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      45% (muscle)
      20/20–1.50/–1.50/13°20/20
      3FMELASNone5820/20+2.50/–0.50/177°5920/25NormalNormalm.8344A>G, MT-TK (

      DiMauro S, Hirano M. MERRF. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. Seattle; 1993.

      ,
      • Wallace D.C.
      • Zheng X.X.
      • Lott M.T.
      • et al.
      Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease.
      )
      85% (blood)
      20/20+2.25/–0.75/10°20/25
      4FCPEONone2720/25–0.25/–3.50/18°3020/25NENESporadic single mtDNA deletion, 5 kb (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      30%–40% (blood)
      20/20–1.00/–2.50/6°20/20
      5FCPEONone6720/20+3.5/–3.75/53°NENESporadic single mtDNA deletion, 5–6 kb (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      NE
      20/25+3.00/–3.00/61°
      6MCPEONone7420/25 20/80+0.25/–1.25/85°

      +0.75/–1.00/90°
      NormalNormalSporadic single mtDNA deletion, 5 kb (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      NE
      Type 2
      7MDRNone4820/20 20/20NENEm.3243A>G, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      25% (blood)
      8MMDNone5420/25+1.00/–1.00/24°5720/32NENEm.3243A>G, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      65% (muscle)
      20/25+1.00/–0.50/169°20/25
      9MRDNone5120/20–0.50/–0.75/4°NormalNormalm.3243A>G, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      26% (blood)
      20/20–0.25/–0.75/2°
      10MAPMPPENone4820/20+0.50/–0.25/172°NormalNormalm.3243A>G, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      25% (blood)
      20/20+0.75/–0.50/173°
      11
      Patients 11 and 12 are related (mother and daughter).
      FGANight vision problems, reduced visual acuity4920/63+0.50/–1.00/178°5220/80NENEm.3243A>G, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      20% (blood)
      20/63+1.25/–0.25/118°20/640
      12
      Patients 11 and 12 are related (mother and daughter).
      FGANight vision problems, reduced visual acuity7420/50–0.75/–1.00/114°NENEm.3243A>G, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      25% (blood)
      20/640+0.25/–0.75/108°
      13MAMDReduced visual acuity, glare, night vision problems7420/200–0.50/–1.00/150°NENEm.3243A>G, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      10% (blood)
      20/200–0.50/–0.50/99°
      Type 3
       Without atrophy
      14FCPEONone2620/16 20/16+0.50/–0.25/57° +0.00/–0.25/96°2620/16NormalNormalSporadic single mtDNA deletion, m.6001_14556del (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      10% (muscle), 60% (blood)
      20/16
      15FCPEOReduced visual acuity1720/32 20/25–1.00/–1.00/70° –0.75/–1.75/113°2020/32ReducedReducedSporadic single mtDNA deletion, 7–8 kb (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      NE
      20/25
      16MCPEONight vision problems1920/1620/16–2.75/–0.25/34° –1.75/–1.50/102°2720/25ReducedReducedSporadic single mtDNA deletion, 5 kb (“common deletion”) (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      NE
      20/25
       With atrophy
      17MDRNight vision problems, glare5820/2020/20–1.00/–0.75/86° –1.00/–0.50/90°6420/20 20/25ReducedReducedm.3255G>A, MT-TL1(

      DiMauro S, Hirano M. MERRF. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. Seattle; 1993.

      ,
      • Nishigaki Y.
      • Tadesse S.
      • Bonilla E.
      • et al.
      A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome.
      )
      21% (blood)
      18FMD, RPNight vision problems, reduced visual acuity, scotoma5020/5020/40–2.00/–3.25/77° –0.50/–0.75/41°5420/50 20/200ReducedReducedm.3244G>A, MT-TL1 (
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      )
      47% (muscle)
      19MAMDNight vision problems, reduced visual acuity6420/3220/800.00/–0.75/7° 0.00/–1.00/179°6820/50 20/640ReducedReducedm.1021T>C, MT-RNR120% (blood)
      20MMDNight vision problems, reduced visual acuity, metamorphopsia6920/4020/50–1.25/–0.25/61° –0.50/–1.00/80°7320/63 20/50ReducedReducedm.9171A>G, MT-ATP694% (blood)
      21MMD, AGNight vision problems, reduced visual acuity6020/63 CF
      Assumed amblyopia resulting from ocular trauma in childhood.
      0.00/–1.00/86° –4.75/–4.00/11°ReducedReducedSporadic single mtDNA deletion, 2 kb (
      • Holt I.J.
      • Harding A.E.
      • Morgan-Hughes J.A.
      Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
      ,
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      )
      50% (muscle)
      Other
      22FNARPNone3720/2520/200.00/–0.50/92° 0.00/–0.50/78°3920/25 20/20NormalReducedm.8993T>G, MT-ATP6 (
      • Holt I.J.
      • Harding A.E.
      • Petty R.K.
      • Morgan-Hughes J.A.
      A new mitochondrial disease associated with mitochondrial DNA heteroplasmy.
      ,
      • Stendel C.
      • Neuhofer C.
      • Floride E.
      • et al.
      Delineating MT-ATP6-associated disease: from isolated neuropathy to early onset neurodegeneration.
      )
      70%–75% (urine)
      23MMDReduced visual acuity3520/6320/200–0.75/–0.50/9° –1.75/–0.75/103°4020/20020/200ReducedReducedRRM2B: c.575C>T, p.Ala192Val, homozygous.
      Multiple mtDNA deletions (muscle)NE
      AG = atrophia gyrate; AMD = age-related macular degeneration; APMPPE = acute posterior multifocal placoid pigment epitheliopathy; BCVA = best-corrected visual acuity; CF = counting fingers; CPEO = chronic progressive external ophthalmoplegia; DR = diabetic retinopathy; F = female; GA = geography atrophy; HM = hand movements; M = male; MD = macular degeneration or dystrophy; MELAS = mitochondrial encephalomyopathy; NARP = neuropathy, ataxia, and retinitis pigmentosa syndrome; NE = not examined; OD = right eye; OS = left eye; RD = retinal dystrophy; RP = retinitis pigmentosa; — = not available.
      Patients 11 and 12 are related (mother and daughter).
      Assumed amblyopia resulting from ocular trauma in childhood.
      At first examination, 32 eyes (18 patients) had a BCVA of 20/40 or better, BCVA was ≥20/25 in 28 eyes (15 patients). Mild, moderate, or severe reduction of BCVA was present in 7 eyes (6 patients), 5 eyes (4 patients), or 1 eye, respectively. In 1 eye, BCVA was reduced to counting fingers because of ocular trauma in childhood. Patient-reported symptoms included vision problems in dim light conditions (n = 9), reduced visual acuity (n = 9), glare (n = 2), scotoma (n = 1), and metamorphopsia (n = 1). The most frequent combination of symptoms was problems in dim light conditions and reduced visual acuity (n = 7). Twelve patients reported no vision problems indicative of a retinal disease (Table 1).

       Phenotypic Variability of Mitochondrial Retinopathy

      Retinal changes showed considerable variability, but specific recurrent patterns allowed grouping into the following different types.
      Type 1 (Fig 1; Fig S1, available at www.ophthalmologyretina.org). Six patients without vision problems relating to retinal disease (26%; mean BCVA, 20/20; mean age, 52 years) revealed mild, focal pigmentary abnormalities on funduscopy associated with increased and decreased AF and alterations at the interface between photoreceptor outer segments and the retinal pigment epithelium (RPE) on OCT scans. On electroretinography testing (n = 3), scotopic and photopic recordings were within normal limits except for 1 individual who showed slightly reduced photopic amplitudes. Some of these patients also showed mild peripheral pigment retinopathy; however, this was not documented systematically.
      Figure thumbnail gr1
      Figure 1Mitochondrial retinopathy type 1. Fundus autofluorescence imaging showing focally increased and decreased autofluorescence (left column) corresponding to alterations at the interface between photoreceptor outer segments and the retinal pigment epithelium on OCT (right column): (A) patient 1 and (B) patient 4.
      Type 2 (Fig 2; Fig S2, available at www.ophthalmologyretina.org). Seven patients (30%; mean BCVA, 20/32; mean age, 51 years) revealed a distinct retinal phenotype in which fundus changes are more severe than in type 1, but where these remain limited to the posterior fundus, even in late disease stages with atrophy. These patients showed multifocal faint white-yellowish or hyperpigmented subretinal deposits and pigment changes, and AF imaging showed hyperautofluorescent dot or fleck-like lesions. Sharply demarcated chorioretinal atrophy occurred in the peripapillary and paracentral macular area and involved the fovea in only the most advanced cases. Electroretinography recordings (n = 2; BCVA, 20/20) were within normal limits. Four patients reported no visual symptoms, whereas the other 3 showed reduced visual acuity (n = 3), vision problems in dim light conditions (n = 3), and glare (n = 1).
      Figure thumbnail gr2
      Figure 2Mitochondrial retinopathy type 2. Fundus autofluorescence imaging (left column) showing hyperautofluorescent dot or fleck-like lesions and, where present, sharply demarcated dark areas representing chorioretinal atrophy. These atrophic areas also show a sharp demarcation from relatively preserved retina on OCT images (right column): (A) patient 8, (B) patient 9, (C) patient 10, and (D) patient 12.
      Type 3 (Fig 3; Fig S3, available at www.ophthalmologyretina.org). Eight patients (35%) revealed widespread (extending beyond the vascular arcade) granular pigmented fundus alterations corresponding to a granular AF pattern. Associated changes on OCT included reflectivity changes primarily at the level of the ellipsoid and interdigitation zone and an increased distance between the ellipsoid band and the RPE layer. Within this group, 3 patients (mean BCVA, 20/20; mean age, 21 years) revealed no chorioretinal atrophy, 3 patients (mean BCVA, 20/32; mean age, 57 years) showed 1 or more bilateral areas of paracentral and peripapillary chorioretinal atrophy that spared the foveal center, and 2 patients (mean BCVA, 20/63; mean age, 65 years) showed more advanced degeneration that included the fovea. The chorioretinal atrophy corresponded to sharply demarcated areas of decreased AF and, on OCT, atrophy of the photoreceptor layer and RPE. On electroretinography testing (n = 8), photopic and scotopic responses were reduced to a similar extent in all except for the youngest patient. All patients in this group, except the one with normal electroretinography recordings, reported vision problems in dim light conditions.
      Figure thumbnail gr3
      Figure 3Mitochondrial retinopathy type 3. Fundus autofluorescence imaging (left column) imaging showing peripapillary atrophy and a widespread granular autofluorescent pattern corresponding to reflectivity changes primarily in the ellipsoid and interdigitation zone and sometimes an increased distance between ellipsoid band and the retinal pigment epithelium layer on OCT (right column): (A, B) patients 15 and 17 without macular atrophy and (C, D) patients 18 and 20 with fovea-sparing macular chorioretinal atrophy.
      Two patients showed a different retinal phenotype and could not be classified as types 1, 2, or 3. Patient 22 showed no visual symptoms, but electroretinography recordings revealed reduced cone responses (approximately 50% of the lower limit of that of control participants) and rod responses in the lower normal range. Funduscopy and AF imaging showed no obvious changes (occult retinopathy), but a distinct retinal phenotype was found on OCT with thinning of the outer nuclear layer, reduced reflectivity of the ellipsoid zone and fading of the interdigitation zone outside the central retina (Fig 4A, B ). Patient 23 showed retinal degeneration mainly involving the posterior pole; however, no foveal sparing was present and the peripapillary area was rather spared. A patchy area of reduced AF at the posterior pole was surrounded by diffuse, partly spot-shaped hyperautofluorescent lesions extending centri-fugally. Reduced AF corresponded to atrophy of the photoreceptor layer and RPE on OCT (Fig 4C, D; Fig S4, available at www.ophthalmologyretina.org). On electroretinography testing, scotopic recordings were slightly reduced and photopic amplitudes were severely reduced.
      Figure thumbnail gr4
      Figure 4Occult mitochondrial retinopathy and RRM2B-associated retinopathy. A, B, An occult retinopathy, characterized by normal retinal appearance on funduscopy and (A) autofluorescence imaging, but distinct changes on (B) OCT was identified in patient 22. B, OCT scan showing a fading of the ellipsoid and interdigitation zone and thinning of the outer nuclear layer, mainly toward the peripheral scan. C, In RRM2B-associated retinopathy (patient 23), a patchy area of reduced autofluorescence is surrounded by diffuse, partly spot-shaped hyperautofluorescent lesions. D, OCT imaging showing widespread atrophy of the photoreceptor layer, despite partial presence of the retinal pigment epithelium. Additional information on RRM2B-associated retinopathy can be found in and .

       Longitudinal Observations and Additional Findings on Retinal Imaging

      Fundus changes showed overall a high symmetry between eyes (Fig 5; Figs S5 and S6, available at www.ophthalmologyretina.org), and longitudinal observations were available for 15 patients. In patients without chorioretinal atrophy at baseline (n = 8), no atrophy developed and visual acuity remained stable (range, 20/25–20/20; median follow-up, 3 years; range, 1–16 years). In patients with pre-existing chorioretinal atrophy (n = 7; median follow-up, 4 years; range, 3–6 years), atrophy progressed remarkably and included an evolution from multiple separate areas of atrophy to larger and eventually confluent areas of atrophy (Fig S7, available at www.ophthalmologyretina.org). Growth of advanced chorioretinal atrophy resulted in foveal involvement in 3 eyes (2 patients) and an associated decline of mean BCVA from 20/40 to 20/100.
      Figure thumbnail gr5
      Figure 5Ultra-widefield autofluorescence images showing symmetry of mitochondrial retinopathy: right and left eye of (A) patient 9, (B) patient 12, (C) patient 17, and (D) patient 19.
      Near-infrared autofluorescence (NIR-AF), which originates from the melanin-containing RPE and choroidal tissue, often was altered considerably. An early loss of RPE-derived NIR-AF caused an unmasking of the choroidal autofluorescent pattern predominantly in patients with type 3 mitochondrial retinopathy, with dark, large choroidal vessels and brighter choroidal stroma in between (Fig 6; Fig S3). Areas of RPE atrophy were not well visible on NIR-AF images because of a lack of contrast with areas of preserved RPE, which revealed a particularly low signal in areas that appeared granular on conventional AF images.
      Figure thumbnail gr6
      Figure 6Blue autofluorescence (left column) and near-infrared autofluorescence (NIR-AF) (right column) showing a distinctive pattern in patients with type 3 mitochondrial retinopathy in (A) patient 17 and (B) patient 19 (left eye, rotated). Because of an early loss of retinal pigment epithelium-derived NIR-AF, no distinction between areas with and without RPE atrophy is obvious using NIR-AF.
      No optic atrophy was observed funduscopically in patients 1 through 22, and when performed (n = 14), OCT-based measures of the peripapillary retinal nerve fiber layer thickness consistently were within the normal range. In contrast, patient 23 showed partial optic atrophy with mild thinning of the retinal nerve fiber layer (Fig S4).
      Two patients showed macular changes reminiscent of macular telangiectasia type 2. Patient 2 showed an asymmetric foveal dip with temporal thinning and a focal wedge-shaped loss of macular pigment temporally in both eyes (Fig S2). Patient 6 demonstrated similar changes in the right eye. The patient’s left eye showed hyporeflective cavities, substantial loss of macular pigment, increased reflectivity on blue reflectance imaging, and mild vascular leakage mainly in the temporal macula (Fig 7).
      Figure thumbnail gr7
      Figure 7Macular changes in mitochondrial retinopathy with similarities to macular telangiectasia type 2. AD, Right macula appearing normal on funduscopy (A), but blue reflectance imaging (B), fluorescein angiography (C), and in particular autofluorescence imaging (D) indicate a temporal wedge-shaped loss of macular pigment. E, The foveal dip is asymmetric because of mild temporal thinning. GI, Left macula showing an increased blue reflectance temporally (G), mild vascular leakage mainly in the temporal macula on fluorescein angiography (H), and an almost complete lack of macular pigment on autofluorescence imaging (I). J, OCT imaging revealing a schitic appearance mainly in the temporal half of the macula. The peripheral retina showed mild pigment retinopathy.

       Systemic Disease Associations, Genetic Findings, and Muscle Biopsy

      Other organ manifestations likely associated with mitochondrial disease were highly variable (Table S1). This included chronic progressive external ophthalmoplegia (CPEO) in 9 patients, of which 3 also had systemic findings (CPEO plus). One patient previously was diagnosed with neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome. Further frequently observed multisystem mitochondrial features included hearing loss (n = 12), diabetes (n = 8), cardiac abnormalities (n = 6), polyneuropathy (n = 5), and ataxia (n = 5).
      Mitochondrial disease was confirmed by genetic testing (Table S1). In patients with type 1 or type 3 mitochondrial retinopathy, a sporadic single large-scale mitochondrial DNA deletion was identified in 9 patients, and previously described pathogenic missense variants of the mitochondrial genome (MT-TL1, MT-TK) were found in 2 patients. Furthermore, a previously described variant of unknown significance was detected in MT-TL1 (patient 18), and a novel variant of unknown significance was identified in MT-RNR1 and MT-ATP6, respectively (patients 19 and 20). All patients with type 2 mitochondrial retinopathy carried the m.3243G>A variant in the MT-TL1 gene. Patient 22 carried a previously described MT-ATP6 variant. In patient 23, a novel homozygous variant in RRM2B was identified (confirmed by segregation analysis, the patient had known consanguineous parents). Structural evaluation of the p.Ala192Val variant and its high polyphen-2 score, 0.964, indicated likely pathogenicity (Fig S8, available at www.ophthalmologyretina.org). Additional targeted next-generation sequencing (n = 9), containing a broad spectrum of genes associated with (syndromic) retinal dystrophies, did not detect additional variants that would explain the retinal phenotype (Table S2, available at www.ophthalmologyretina.org).
      A muscle biopsy was performed in 13 patients and identified distinct characteristics of mitochondrial disease in 11 patients (Table S1; Fig S9, available at www.ophthalmologyretina.org). In addition, myopathic or neurogenic alterations, or both, were observed in 7 patients. In 2 patients (patients 1 and 19), the muscle biopsy results alone were not conclusive to confirm the clinical diagnosis of a mitochondrial disease.

       Exemplary Cases Demonstrating the Value of Retinal Phenotyping

      The following 2 case reports exemplify the often multidisciplinary approach to diagnosing mitochondrial disease.

       Patient 17

      A 58-year-old patient with BCVA of 20/20 in both eyes reported vision problems in dim light conditions of approximately 5 years’ duration. He was taking medication for diabetes mellitus and psoriatic arthritis and had sensorineural hearing loss. His deceased mother had received a diagnosis of retinal degeneration and diabetes mellitus. Retinal examination revealed changes consistent with mitochondrial retinopathy type 3: a widespread mottled fundus pigmentation and slightly constricted vessels (Fig 8A–C ), paracentral atrophic areas of the outer retina and RPE that were associated with paracentral scotomata on visual field testing, and electroretinography examination results showing reduced scotopic and photopic responses. A subsequent neurologic examination revealed mild afferent ataxia with gait abnormalities, mild sensorimotor axonal and demyelinating polyneuropathy, as well as intermittent dysarthria and anomic aphasia. Histologic examination of a muscle biopsy sample with combined SDH and COX staining showed numerous COX-negative and SDH-positive fibers (Fig 8D) indicating mitochondrial disease. Mild neurogenic changes were also present. Genetic analysis identified a pathogenic variant in the MT-TL1 gene (m.3255G>A) previously reported in patients with myoclonic epilepsy with ragged red fibers and Kearns-Sayre syndrome.
      • Moraes C.T.
      • DiMauro S.
      • Zeviani M.
      • et al.
      Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
      ,

      DiMauro S, Hirano M. MERRF. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. Seattle; 1993.

      Figure thumbnail gr8
      Figure 8Mitochondrial retinopathy in a patient with familial diabetes and retinal degeneration: (A) ultra-widefield fundus imaging, (B) OCT, and (C) ultra-widefield fundus autofluorescence of patient 17. D, Histologic examination of muscle biopsy sample with combined succinate dehydrogenase (SDH) and cytochrome-c-oxidase (COX) staining showing numerous COX-negative and SDH-positive fibers. Scale bar, 50 μm.

       Patient 21

      A 60-year-old patient with BCVA of 20/63 in the right eye and counting fingers in the left eye reported vision problems in dim light conditions and declining visual acuity of approximately 8 years’ duration. He previously had received a diagnosis of central areolar choroidal dystrophy. Funduscopy revealed granular fundus alterations and chorioretinal atrophy that included the peripapillary region, but spared a small foveal island (Fig 9). Photopic and scotopic responses were reduced on electroretinography testing. Various multisystem disorders were diagnosed, including sensorineural hearing loss diagnosed at the age of 48 years, dilated cardiomyopathy (New York Heart Association classification II–III), chronic atrial fibrillation, cardiac arrhythmia, exertional dyspnea, as well as cognitive and psychomotor changes; these alterations were never seen as part of a systemic disease. Because the retinopathy indicated a mitochondrial disease, a muscle biopsy was performed that revealed numerous COX-negative and SDH-positive fibers. Subsequent molecular genetic testing identified a single mitochondrial DNA deletion in skeletal muscle tissue. This patient illustrates the value of recognizing mitochondrial retinopathy in a patient with a previously indeterminate multisystemic disease.
      Figure thumbnail gr9
      Figure 9Mitochondrial retinopathy in patient 21, with previously indeterminate multisystemic disease: (A) fundus photography, (B) fundus autofluorescence imaging, and (C) OCT imaging.

      Discussion

      Mitochondrial disease may present with highly variable severity. For the retina, this was investigated previously in greatest detail for the m.3243G>A variant, for which 4 different severity grades were suggested, ranging from mild pigmentary abnormalities at the level of the RPE to fovea-involving chorioretinal atrophy.
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      ,
      • Massin P.
      • Virally-Monod M.
      • Vialettes B.
      • et al.
      Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.
      Fundus changes associated with the m.3243G>A variant usually remain limited to the posterior pole, with normal responses on full field electroretinography testing.
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      • Massin P.
      • Virally-Monod M.
      • Vialettes B.
      • et al.
      Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.
      • Müller P.L.
      • Treis T.
      • Pfau M.
      • et al.
      Progression of retinopathy secondary to maternally inherited diabetes and deafness—evaluation of predicting parameters.
      • Müller P.L.
      • Maloca P.
      • Webster A.
      • et al.
      Structural features associated with the development and progression of RORA secondary to maternally inherited diabetes and deafness.
      • Smith P.R.
      • Bain S.C.
      • Good P.A.
      • et al.
      Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the mitochondrial DNA 3243 tRNA(Leu) A to G mutation.
      • Latkany P.
      • Ciulla T.A.
      • Cacchillo P.F.
      • Malkoff M.D.
      Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation.
      • Michaelides M.
      • Jenkins S.A.
      • Bamiou D.E.
      • et al.
      Macular dystrophy associated with the A3243G mitochondrial DNA mutation. Distinct retinal and associated features, disease variability, and characterization of asymptomatic family members.
      • Rath P.P.
      • Jenkins S.
      • Michaelides M.
      • et al.
      Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence.
      • van den Ouweland J.M.
      • Lemkes H.H.
      • Ruitenbeek W.
      • et al.
      Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.
      • Goto Y.
      • Nonaka I.
      • Horai S.
      A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
      Other retinal phenotypes have been reported in patients with various mitochondrial diseases, but terminology and depth of phenotyping have been inconsistent. For instance, Kearns and Sayre described, in 1958, patients with “pigmentary degeneration” on funduscopy, night vision abnormalities, and some histologic similarities, but also clinical differences, to retinitis pigmentosa (RP).
      • Kearns T.P.
      • Sayre G.P.
      Retinitis pigmentosa, external ophthalmoplegia, and complete heart block: unusual syndrome with histologic study in one of two cases.
      In subsequent publications, the retinal phenotype of Kearns-Sayre syndrome was described as RP, atypical RP, tapetoretinal degeneration, salt-and-pepper retinopathy, and pigmentary retinopathy.
      • Ascaso F.J.
      • Lopez-Gallardo E.
      • Del Prado E.
      • et al.
      Macular lesion resembling adult-onset vitelliform macular dystrophy in Kearns-Sayre syndrome with multiple mtDNA deletions.
      • Gronlund M.A.
      • Honarvar A.K.
      • Andersson S.
      • et al.
      Ophthalmological findings in children and young adults with genetically verified mitochondrial disease.
      • Khambatta S.
      • Nguyen D.L.
      • Beckman T.J.
      • Wittich C.M.
      Kearns-Sayre syndrome: a case series of 35 adults and children.
      • Padhy S.K.
      • Kumar V.
      • Mandal S.
      Pigmentary retinopathy in Kearns-Sayre syndrome.
      • Mullie M.A.
      • Harding A.E.
      • Petty R.K.
      • et al.
      The retinal manifestations of mitochondrial myopathy. A study of 22 cases.
      • Nguyen M.T.B.
      • Micieli J.
      • Margolin E.
      Teaching NeuroImages: Kearns-Sayre syndrome.
      • Ortiz A.
      • Arias J.
      • Cardenas P.
      • et al.
      Macular findings in spectral domain optical coherence tomography and OCT angiography in a patient with Kearns-Sayre syndrome.
      • Kozak I.
      • Oystreck D.T.
      • Abu-Amero K.K.
      • et al.
      New observations regarding the retinopathy of genetically confirmed Kearns-Sayre syndrome.
      • McKechnie N.M.
      • King M.
      • Lee W.R.
      Retinal pathology in the Kearns-Sayre syndrome.
      We believe that most previously described cases match the phenotype classified herein as mitochondrial retinopathy type 3 and that the diagnosis of RP may have been imprecise. The macular involvement seems to follow a similar pattern as that observed in patients with the m.3243G>A variant
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      (mitochondrial retinopathy type 2), but a distinctive feature of type 3 disease is the more widespread retinal involvement, as shown on widefield imaging and full-field electroretinography testing.
      Mitochondrial retinopathy type 1 shows only mild fundus changes and may represent grade 1 changes described previously.
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      Although currently it is unclear if type 1 changes may progress to type 2 or 3 disease, type 1 disease in older patients will be at the mild end of the spectrum of mitochondrial retinopathy.
      Overall, the broad view on retinal changes associated with mitochondrial disease allowed a classification into different subtypes (Table S3, available at www.ophthalmologyretina.org) of mitochondrial retinopathy. This classification may be extended in the future if additional consistently associated phenotypes are identified. For instance, the occult retinopathy in patient 22 and the characteristic retinal phenotype observed in patient 23 indicate that rare types of mitochondrial retinopathy exist; however, additional patients with such phenotypes would need to be identified to confirm whether this is indeed the case. Potential overlaps between phenotypes, and if change from one pattern to another may occur, also remain to be investigated.

       Pathophysiologic Considerations and Differential Diagnosis

      Structural abnormalities identified in this cohort indicate that the primarily affected cell layer is usually the RPE, supporting previous clinical and histologic observations.
      • McKechnie N.M.
      • King M.
      • Lee W.R.
      Retinal pathology in the Kearns-Sayre syndrome.
      • Chang T.S.
      • Johns D.R.
      • Walker D.
      • et al.
      Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes.
      • Runge P.
      • Calver D.
      • Marshall J.
      • Taylor D.
      Histopathology of mitochondrial cytopathy and the Laurence-Moon-Biedl syndrome.
      • Eagle Jr., R.C.
      • Hedges T.R.
      • Yanoff M.
      The atypical pigmentary retinopathy of Kearns-Sayre syndrome. A light and electron microscopic study.
      • Flynn J.T.
      • Bachynski B.N.
      • Rodrigues M.M.
      • et al.
      Hyperglycemic acidotic coma and death in Kearns-Sayre syndrome.
      The most extensive and specific changes were observed on autofluorescence imaging that mainly relies on signals originating in the RPE, such as lipofuscin and melanin.
      • Keilhauer C.N.
      • Delori F.C.
      Near-infrared autofluorescence imaging of the fundus: visualization of ocular melanin.
      Early changes on OCT imaging occur at the interface between photoreceptor cells and the RPE cell layer, where postmortem specimens showed loss of the normal apical microvilli structure of RPE cells in areas with preserved photoreceptors.
      • McKechnie N.M.
      • King M.
      • Lee W.R.
      Retinal pathology in the Kearns-Sayre syndrome.
      • Chang T.S.
      • Johns D.R.
      • Walker D.
      • et al.
      Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes.
      • Runge P.
      • Calver D.
      • Marshall J.
      • Taylor D.
      Histopathology of mitochondrial cytopathy and the Laurence-Moon-Biedl syndrome.
      Patients 22 and 23 were exceptions in this cohort because findings on retinal imaging indicated photoreceptor atrophy, whereas the RPE layer remained apparently unaffected or less affected.
      Histologic studies of mitochondrial retinopathy reported a depletion of melanin granules from RPE cells.
      • McKechnie N.M.
      • King M.
      • Lee W.R.
      Retinal pathology in the Kearns-Sayre syndrome.
      ,
      • Runge P.
      • Calver D.
      • Marshall J.
      • Taylor D.
      Histopathology of mitochondrial cytopathy and the Laurence-Moon-Biedl syndrome.
      • Eagle Jr., R.C.
      • Hedges T.R.
      • Yanoff M.
      The atypical pigmentary retinopathy of Kearns-Sayre syndrome. A light and electron microscopic study.
      • Flynn J.T.
      • Bachynski B.N.
      • Rodrigues M.M.
      • et al.
      Hyperglycemic acidotic coma and death in Kearns-Sayre syndrome.
      Although the mechanism for this finding remains unknown, it may explain the lack of normal NIR-AF signal that is associated with a granular pattern on short-wavelength autofluorescence images. Comparable observations on multimodal imaging have been made in patients with choroideremia, indicating similar structural alterations in RPE cells.
      • Birtel J.
      • Salvetti A.P.
      • Jolly J.K.
      • et al.
      Near-infrared autofluorescence in choroideremia: anatomic and functional correlations.
      ,
      • Mucciolo D.P.
      • Murro V.
      • Sodi A.
      • et al.
      Peculiar clinical findings in young choroideremia patients: a retrospective case review.
      Lack of (physiologic) RPE melanin may lead to decompensation of mechanisms counteracting oxidative stress, hence, eventually leading to cell death.
      • Taubitz T.
      • Fang Y.
      • Biesemeier A.
      • et al.
      Age, lipofuscin and melanin oxidation affect fundus near-infrared autofluorescence.
      Despite pronounced retinal alterations, many patients have only mild symptoms and preserve good visual acuity because of relative foveal sparing, whereas vision problems in dim light conditions frequently are present. Whether the abnormal RPE–photoreceptor interface may explain the reduced rod function (e.g., resulting from an impaired recovery of photopigment) that is typically associated with widespread changes on autofluorescence images (type 3 disease) remains to be investigated using more refined electroretinography test protocols, because a primary effect of mitochondrial dysfunction on rods cannot be excluded based on this dataset. Ganglion cells, which also have a high energy demand, seem to be resilient to degeneration in most patients with mitochondrial retinopathy. It will be interesting to better understand pathophysiologic differences compared with patients with Leber hereditary optic neuropathy and whether some patients with Leber hereditary optic neuropathy may demonstrate mild retinal alterations.
      Neurosensory alterations that may occur independent of RPE changes were observed in 2 patients with features typical for early macular telangiectasia type 2,
      • Charbel Issa P.
      • Gillies M.C.
      • Chew E.Y.
      • et al.
      Macular telangiectasia type 2.
      • Charbel Issa P.
      • Heeren T.F.
      • Kupitz E.H.
      • et al.
      Very early disease manifestations of macular telangiectasia type 2.
      • Charbel Issa P.
      • Berendschot T.T.
      • Staurenghi G.
      • et al.
      Confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia.
      a macular disease with complex pathophysiology that likely involves mitochondrial dysfunction.
      • Zucker C.L.
      • Bernstein P.S.
      • Schalek R.L.
      • et al.
      A connectomics approach to understanding a retinal disease.
      A recent genome-wide analysis identified susceptibility loci that include genes encoding mitochondrial enzymes,
      • Scerri T.S.
      • Quaglieri A.
      • Cai C.
      • et al.
      Genome-wide analyses identify common variants associated with macular telangiectasia type 2.
      and patients with macular telangiectasia type 2 may show low serine levels and increased levels of deoxysphingolipids, both of which have been linked to disrupted mitochondrial function.
      • Gantner M.L.
      • Eade K.
      • Wallace M.
      • et al.
      Serine and lipid metabolism in macular disease and peripheral neuropathy.
      • Alecu I.
      • Tedeschi A.
      • Behler N.
      • et al.
      Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.
      • Zhang T.
      • Gillies M.C.
      • Madigan M.C.
      • et al.
      Disruption of de novo serine synthesis in Muller cells induced mitochondrial dysfunction and aggravated oxidative damage.
      Advanced mitochondrial retinopathy with macular atrophy would preclude the diagnosis of macular telangiectasia type 2, which is always limited to a specific macular area.
      • Heeren T.F.C.
      • Chew E.Y.
      • Clemons T.
      • et al.
      Macular telangiectasia type 2—visual acuity, disease endstage and the MacTel area. MacTel Project report no. 8.
      Hence, screening of a larger number of patients with non-atrophic mitochondrial retinopathy will be necessary to confirm a true association with macular telangiectasia type 2.
      The differential diagnosis may depend on the type of mitochondrial retinopathy and includes age-related macular degeneration, previous central serous chorioretinopathy, or retinal dystrophies such as Stargardt disease. Similar retinal phenotypes also may be observed in patients with Danon disease, rubella retinopathy, and similar postinflammatory conditions
      • Birtel J.
      • Yusuf I.H.
      • Priglinger C.
      • et al.
      Diagnosis of inherited retinal diseases.
      as well as toxic retinopathies such as pentosan polysulfate maculopathy.
      • Yusuf I.H.
      • Charbel Issa P.
      • Lotery A.J.
      Pentosan polysulfate maculopathy-prescribers should be aware.
      A very rare inherited retinal disease associated with mutations in the RCBTB1 gene recently was described with a similar retinal phenotype as type 3 mitochondrial retinopathy.
      • Coppieters F.
      • Ascari G.
      • Dannhausen K.
      • et al.
      Isolated and syndromic retinal dystrophy caused by biallelic mutations in RCBTB1, a gene implicated in ubiquitination.
      Such findings may indicate shared pathophysiologic pathways or involvement of the RCBTB1 gene in mitochondrial function.

       Value of Retinal Phenotyping for Diagnosing Mitochondrial Disease

      The clinical diagnosis of a mitochondrial disease often is challenging, and patients may experience a burdensome diagnostic odyssey.
      • Grier J.
      • Hirano M.
      • Karaa A.
      • et al.
      Diagnostic odyssey of patients with mitochondrial disease: results of a survey.
      Genetic testing, histologic analysis of a muscle biopsy, or both may confirm the suspected diagnosis of a mitochondrial disease. However, results of both diagnostic approaches may remain inconclusive. Furthermore, targeted next-generation sequencing panels for retinal dystrophies currently include often only few mitochondrial genes.
      • Birtel J.
      • Eisenberger T.
      • Gliem M.
      • et al.
      Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
      Detailed, non-invasive retinal phenotyping may support or even confirm the diagnosis of a mitochondrial disease, and hence may be seen as an additional useful biomarker.
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      This includes that retinal examination may be supportive in evaluating the pathogenicity of novel identified mitochondrial variants if a characteristic retinal phenotype is present.
      The retinal phenotype also may be the first indication of a mitochondrial disease, as exemplified in almost half of the patients presented herein. The characteristic retinal phenotype may lead to the diagnosis of mitochondrial disease in patients with otherwise mild systemic disease, as well as in patients with severe multisystem disease of unknown cause. This is of importance because an early and precise diagnosis is crucial, as it may lead to assessment of (treatable) systemic manifestations, lifestyle adjustments, and avoidance of drugs that may impact mitochondrial function. With various treatment options currently under investigation, a precise diagnosis may become even more important.

       Study Limitations

      This study is limited by the relatively small number of included patients, an intrinsic challenge of reporting phenotypic findings in rare diseases. The small sample size also may explain why no obvious association between severity of retinopathy and systemic disease manifestations or genotype was identified, although this also may be explained by various degrees of heteroplasmy and tissue segregation effects. The frequency of retinopathy in patients with mitochondrial disease remains to be determined, because the presence of retinal changes was a prerequisite in this cohort.

      Conclusions

      Mitochondrial retinopathy presents with a spectrum of distinct phenotypes. Specific retinal changes may be a characteristic finding in a variety of mitochondrial diseases and—in some patients—may be crucial for achieving the systemic diagnosis. Mild, asymptomatic mitochondrial retinopathy might be underreported,
      • de Laat P.
      • Smeitink J.A.M.
      • Janssen M.C.H.
      • et al.
      Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
      but severe mitochondrial retinopathy may be associated with considerable vision loss and disease burden. Ophthalmologists may play an important role in the diagnosis of patients with mitochondrial disease.

      Supplementary Data

      References

        • Schapira A.H.
        Mitochondrial diseases.
        Lancet. 2012; 379: 1825-1834
        • Koopman W.J.
        • Willems P.H.
        • Smeitink J.A.
        Monogenic mitochondrial disorders.
        N Engl J Med. 2012; 366: 1132-1141
        • Craven L.
        • Alston C.L.
        • Taylor R.W.
        • Turnbull D.M.
        Recent advances in mitochondrial disease.
        Annu Rev Genomics Hum Genet. 2017; 18: 257-275
        • Wallace D.C.
        • Singh G.
        • Lott M.T.
        • et al.
        Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy.
        Science. 1988; 242: 1427-1430
        • Holt I.J.
        • Harding A.E.
        • Morgan-Hughes J.A.
        Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies.
        Nature. 1988; 331: 717-719
        • Zeviani M.
        • Moraes C.T.
        • DiMauro S.
        • et al.
        Deletions of mitochondrial DNA in Kearns-Sayre syndrome.
        Neurology. 1988; 38: 1339-1346
        • de Laat P.
        • Smeitink J.A.M.
        • Janssen M.C.H.
        • et al.
        Mitochondrial retinal dystrophy associated with the m.3243A>G mutation.
        Ophthalmology. 2013; 120: 2684-2696
        • Massin P.
        • Virally-Monod M.
        • Vialettes B.
        • et al.
        Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. GEDIAM Group.
        Ophthalmology. 1999; 106: 1821-1827
        • Müller P.L.
        • Treis T.
        • Pfau M.
        • et al.
        Progression of retinopathy secondary to maternally inherited diabetes and deafness—evaluation of predicting parameters.
        Am J Ophthalmol. 2020; 213: 134-144
        • Müller P.L.
        • Maloca P.
        • Webster A.
        • et al.
        Structural features associated with the development and progression of RORA secondary to maternally inherited diabetes and deafness.
        Am J Ophthalmol. 2020; 218: 136-147
        • Smith P.R.
        • Bain S.C.
        • Good P.A.
        • et al.
        Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness caused by the mitochondrial DNA 3243 tRNA(Leu) A to G mutation.
        Ophthalmology. 1999; 106: 1101-1108
        • Latkany P.
        • Ciulla T.A.
        • Cacchillo P.F.
        • Malkoff M.D.
        Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation.
        Am J Ophthalmol. 1999; 128: 112-114
        • Michaelides M.
        • Jenkins S.A.
        • Bamiou D.E.
        • et al.
        Macular dystrophy associated with the A3243G mitochondrial DNA mutation. Distinct retinal and associated features, disease variability, and characterization of asymptomatic family members.
        Arch Ophthalmol. 2008; 126: 320-328
        • Rath P.P.
        • Jenkins S.
        • Michaelides M.
        • et al.
        Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence.
        Br J Ophthalmol. 2008; 92: 623-629
        • van den Ouweland J.M.
        • Lemkes H.H.
        • Ruitenbeek W.
        • et al.
        Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.
        Nat Genet. 1992; 1: 368-371
        • Goto Y.
        • Nonaka I.
        • Horai S.
        A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.
        Nature. 1990; 348: 651-653
        • Viscomi C.
        Toward a therapy for mitochondrial disease.
        Biochem Soc Trans. 2016; 44: 1483-1490
        • Birtel J.
        • Gliem M.
        • Holz F.G.
        • Herrmann P.
        [Imaging and molecular genetic diagnostics for the characterization of retinal dystrophies].
        Ophthalmologe. 2018; 115: 1021-1027
        • Dubowitz V.
        • Sewry C.
        • Oldfors A.
        Muscle Biopsy: A Practical Approach.
        4th ed. Saunders Ltd, 2013
        • Pfeffer G.
        • Chinnery P.F.
        Diagnosis and treatment of mitochondrial myopathies.
        Ann Med. 2013; 45: 4-16
        • Moraes C.T.
        • DiMauro S.
        • Zeviani M.
        • et al.
        Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.
        N Engl J Med. 1989; 320: 1293-1299
      1. DiMauro S, Hirano M. MERRF. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. Seattle; 1993.

        • Wallace D.C.
        • Zheng X.X.
        • Lott M.T.
        • et al.
        Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease.
        Cell. 1988; 55: 601-610
        • Nishigaki Y.
        • Tadesse S.
        • Bonilla E.
        • et al.
        A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome.
        Neuromuscul Disord. 2003; 13: 334-340
        • Holt I.J.
        • Harding A.E.
        • Petty R.K.
        • Morgan-Hughes J.A.
        A new mitochondrial disease associated with mitochondrial DNA heteroplasmy.
        Am J Hum Genet. 1990; 46: 428-433
        • Stendel C.
        • Neuhofer C.
        • Floride E.
        • et al.
        Delineating MT-ATP6-associated disease: from isolated neuropathy to early onset neurodegeneration.
        Neurol Genet. 2020; 6: e393
        • Kearns T.P.
        • Sayre G.P.
        Retinitis pigmentosa, external ophthalmoplegia, and complete heart block: unusual syndrome with histologic study in one of two cases.
        AMA Arch Ophthalmol. 1958; 60: 280-289
        • Ascaso F.J.
        • Lopez-Gallardo E.
        • Del Prado E.
        • et al.
        Macular lesion resembling adult-onset vitelliform macular dystrophy in Kearns-Sayre syndrome with multiple mtDNA deletions.
        Clin Exp Ophthalmol. 2010; 38: 812-816
        • Gronlund M.A.
        • Honarvar A.K.
        • Andersson S.
        • et al.
        Ophthalmological findings in children and young adults with genetically verified mitochondrial disease.
        Br J Ophthalmol. 2010; 94: 121-127
        • Khambatta S.
        • Nguyen D.L.
        • Beckman T.J.
        • Wittich C.M.
        Kearns-Sayre syndrome: a case series of 35 adults and children.
        Int J Gen Med. 2014; 7: 325-332
        • Padhy S.K.
        • Kumar V.
        • Mandal S.
        Pigmentary retinopathy in Kearns-Sayre syndrome.
        BMJ Case Rep. 2018; 2018
        • Mullie M.A.
        • Harding A.E.
        • Petty R.K.
        • et al.
        The retinal manifestations of mitochondrial myopathy. A study of 22 cases.
        Arch Ophthalmol. 1985; 103: 1825-1830
        • Nguyen M.T.B.
        • Micieli J.
        • Margolin E.
        Teaching NeuroImages: Kearns-Sayre syndrome.
        Neurology. 2019; 92: e519-e520
        • Ortiz A.
        • Arias J.
        • Cardenas P.
        • et al.
        Macular findings in spectral domain optical coherence tomography and OCT angiography in a patient with Kearns-Sayre syndrome.
        Int J Retina Vitreous. 2017; 3: 24
        • Kozak I.
        • Oystreck D.T.
        • Abu-Amero K.K.
        • et al.
        New observations regarding the retinopathy of genetically confirmed Kearns-Sayre syndrome.
        Retin Cases Brief Rep. 2018; 12: 349-358
        • McKechnie N.M.
        • King M.
        • Lee W.R.
        Retinal pathology in the Kearns-Sayre syndrome.
        Br J Ophthalmol. 1985; 69: 63-75
        • Chang T.S.
        • Johns D.R.
        • Walker D.
        • et al.
        Ocular clinicopathologic study of the mitochondrial encephalomyopathy overlap syndromes.
        Arch Ophthalmol. 1993; 111: 1254-1262
        • Runge P.
        • Calver D.
        • Marshall J.
        • Taylor D.
        Histopathology of mitochondrial cytopathy and the Laurence-Moon-Biedl syndrome.
        Br J Ophthalmol. 1986; 70: 782-796
        • Eagle Jr., R.C.
        • Hedges T.R.
        • Yanoff M.
        The atypical pigmentary retinopathy of Kearns-Sayre syndrome. A light and electron microscopic study.
        Ophthalmology. 1982; 89: 1433-1440
        • Flynn J.T.
        • Bachynski B.N.
        • Rodrigues M.M.
        • et al.
        Hyperglycemic acidotic coma and death in Kearns-Sayre syndrome.
        Trans Am Ophthalmol Soc. 1985; 83: 131-161
        • Keilhauer C.N.
        • Delori F.C.
        Near-infrared autofluorescence imaging of the fundus: visualization of ocular melanin.
        Invest Ophthalmol Vis Sci. 2006; 47: 3556-3564
        • Birtel J.
        • Salvetti A.P.
        • Jolly J.K.
        • et al.
        Near-infrared autofluorescence in choroideremia: anatomic and functional correlations.
        Am J Ophthalmol. 2019; 199: 19-27
        • Mucciolo D.P.
        • Murro V.
        • Sodi A.
        • et al.
        Peculiar clinical findings in young choroideremia patients: a retrospective case review.
        Ophthalmologica. 2019; 242: 195-207
        • Taubitz T.
        • Fang Y.
        • Biesemeier A.
        • et al.
        Age, lipofuscin and melanin oxidation affect fundus near-infrared autofluorescence.
        EBioMedicine. 2019; 48: 592-604
        • Charbel Issa P.
        • Gillies M.C.
        • Chew E.Y.
        • et al.
        Macular telangiectasia type 2.
        Prog Retin Eye Res. 2013; 34: 49-77
        • Charbel Issa P.
        • Heeren T.F.
        • Kupitz E.H.
        • et al.
        Very early disease manifestations of macular telangiectasia type 2.
        Retina. 2016; 36: 524-534
        • Charbel Issa P.
        • Berendschot T.T.
        • Staurenghi G.
        • et al.
        Confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia.
        Invest Ophthalmol Vis Sci. 2008; 49: 1172-1177
        • Zucker C.L.
        • Bernstein P.S.
        • Schalek R.L.
        • et al.
        A connectomics approach to understanding a retinal disease.
        Proc Natl Acad Sci U S A. 2020; 117: 18780-18787
        • Scerri T.S.
        • Quaglieri A.
        • Cai C.
        • et al.
        Genome-wide analyses identify common variants associated with macular telangiectasia type 2.
        Nat Genet. 2017; 49: 559-567
        • Gantner M.L.
        • Eade K.
        • Wallace M.
        • et al.
        Serine and lipid metabolism in macular disease and peripheral neuropathy.
        N Engl J Med. 2019; 381: 1422-1433
        • Alecu I.
        • Tedeschi A.
        • Behler N.
        • et al.
        Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.
        J Lipid Res. 2017; 58: 42-59
        • Zhang T.
        • Gillies M.C.
        • Madigan M.C.
        • et al.
        Disruption of de novo serine synthesis in Muller cells induced mitochondrial dysfunction and aggravated oxidative damage.
        Mol Neurobiol. 2018; 55: 7025-7037
        • Heeren T.F.C.
        • Chew E.Y.
        • Clemons T.
        • et al.
        Macular telangiectasia type 2—visual acuity, disease endstage and the MacTel area. MacTel Project report no. 8.
        Ophthalmology. 2020; 127: 1539-1548
        • Birtel J.
        • Yusuf I.H.
        • Priglinger C.
        • et al.
        Diagnosis of inherited retinal diseases.
        Klin Monbl Augenheilkd. 2021; 238: 249-259
        • Yusuf I.H.
        • Charbel Issa P.
        • Lotery A.J.
        Pentosan polysulfate maculopathy-prescribers should be aware.
        JAMA Ophthalmol. 2020; 138: 900-902
        • Coppieters F.
        • Ascari G.
        • Dannhausen K.
        • et al.
        Isolated and syndromic retinal dystrophy caused by biallelic mutations in RCBTB1, a gene implicated in ubiquitination.
        Am J Hum Genet. 2016; 99: 470-480
        • Grier J.
        • Hirano M.
        • Karaa A.
        • et al.
        Diagnostic odyssey of patients with mitochondrial disease: results of a survey.
        Neurol Genet. 2018; 4e230
        • Birtel J.
        • Eisenberger T.
        • Gliem M.
        • et al.
        Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
        Sci Rep. 2018; 8: 4824