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Leber hereditary optic neuropathy harboring a rare m.12811 T>C mitochondrial DNA mutation

Published:January 22, 2021DOI:https://doi.org/10.1016/j.jcjo.2020.12.022
      Leber hereditary optic neuropathy (LHON) is the first hereditary disease recognized to be caused by mitochondrial DNA (mtDNA) mutation.
      • Leber T.
      Uber hereditare und congenital-angelegte Sehnervenleiden [About hereditary and congenital optic nerve disorders].
      It is the most commonly inherited optic neuropathy resulting in bilateral visual impairment.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      More than 90% of LHON cases harbor 1 of the 3 major mtDNA mutations m.11778G>A, m.3460G>A, and m.14484T>C; however, other variants have been previously identified.
      • Yu-Wai-Man O
      • Votruba M
      • Moore AT
      • Chinnery PF.
      Treatment strategies for inherited optic neuropathies: past, present and future.
      • Kisilevsky E
      • Freund P
      • Margolin E.
      Mitochondrial disorders and the eye.
      • Huoponen K
      • Lamminen T
      • Juvonen V
      • Aula P
      • Nikoskelainen E
      • Savontaus ML.
      The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy.
      We report on a case of LHON with an m.12811T>C mtDNA mutation, a rare variant mutation that has only been previously reported as a secondary mutation of LHON.
      • Huoponen K
      • Lamminen T
      • Juvonen V
      • Aula P
      • Nikoskelainen E
      • Savontaus ML.
      The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy.
      ,
      • Dai Y
      • Wang C
      • Nie Z
      • et al.
      Mutation analysis of Leber's hereditary optic neuropathy using a multi-gene panel.
      Nevertheless, its phenotypic features have not been well described in previous literature. To our knowledge, this is the first reported case of the m.12811T>C mutation in which its clinical course and features were investigated.
      A 53-year-old male presented with a 2-month onset of bilateral, progressive, painless blurred vision. Ocular symptoms first appeared in the right eye followed by the left within 2 weeks. The patient had a history of hypertension and no family history of ocular disease. He was a heavy smoker (40 cigarettes daily over 25 years), a heavy drinker (liquor >750 mL/d), and had a poor diet (a bowl of instant noodles daily) before the onset of his symptoms.
      Initial best-corrected visual acuity was 20/100 on the right and 20/200 on the left eye with normal intraocular pressure. Slit-lamp examination of the anterior segment was unremarkable. Pupillary light reflex remained prompt and relative afferent pupillary defect (RAPD) was not observed. Fundoscopy revealed no optic disc hyperemia or swelling. Peripapillary telangiectatic blood vessels were not observed.
      Further examination showed decreased critical flicker frequency values of 13.2 Hz on the right and 13.8 Hz on the left eye. Optic coherence tomography (OCT) revealed no foveal or disc abnormalities. Central scotoma was observed bilaterally on the Humphrey Field Analyzer (HFA) 30-2 visual field test (Fig. 1). Flash electroretinography was normal. Gadolinium-enhanced orbital magnetic resonance imaging (MRI) did not reveal any inflammation around the optic nerve.
      Fig 1
      Fig. 1Visual field test results at initial visit. Humphrey Field Analyzer 30-2 visual field test result shown in grey scale and pattern deviation probability map. Central scotoma was observed in both eyes with overall decreased mean deviation values. MD, mean deviation, PSD, pattern standard deviation.
      Laboratory data did not reveal any vitamin deficiency. Mitochondrial genetic analysis identified an m.12811T>C (p.Tyr159His) mutation of the mtDNA, a rare variant mutation in LHON.
      • Yu-Wai-Man O
      • Votruba M
      • Moore AT
      • Chinnery PF.
      Treatment strategies for inherited optic neuropathies: past, present and future.
      • Kisilevsky E
      • Freund P
      • Margolin E.
      Mitochondrial disorders and the eye.
      • Huoponen K
      • Lamminen T
      • Juvonen V
      • Aula P
      • Nikoskelainen E
      • Savontaus ML.
      The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy.
      The percent heteroplasmy of the patient's mtDNA was below the limit of quantification (i.e., <20% for our laboratory).
      With the improvement of dietary habits as well as the cessation of smoking and alcohol consumption, the patient's best-corrected visual acuity recovered to 20/20 bilaterally within 3 months from onset. Critical flicker frequency values also improved to 28.7 Hz on the right and 28.2 Hz on the left eye after 6 months. Follow-up OCT map image after 4 months revealed thinning of the retinal nerve fiber layer (RNFL) in the temporal quadrant of the optic disc, namely the papillomacular bundle (PMB) (Fig. 2). RNFL thinning was also observed in the macula regions (Fig. 2). Follow-up visual field test showed bilateral recovery of retinal sensitivities on HFA 30-2; however, some decrease in foveal sensitivity remained on HFA 10-2 after 5 months.
      Fig 2
      Fig. 2Optic coherence tomography (Swept-source OCT DRI OCT Triton, Topcon Corporation, Tokyo, Japan) images of the optic disc and macula at 4 months follow-up. Optic disc thickness map (A) revealed bilateral thinning of the retinal nerve fiber layer in the temporal quadrant of the optic disc (papillomacular bundle). Macular thickness map (B) also showed retinal nerve fiber layer thinning in the macula region bilaterally. RNFL, retinal nerve fiber layer; ILM, inner limiting membrane; IPL, internal plexiform layer; INL, inner nuclear layer.
      LHON occurs as a result of selective degeneration of the retinal ganglion cells, especially in within the PMB, which are highly susceptible to mitochondrial dysfunction due to their high metabolic activities.
      • Leber T.
      Uber hereditare und congenital-angelegte Sehnervenleiden [About hereditary and congenital optic nerve disorders].
      In the acute phase, RNFL thickening, associated with impaired axonal transport, is observed starting in the temporal quadrant.
      • Kisilevsky E
      • Freund P
      • Margolin E.
      Mitochondrial disorders and the eye.
      Vision loss and cecocentral scotoma develops as the PMB becomes damaged due to impaired mitochondria function.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      In the chronic phase, optic nerve pallor and temporal PMB and macular thinning can manifest after 6 to 36 weeks.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      Light reflexes usually remain prompt and RAPD is usually negative, as seen in our patient.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      ,
      • Kisilevsky E
      • Freund P
      • Margolin E.
      Mitochondrial disorders and the eye.
      Visual impairment is usually permanent; however, spontaneous recovery may occur within the first year,
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      as observed in the present case.
      Typical features of LHON in the acute phase was absent in the present case, suggesting that the patient was under transition from the acute to chronic phase of the disease, the m.12811T>C mutation had a mild phenotype, or both. Since the m.12811T>C mutation does not alter the polarity of the resulting peptide and also preserves the evolutionary conserved amino acids, it may be possible to express a milder phenotype.
      • Huoponen K
      • Lamminen T
      • Juvonen V
      • Aula P
      • Nikoskelainen E
      • Savontaus ML.
      The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy.
      However, because not much has been known on the m.12811T>C mutation so far, it may be controversial to make any assumption about its clinical course.
      Patients with LHON express great variety in phenotype severity due to the unique nature of mitochondrial genetics.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      Although all mitochondria in a cell contain identical copies of the mtDNA, a mutation may emerge in one of the copies, resulting in the coexistence of both wildtype and mutant mtDNA; hence creating heteroplasmy among the mitochondria in a cell.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      If the portion of the mutant mtDNA exceeds a critical threshold, the mutant phenotype is expressed. These heteroplasmic cells then divide into daughter cells by random segregation, passing on the mutant mtDNA. Because the degree of heteroplasmy differs among those with LHON, a wide variability of phenotypes can emerge as a result.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      That being said, although heteroplasmy has been associated with rates of conversion to the mutant phenotype, there have also been previous report of asymptomatic homoplasmic mutant carriers of LHON.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      Therefore, genetic mutation of the mtDNA alone may not be sufficient to express the mutant phenotype of the disease. As with the present patient, environmental risk factors including smoking, nutrition deficiency, and alcohol consumption may interfere with mitochondrial metabolism, triggering or exacerbating the expression of the mutant phenotype.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      Consequently in the present case, the patient's symptoms improved significantly with improved lifestyle, which is consistent with characteristics of type II LHON previously described by Carelli et al.
      • Carelli V
      • d'Adamo P
      • Valentino ML
      • et al.
      Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion.
      These findings suggest that environmental factors may play an important role in the expression or suppression of m.12811T>C mutation.
      Diagnosis of LHON solely from ocular exams may be difficult as the fundus appears normal in 20% to 40% of cases.
      • Meyerson C
      • Stavern GV
      • McClelland C.
      Leber hereditary optic neuropathy: current perspectives.
      Based on our findings, differential diagnosis of nutritional optic neuropathy, optic neuritis, and occult macular dystrophy were considered. Initial OCT revealed no macular abnormality with retinal thinning only observed in the inner retinal layers in chronic phase (Fig. 2). Combined with the subacute recovery of visual function, occult macular dystrophy was unlikely for the present case. Although our clinical course mimicked that of nutritional optic neuropathy, lab data was unlikely for vitamin deficiency. The absence of inflammation on MRI and negative RAPD despite the poor visual function, combined with the characteristic OCT findings also supported the diagnosis for LHON, which was confirmed by genetic analysis.
      In the present discussion, we reported a rare variant m.12811T>C mutation of LHON. The case presented with a mild phenotype with good visual function recovery. Environmental risk factors may play an important role in the phenotype expression of the 12811T>C mutation in LHON.

      Footnotes and Disclosure:

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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