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Leber hereditary optic neuropathy: 41-year interval between fellow eye involvement

Published:September 13, 2019DOI:https://doi.org/10.1016/j.jcjo.2019.07.008
      Leber hereditary optic neuropathy (LHON) is an inherited mitochondrial disorder that typically presents in young men with painless, subacute, bilateral (simultaneous or sequential) central vision loss.
      • Kermode A.G.
      • Moseley I.F.
      • Kendall B.E.
      • Miller D.H.
      • MacManus D.G.
      • McDonald W.I.
      Magnetic resonance imaging in Leber's optic neuropathy.
      • Prado R.C.
      • Moura F.C.
      Leber hereditary optic neuropathy with interval of visual loss greater than 12 months.
      Most cases have nonsimultaneous involvement of the contralateral eye in an interval less than 1 year.
      • Prado R.C.
      • Moura F.C.
      Leber hereditary optic neuropathy with interval of visual loss greater than 12 months.
      • Dimitriadis K.
      • Leonhardt M.
      • Yu-Wai-Man P.
      • et al.
      Leber's hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients.
      However, there are reports of loss of vision in the fellow eye over 1 year later. To date, the longest interval between affected eyes is 18 years.
      • Ohden K.L.
      • Tang P.H.
      • Lilley C.C.
      • Lee M.S.
      Atypical Leber hereditary optic neuropathy: 18 year interval between eyes.
      We present a patient with an interval of 41 years. To our knowledge, this is the longest interval between fellow eye involvement in LHON to be reported in the English-language ophthalmic literature.
      A 52-year-old Indian male presented with subacute, progressive, unilateral loss of vision 2 years before presentation. At the age of 9 years in India he presented with subacute loss of vision in his right eye (OD) and was diagnosed with “inadequate intraocular circulation.” His vision remained stable OD for the next 41 years. His medical history was significant for gastroesophageal reflux disease and sinus surgery in the remote past. He denied any family history of visual loss. Medications included calcium carbonate 600 mg daily, vitamin D3 400 IU daily, and omeprazole 20 mg daily. He was married and denied recent or past tobacco, alcohol, or substance use.
      His visual acuity measured 20/20 in both eyes (OU). Tonometry by applanation yielded 18 mm Hg OD and 20 mm Hg in the left eye (OS). His pupils were 4 mm in the dark and 3 mm in the light bilaterally with no relative afferent pupillary defect. His extraocular movements were intact OU. His color plates were 8/14 OD and 6/14 OS. Slit-lamp examination revealed 1+ nuclear sclerotic cataracts OU. Fundus examination showed rim pallor and a cup-to-disk ratio of 0.65 OU (Fig. 1A).
      Fig 1
      Fig. 1(A) Fundus photographs. Note rim pallor and cup-to-disk ratio of 0.65 OU. (B) Humphrey visual field. Note central scotoma with breakout to the temporal periphery and inferior arcuate defect in right eye and a temporal hemianopic field defect in the left eye. While the patient's visual acuity was 20/20, the foveal threshold registered 0 in both eyes. (C) Optical coherence tomography. Note optic nerve thinning with a retinal nerve fibre layer of 46 on the right and 54 on the left with papillomacular bundle dropout superimposed on glaucomatous cupping. Line scan also suggests thinning.
      Fig 1
      Fig. 1(A) Fundus photographs. Note rim pallor and cup-to-disk ratio of 0.65 OU. (B) Humphrey visual field. Note central scotoma with breakout to the temporal periphery and inferior arcuate defect in right eye and a temporal hemianopic field defect in the left eye. While the patient's visual acuity was 20/20, the foveal threshold registered 0 in both eyes. (C) Optical coherence tomography. Note optic nerve thinning with a retinal nerve fibre layer of 46 on the right and 54 on the left with papillomacular bundle dropout superimposed on glaucomatous cupping. Line scan also suggests thinning.
      Humphrey visual field showed a central scotoma with breakout to the temporal periphery and inferior arcuate defect with a mean deviation of −12.01 decibels (dB) OD and a mild central scotoma with a temporal hemianopic field defect with a mean deviation of −2.53 dB OS (Fig. 1B).
      Optical coherence tomography yielded optic nerve thinning with a retinal nerve fibre layer of 46 μm OD and 54 μm OS with papillomacular bundle dropout superimposed on glaucomatous cupping, but the rim was pale OU (Fig. 1C).
      Laboratory studies for vitamin B12, methylmalonic acid, intrinsic factor antibody, QuantiFERON, rapid plasma reagin, antineutrophil cytoplasmic antibodies, antinuclear antibody, fluorescent treponemal antibody absorption, complete blood count, angiotensin-converting enzyme, and Bartonella henselae IgG and IgM, myelin oligodendrocyte protein, and neuromyelitis optica were negative. Magnetic resonance imaging of the brain and orbit with and without contrast showed only optic nerve and chiasm atrophy (Fig. 2).
      Fig 2
      Fig. 2Magnetic resonance imaging demonstrating flattening of the optic chiasm.
      As testing for infectious, inflammatory, and demyelinating causes was negative, genetic investigation was offered to the patient. OPA1 was favoured over LHON as the best diagnosis as this case did not align with the typical history of LHON, which classically occurs subacutely bilaterally, simultaneously, or sequentially with involvement of the fellow eye within months. However, the patient elected to undergo genetic testing, which returned positive with m.11778G>A Arg340His missense mitochondrial mutation, thus confirming the diagnosis of the 11778 variant of LHON.
      In LHON, the most common mutations are 11778, 14484, and 3460, all of which disrupt the function of complex 1 of the electron transport chain in cellular respiration. These 3 mutations account for 90%–95% of LHON cases.
      • Ohden K.L.
      • Tang P.H.
      • Lilley C.C.
      • Lee M.S.
      Atypical Leber hereditary optic neuropathy: 18 year interval between eyes.
      • Yu-Wai-Man P.
      • Chinnery P.F.
      • et al.
      Leber hereditary optic neuropathy. 2000 Oct 26 [Updated 2016 Jun 23].
      The most common mutation is 11778.
      • Yu-Wai-Man P.
      • Chinnery P.F.
      • et al.
      Leber hereditary optic neuropathy. 2000 Oct 26 [Updated 2016 Jun 23].
      While the peak age of onset for all cases is second and third decades of life, the average age of onset in the 11778 mutation is 22–24 years.
      • Yu-Wai-Man P.
      • Chinnery P.F.
      • et al.
      Leber hereditary optic neuropathy. 2000 Oct 26 [Updated 2016 Jun 23].
      However, both the patient with the 18-year interval (Ohden's patient) and our patient had onset before age 10 years (age 5 and 9 years, respectively). This suggests a possible relationship between increased interval and onset of first eye involvement at a young age. It is worth noting that the age of second eye involvement for Ohden's patient was 23 years, whereas our patient exhibited fellow eye involvement at age 50 years.
      LHON typically has a sequential course with development of symptoms in the fellow eye less than 1 year after onset. However, extended intervals have been seen with 2 patients with childhood onset and subsequent diagnosis with the 11778 variant. Despite the majority of patients having bilateral involvement within a year, clinicians should be aware that the first and second eye involvement can be separated by years and that the diagnosis of LHON should be considered in any unexplained bilateral simultaneous or sequential optic neuropathy with central visual loss. To our knowledge, this is the longest duration of fellow eye involvement to be reported in LHON in the English-language ophthalmic literature.

      Footnotes and Disclosure:

      The patient consented to the publishing of this information and signed a form verifying her consent.

      Appendix. Supplementary materials

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