Leber's hereditary optic neuropathy: Report of a simple case associated with a rare variant mutation.

Sir,

We present a case of a young male with a homoplasmic m. 4924G>A (P.S152N) rare variant mutation, hitherto not described in Leber's hereditary optic neuropathy (LHON), alongside the commonly detected homoplasmic M.11778 G>A (P.R340H, ND4) mutation.

A 17-year-old Saudi man had progressive, painless, central visual loss in his right eye. In the beginning, he noticed a “dark patch obscuring the central vision.” The area of darkness grew gradually over 6 months until he could barely perceive hand movements. When he presented to us, he had already been losing vision similarly in his left eye for about 2 months.

His pupils were equal in size. Direct and consensual light reflex was present on both sides. Relative afferent pupillary defect was present on the right side. Extraocular movements were normal in all directions of gaze. His visual acuity was 20/400 in the left eye and perception of hand movements at 30 cm in the right eye. Intraocular pressure was 17 mmHg in the right eye and 16 mmHg in the left eye. Color vision tested with the Ishihara chart was impaired in both eyes. There was a central scotoma in the left eye [Figure 1]. Fundus examination showed optic atrophy on the right side and optic disc swelling on the left side [Figure 2]. The rest of his systemic and neurological examination was normal.

Figure 1

Full-field 120-point screen on Carl Zeiss Meditech showing a central scotoma

Figure 2

Fundus photograph showing optic atrophy on the right side and optic disc swelling on the left side

His complete blood count, renal and liver profile, Vitamin B12, and thyroid functions were normal. Tests for antinuclear antibodies, anti-double-stranded DNA, anti-neutrophil cytoplasmic antibody, and HIV were negative. Cerebrospinal fluid (CSF) opening pressure was 21 cm of water, CSF protein was 35.6 mg/dl, glucose was 60 mg/dl, and there was one white cell. Neuromyelitis optica antibodies (aquaporin-4 IgG) were negative. Magnetic resonance imaging (MRI) brain and orbit were normal [Figure 3]. Visual-evoked potential (VEP) showed a low amplitude with normal latency [Figure 4].

Figure 3

Magnetic resonance imaging of orbits showing normal optic nerves

Figure 4

Pattern-evoked visual potentials showing visual-evoked potential amplitude of 2.18 μv on the right and 1.07 μv on the left. P100 latency is 95.7 ms on the right side and 93.4 ms on the left side

Comprehensive mitochondrial DNA (mtDNA) analysis was done at the Medical Genetics Laboratories, Baylor College of Medicine, Houston, Texas, by massively parallel sequencing (MitoNGS). There were homoplasmic M.11778 G>A (P.R340H, ND4) mutation and a homoplasmic m. 4924G>A (P.S152N) rare variant mutation.

In 1871, Theodor Leber described hereditary optic neuropathy, which came to bear his name. In 1988, Wallace et al. determined that it was transmitted by maternal mtDNA mutation.[1] Three mutations (11778/ND4, 14484/ND6, and 3460/ND1) account for about 95% of the cases.[12]

In India, m. 3460G>A, m. 11778G>A, and m. 14484T>C are the most common mutations. Among 127 patients from three renowned centers, 8 LHON patients had the m. 14484T>C mutation accounting for 4.2% of the cases compared with 10% seen in European and Chinese patients.[3] In another Indian study, G3460A and G11778A in the mitochondrial genes MTND1 and MTND4 were found in one family each.[4]

Patients with LHON may rarely have dystonia, spastic paralysis, or cardiac conduction defects.[15] Our patient did not have these features. Oral and genital ulcers and features of uveitis occur in Behcet disease. He neither had the above-mentioned symptoms nor had joint pains, skin rash, or other clinical or laboratory features of systemic lupus erythematosus. He did not use tobacco and alcohol, which can lead to tobacco–alcohol amblyopia syndrome. Although neuromyelitis optica can present initially with bilateral visual loss, the absence of aquaporin-4 IgG antibodies in our patient's CSF makes it unlikely.

As in most others, CSF analysis in our patient was normal, but there are occasional LHON patients who may have oligoclonal bands. This is important because some women with LHON may present with a multiple sclerosis-like illness, especially when they harbor the 11778 mutation.[67]

We found optic nerve atrophy on one side and disc edema on the contralateral side, which raised the possibility of Foster–Kennedy syndrome. However, MRI of the orbits and brain was normal in our patient. This ruled out optic nerve compression from tumors, which can have a clinical presentation similar to LHON.

In a study of evoked potentials conducted in Serbia and Italy, most patients suffering from LHON confirmed by genetic studies had prolonged P100 latency and most unaffected members had a low-amplitude VEP with normal latency.[8] This suggests that low-amplitude VEP probably occurs early and it is followed by prolonged distal latency with disease progression. Interestingly, in this study, all affected individuals had abnormal brain stem auditory-evoked responses, indicative of peripheral and central auditory pathway involvement. Our patient came to us relatively early and this maybe the reason that he had low-amplitude VEP with a normal P100 latency.

Idebenone has been evaluated in a randomized control trial and has been found useful on post hoc analysis in patients with “discordant” visual acuity.[9]

Gene therapy with RPE65 carried on a recombinant adenovirus produces a partial, unpredictable, and short-lasting improvement.[10] Perhaps, research in this area will open up other avenues for treating this disabling malady.

The presence of homoplasmic m. 4924G>A (P.S152N) rare variant mutation in our patient was a unique finding. On review of the Online Mendelian Inheritance database in Man,[11] this mutation has not been mentioned among the 17 mtDNA missense mutations thought to cause LHON. It may have a secondary role[312] in disease manifestation, but if more reports of this mutation appear, it may be added to the expanding list of causative mtDNA point mutations in LHON.

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Conflicts of interest

There are no conflicts of interest.