Year: 2016
Type: article
Abstract: To the Editor: Leber's hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy characterized by subacute sequential visual loss in both eyes.1 Mitochondrial deoxyribonucleic acid (mtDNA) point mutations at the 11778, 14484, or 3460 locus are present in 95% of individuals with the condition.2 Ophthalmoscopic findings include retinal microangiopathy, optic nerve edema, and optic atrophy. The majority of individuals with the condition are male and aged 15 to 35, but a growing body of evidence shows that the initial clinical manifestation can occur as late as the eighth decade of life.3, 4 These older adults with LHON may be in the unique position to help identify carriers of the disease in subsequent generations and to spare affected relatives from the extensive and invasive clinical examination that is often performed before considering a rare genetic disease, as presented in these case reports. A 79-year-old Caucasian man presented with a 4-week history of vision loss. Medical history was significant for gout, hypertension, high prostate-specific antigen level, and bilateral cataract extraction 5 months before with postoperative visual acuity of 20/30 in the right eye (OD) and 20/25 in the left eye (OS). He had no other neurological deficits, reported rare alcohol consumption, and had never smoked. Initially, he had noticed blurring of his right central vision, followed by blurred vision in the left eye and bilateral loss of color vision. This prompted an extensive examination including magnetic resonance imaging, lumbar puncture, and an array of laboratory tests, which failed to reveal the etiology of his loss of vision. When he was first seen in our department, his best corrected visual acuity had deteriorated to 20/400 in both eyes. Fundus examination showed moderate cupping and pallor of the right optic nerve and mild disc edema in the left eye. No vascular abnormalities were observed. Genetic testing revealed a mtDNA mutation at locus 11778, diagnostic for LHON. He was counseled on the heritable nature of his disease and encouraged to spread the word among his extensive, close-knit family. Six months later, his 23-year-old maternal grandnephew experienced sudden painless vision loss in his left eye after an episode of binge drinking. He had heard about his great-uncle's vision problem and presented promptly for examination. Visual acuity was 20/30 OD and counting fingers OS with a left afferent pupillary defect. Loss of color vision, visual field defects (Figure 1A), and optic disc edema with peripapillary telangiectasias were found in both eyes. There was segmental pallor of the left optic nerve (Figure 1B). Over the next month, vision loss progressed to light perception only in both eyes, with bilateral optic atrophy and nerve pallor. As these cases show, LHON is a devastating disease. Visual recovery is rare.5 The cases described above, one of the oldest individuals reported to manifest LHON followed by a classic manifestation in a young relative, also exemplify the inability to predict whether and when an individual carrying the LHON mutation may develop loss of vision. Approximately 0.1% of the Caucasian population carries one of the three main mitochondrial point mutations, but the prevalence of clinical disease is only one in 50,000.6 Environmental factors, especially tobacco and heavy alcohol consumption, are considered potential triggers of vision loss,7 although this observation has been challenged in a large case–control study.8 Others have correlated the quantity of mutant mtDNA transmitted by the mother to her offspring with the risk of clinical manifestation, yet most familial LHON mtDNA mutations are homoplastic. Heteroplasmy (the presence of mutant and normal mtDNA in an individual) has been detected in only 15% of LHON families, probably indicating a recent mutation.9 Secondary mtDNA mutations, such as the European haplogroup J, may act as a genetic background to promote LHON manifestation, but their role is also uncertain.10 Given the variability associated with the clinical manifestation of LHON, finding evidence of the 11778 mutation in the older man gave his young relative the advantage of a rapid diagnosis, avoiding unnecessary diagnostic procedures and providing him a small window of opportunity to prepare for his visual disability. These cases also show that genetic testing for LHON may be a valid consideration, even in a septuagenarian, before dismissing sequential loss of vision as a consequence of ischemia or glaucoma or embarking on an exhaustive search for a neoplastic, infectious, or inflammatory cause. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Funded by National Institutes of Health grant 5K08EY016357 (NEI). Author Contributions: Malouf, Mathews: acquisition of subjects and data, manuscript preparation. Levin: acquisition of subjects and data, review and editing of manuscript. Sponsor's Role: None.
DOI: 10.1111/jgs.13899
Institution: University of Maryland, Baltimore
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G2076111021, G9000199208
OpenAlex ID: W2301493519