Leber Hereditary Optic Neuropathy Presenting in a 75-Year-Old Man

Abstract

We recently examined a white man who developed Leber hereditary optic neuropathy (LHON) at age 75. The patient was referred to us with bilateral visual failure of presumed psychogenic nature. He had presented to his local eye unit 6 months earlier with visual blurring initially in his left eye. Within 6 weeks visual acuity had dropped to counting fingers in the right eye and hand movements in the left eye. No ophthalmoscopic abnormalities were noted, findings from his neurological examination were normal except for well-controlled hypertension, and his medical history was unremarkable. He was a lifelong non-smoker, and for several years he had been drinking 48 to 96 fluid ounces of beer per day. Brain MRI was normal, and extensive investigation at the time had failed to identify an underlying cause for his visual loss. When we first examined him, visual acuities were unchanged; there was no afferent pupillary defect, but bilateral optic disc pallor and large central scotomas were evident. On closer questioning, he gave a clear family history of five other affected family members having experienced poor vision in their 20s to 40s, and some of them were registered as blind with social services. This prompted mitochondrial genetic analysis, which identified a G3460A primary LHON mutation. He was homoplasmic for the mutation, belonged to the mtDNA haplogroup H, and genotyping revealed the DXS8090(160)-DXS1068(256) X-chromosomal haplotype at the Xp21.1 locus. This man is one of the oldest reported individuals to have LHON. More than 95% of carriers become affected by age 50 (1-3). What are the possible precipitants of visual loss in these late cases? The predominance of affected males has been linked to an X-linked nuclear modifier gene and we have recently identified a high-risk haplotype at Xp21.1, DXS8090(166)-DXS1068(268), which increases the risk of visual failure 35-fold for the G11778A and T14484C LHON mutations but not for G3460A (4). Our patient did not harbor this visual loss susceptibility haplotype, but he did have a high alcohol intake. Although it is tempting to link this in some way, there are conflicting data regarding the strength of the association between excessive alcohol consumption and a higher risk of developing visual symptoms in LHON (5,6). Furthermore, there is no suggestion that he had been exposed to other exogenous toxins that have previously been reported to precipitate visual loss among LHON carriers (2,3). The secondary factors influencing disease expression in LHON still need to be clarified and our patient highlights the difficulties of genetic counseling in this condition. Patrick Yu-Wai-Man, MRCOphth Department of Ophthalmology, Royal Victoria Infirmary, Mitochondrial Research Group, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom, [email protected] David E. Bateman, FRCP Department of Neurology, Cumberland Infirmary, Carlisle, United Kingdom Gavin Hudson, PhD Mitochondrial Research Group, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom Philip G. Griffiths, FRCOphth Department of Ophthalmology, Royal Victoria Infirmary, Mitochondrial Research Group, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom Patrick F Chinnery, FRCP Mitochondrial Research Group, The Medical School, Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom