Mitochondrial maculopathy: geographic atrophy of the macula in the MELAS associated A to G 3243 mitochondrial DNA point mutation☆

Abstract PURPOSE: To report ocular findings in the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) in a family with the A to G 3243 mitochondrial (mt) DNA point mutation. METHODS: Case reports. Ocular findings are described from four family members with the MELAS associated A to G 3243 mt DNA point mutation. RESULTS: Findings included ophthalmoplegia, neurosensory deafness, reduction of photopic and scotopic electroretinogram b-wave amplitudes, and myopathy, as well as macular retinal pigment epithelial atrophy. No family members had nyctalopia, attenuation of retinal blood vessels, or retinal bone spicule pigmentation. CONCLUSION: The finding of slowly progressive macular retinal pigment epithelial atrophy expands the reported phenotypic diversity of patients with A3243G mt DNA mutations. MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a maternally inherited disorder associated with abnormal mitochondria, manifesting in tissues highly dependent on oxidative metabolism. Ocular changes in MELAS syndrome have included reversible scotomata, ophthalmoplegia, pigmentary retinopathy, marked attenuation of the scotopic electroretinogram, myopia, and nuclear cataract. 1 , 2 We highlight some of these ocular manifestations in a family with MELAS syndrome and describe a distinct maculopathy. A 48-year-old woman was referred for evaluation of an asymptomatic maculopathy. Her medical history included mild sensorineural hearing loss; her family history included a mother with congestive heart failure, diabetes mellitus, ophthalmoplegia, and parafoveal atrophy as well as a deceased brother who had an unknown ocular disease, deafness, diabetes, and heart failure. Ocular examination disclosed best-corrected visual acuities of RE: 20/25 and LE: 20/30, normal results from Ishihara color plate testing, significant limitation of gaze in all fields (as much as 70% of expected), and several patches of macular retinal pigment epithelial atrophy bilaterally, which were noted to have become slightly larger compared with fundus photographs taken 8 years earlier. These regions of atrophy correlated with scotomata on Amsler grid and visual field testing Figure 1 , Figure 2 . Download : Download high-res image (393KB) Download : Download full-size image Figure 1 . Retinal pigment epithelial atrophy (arrows) of the right eye in a patient with heteroplasmy for wild-type and A to G 3243 mt DNA mutation. Download : Download high-res image (255KB) Download : Download full-size image Figure 2 . Retinal epithelial atrophy (arrow) of the left eye of the patient in Figure 1 . Her electroretinogram disclosed reduction of photopic and scotopic b-wave amplitudes with normal implicit times. Screening for mitochondrial disorders was suggested but refused by the patient. Several months later, the patient’s sister was diagnosed with MELAS syndrome after presenting with stroke; she was found to have bilateral neurosensory deafness, bicuspid aortic valve, and diabetes mellitus, and a muscle biopsy was positive for ragged red muscle fibers. She was noted to have ophthalmoplegia but did not have ophthalmic complaints. No family members had nyctalopia, waxy pallor of the optic nerve, or attenuation of the retinal vessels. The four tested members of the family, including the sister with MELAS syndrome as well as the original patient and her daughter and son, were found to have the A to G 3243 mt DNA mutation heteroplasmic with wild-type mt DNA. This report amplifies and corroborates some of the ophthalmic features of MELAS syndrome by describing geographic atrophy of the macula in families with the syndrome. The symptoms associated with MELAS syndrome typically appear in childhood and often cause death by the fourth decade. 3 Two mt DNA mutations have been associated with this syndrome and are both located in the tRNAleu (UUR) gene. In 80% of cases, the mutation is an A to G transition at mt-3243, and in 10% of cases, the mutation is an A to G transition at mt-3271. 4 Many maternal relatives of patients with MELAS syndrome exhibit a scarcity of symptoms secondary to the presence of “heteroplasmy,” a mixture of mutant and wild-type intracellular mitochondria. The mutant phenotype is expressed only when an intracellular threshold of mt DNA has been reached. Mitochondrial mutation is uncommon in the general population; however, patients with the mutation were recently shown to have a wider range of phenotypic diversity than previously reported. 5 Nutritional supplementation should be considered, although no large, well-designed trial has studied its efficacy. 1 Atrophic macular pigment epithelial atrophy associated with motility disorders and deafness should precipitate an evaluation for mitochondrial disorders.