Genetic Survey of the Primary Mitochondrial Mutations along with Clinical Correlation in suspected Leber Hereditary Optic Neuropathy (LHON) patients from an Indian Cohort

Abstract

Purpose : Reports from various populations show that ninety five percent of individuals with LHON harbor any one of the three point mutations (primary mutations) in mtDNA: m.3460G>A (MT-ND1), m.11778G>A (MT-ND4) or m.14484T>C (MT-ND6). Molecular genetic diagnosis is confirmatory for LHON. The purpose of this study is to screen for the primary mitochondrial mutations in suspected LHON cases and to clinically correlate the mutation positive cases.

Methods : One hundred and eighty-five patients suspected with LHON were recruited in the study from the Neuro Opthalmology clinic, Medical Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India. Detailed ophthalmic examination of the anterior and posterior segments by snellens chart, slit lamp examination, biomicroscopy and indirect ophthalmoscopy were done. Visual fields were analyzed with visual field analyzer. Molecular genetic screening was done by PCR-restriction digestion (PCR-RE) and direct sequencing in ABI 3500 Genetic Analyser.

Results : All the cases were screened by Sanger sequencing and PCR-RE to know the plasmy status of the mutation. Primary mutation m. G11778A, was detected in forty-eight cases and 33 and 15 cases were homoplasmic and heteroplasmic, respectively. m. T14484C was identified in eight cases (7 – homoplasmy and 1- heteroplasmy) and m. G3460A was not detected in this case series. Among the patients who carried m. G11778A mutation four were females 8 % (4/48) and 44 were males 92% (44/48). All the eight m.T14484C mutation positive cases were males. The mean age of onset is +20.42 in primary mutation positive patients. There was no significant difference between the age of onset and the plasmy status. The most common clinical presentation in these patients was bilateral loss of vision along with scotomas in the visual field (central and cecocentral) and optic disc atrophy. The phenotypic variability between the homoplasmic and heteroplasmic individuals and their response to COQ and Idebenone is being clinically correlated.

Conclusions : This study on Indian cohort shows the frequency of the primary mutations to be 30% (56/185) which is much lower compared to other ethnic groups. Screening the entire mitochondrial genome would probably identify novel and/or known less common mtDNA mutations causing LHON in this population.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.