Authors: Heidi M. Britton, Colton Wendell, Hillary Vallance, Andre Mattman, Claire Sheldon

Author Disclosure Block: H.M. Britton: None. C. Wendell: None. H. Vallance: None. A. Mattman: None. C. Sheldon: None.

Abstract Body:

Purpose: Ocular manifestations of mitochondrial disease are often under recognized. This study aims to i) estimate the prevalence mitochondrial disease, including LHON, MELAS, MERRF, NARP, and CPEO + KSS in British Columbia, Canada, ii) provide an expanded description of the clinical presentation of these diseases. Together these data will provide an unmatched picture of the clinical burden of mitochondrial disease and ultimately inform future studies.

Study Design: Retrospective chart review involving three tertiary institutions in Vancouver, British Columbia.

Methods: The Biochemical Genetics Lab at BCCH/Women's Hospital and the Adult Metabolic Disease Clinic at Vancouver General Hospital coordinate and document all clinical genetic analyses in British Columbia. Charts of subjects diagnosed with mtDNA point mutations between January 1^st 1996 - June 18^th 2019 (LHON, MELAS, MERFF, NARP) and for CPEO (Chronic Progressive External Ophthalmoplegia) January 1^st 2016 - June 18^th 2019 were reviewed. Phenotypic and genotypic information were collected using a secure, custom-make REDCap database.

Results: For subjects with any mtDNA point mutations, the overall prevalence was 3.60 per 100,000 (95% CI 3.04 to 4.27 per 100,000). Of these, we identified 49 subjects with genetically confirmed LHON yielding a minimum point prevalence (MPP) of 1.32 per 100,000 (95% CI 1.00-1.74 per 100,000). Overall, subjects ranged in age from 7.5-89.4yrs, were 51.0% male, with heteroplasmy found in 25% of subjects. Those with confirmed symptomatic LHON were 67% male, below the previously-reported 75% preponderance. The majority (n=47/49) were LHON primary mutations (n=29, m.11778G>A; n=16, m.14484T>C; n= 2, m.3460G>A). Genetically-confirmed MELAS (m.A3243G) was identified in 69 subjects, with a MPP = 1.86 per 100,000 (95% CI 1.47-2.35 per 100,000); MERRF in 12 subjects, MPP = 0.32 per 100,000 (95% CI 0.18-0.56 per 100,000); NARP in 4 subjects, MPP = 0.11 per 100,000 (95% CI 0.04-0.28 per 100,000). For subjects with mtDNA depletions, CPEO was found in 30 subjects, MPP = 0.74 per 100,000 (95% CI 0.52-1.06 per 100,000) and Kearns-Sayre syndrome in 4 subjects, MPP 0.10 per 100,000 (95% CI 0.04-0.25 per 100,000). Statistics on mutation /deletion location, heteroplasmy, gender, and ages at diagnosis are further presented.

Conclusions: In British Columbia, approximately 1 in 25,000 people possess mitochondrial DNA point mutations, a prevalence greater than all ocular cancers combined. However, ocular manifestations of these diseases are under-recognized. Although descriptive, this study provides clarity into the epidemiology of these varied genotypes and their diverse ocular phenotypes.