Endothelial Corneal Dystrophy Associated with A3243G Mitochondrial DNA Point Mutation

Abstract

Purpose : The A3243G mitochondrial DNA (mtDNA) point mutation leads to a spectrum of syndromes ranging from MIDD (maternally inherited diabetes and deafness) to MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes). Given the role of mitochondria in the metabolism of corneal endothelial cells in vitro, we tested the hypothesis that corneal endothelial dystrophy is present in patients carrying the A3243G mtDNA point mutation.

Methods : We performed a cross sectional, observational clinical study to identify endothelial corneal abnormalities in patients diagnosed with MIDD or MELAS. Slit-lamp corneal examination and specular microscopy were performed. Patients who were diagnosed based on clinical examination were genetically tested for the mitochondrial point mutation A3243G with pyrosequencing, a sensitive method that detects low rates of heteroplasmy.

Results : A3243G mtDNA point mutation was confirmed in all patients tested using pyrosequencing. Corneal endothelial changes were observed using slit-lamp examination, primarily guttata and beaten-bronze appearance. One patient had a retrocorneal opacity. None of the patients had signs or symptoms of corneal edema. The average corneal thickness was 536 μm. Specular microscopy showed mainly polymegathism along with guttata. Given that mitochondrial DNA mutation load can be variable in each eye due to heteroplasmy, measurements of individual eyes were analyzed separately, n=6. The average endothelial cell area was 402 μm² vs 358 μm² in controls, P = 0.04. The average coefficient of variation of cell size was 39.5% vs 33.3% in controls, P = 0.002. The endothelial cell count was 2519 cells per mm² vs 2796 cells per mm² in controls, P = 0.04. When compared to the average population, the average coefficient of variation was significantly higher than predicted for the patients' age.

Conclusions : In MIDD, endothelial corneal dystrophy is a highly penetrant phenotype. Patients with the A3243G mtDNA point mutation exhibit signs of endothelial corneal dystrophy. This previously uncharacterized corneal dystrophy is mainly associated with polymegathism along with mild guttata, while maintaining appropriate corneal thickness. The prevalence of MIDD in the diabetic population ranges from 0.5% to 2.8%. This observation will help further unravel the role of mitochondria in the pathogenesis of endothelial corneal dystrophies.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.