Investigating the presence of Fuchs endothelial corneal dystrophy in patients with myotonic dystrophy, type 1

Abstract

Purpose : RNA toxicity due to CTG trinucleotide repeat (TNR) expansion in non-coding DNA in the transcription factor 4 (TCF4) and the dystrophia myotonica protein kinase (DMPK) genes has been described in the pathogenesis of Fuchs endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. Several case series have reported conflicting results regarding the presence of corneal abnormalities in patients with DM1. We investigated whether TNR expansion in DMPK increases the prevalence of clinical FECD in DM1 patients.

Methods : We evaluated FECD grade (modified Krachmer scale) by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG trinucleotide repeat length in TCF4 and DMPK was determined by Genescan or Southern blotting of DNA extracted from peripheral blood leukocytes in 24 of the 26 participants.

Results : The prevalence of FECD grade 2 or higher in 5 (36%) of the 14 probands was significantly greater than in the general population (p < 0.001), using the generous assumption of 10% prevalence in the latter. FECD segregated with the presence of DM1. In the largest family cohort, 6 of the 8 family members examined had both FECD and DM1 and 2 family members had neither FECD nor DM1. All 24 subjects who provided DNA samples, including 4 FECD-affected and 8 unaffected probands, were bi-allelic for non-expanded TNR length in TCF4, ranging from 12 to 29 repeats. Considering our previous data that at least 70% of subjects with FECD harbored TCF4 TNR expansion, the probability of 4 consecutive FECD probands lacking TNR expansion was 0.008. The presence of FECD in DM1 patients was not predicted by the clinical signs/severity of DM1 or DMPK TNR length.

Conclusions : FECD was common in patients with DM1, and the diseases co-segregated within families. TNR expansion in TCF4, which we have previously found to be present in the majority of FECD patients, was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion may contribute to clinical FECD.

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