Genotype-Specific Lesion Growth Rates in Stargardt Disease.

Rachael C Heath Jeffery,Terri L Mclaren,Johnny Lo,Ian J Constable,Tina M Lamey,Fred K Chen,Ian L Mcallister,John N De Roach,Jennifer A Thompson

doi:10.3390/genes12121981

Abstract

Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic ABCA4 mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) 30° × 30° images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21–86) were recruited. Patients with c.3113C>T or c.6079C>T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p < 0.001 and 0.14 to 0.21; p < 0.001) respectively, as compared to those patients harbouring c.5882G>A at 0.06 mm/year (95% CI 0.03–0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset.

Highlights

Stargardt disease (STGD1, OMIM#248200) is one of the most common monogenic inherited retinal diseases [1,2]
A meta-analysis of seven studies showed a bimodal distribution in the effective radius growth rate (GR) peaking at 0.029 and 0.110 mm/year, suggesting two potential subpopulations related to genetic heterogeneity [6]
We expand on this work by evaluating the effective radius GR in five genotype-specific cohorts to elucidate the basis of this bimodal distribution in GR

Summary

Introduction

Stargardt disease (STGD1, OMIM#248200) is one of the most common monogenic inherited retinal diseases [1,2]. The growth rate (GR) of retinal pigment epithelial atrophy, known as definitely decreased autofluorescence (DDAF), is a widely accepted clinical trial endpoint [3]. A meta-analysis of seven studies showed a bimodal distribution in the effective radius GR peaking at 0.029 and 0.110 mm/year (overall mean of 0.104 mm/year), suggesting two potential subpopulations related to genetic heterogeneity [6]. We recently reported genotype-dependent variation in DDAF GR using ultra-widefield (UWF) AF, where patients harbouring mild or hypomorphic variants showed a significantly slower SRA GR as compared to those with biallelic severe variants or those with one intermediate and one severe variant in trans [3].

Methods

Results

Conclusion