The Rapid-Onset Chorioretinopathy (ROC) Phenotype of Stargardt Disease

Abstract

Purpose : To characterize patients affected by a uniquely severe rapid-onset chorioretinopathy (ROC) phenotype of ABCA4 disease.

Methods : Sixteen patients were selected from a large clinically diagnosed and genetically confirmed cohort (n=350) of patients with ABCA4 disease with matching phenotypic characteristics on funduscopy, short-wavelength (SW-AF, 488-nm), and near-infrared (NIR-AF, 787-nm) autofluorescence images. Further clinical assessments were obtained from enhanced depth imaging-optical coherence tomography (EDI-OCT), full-field electroretinogram (ffERG) testing and analysis of quantitative autofluorescence (qAF).

Results : All patients exhibited late-stage disease features including pigment migration in the macula and retinal vessel attenuation at an early age and reported a symptomatic onset of 7.4 years (average for ABCA4 disease is 21.9 years, p<0.0001). Widespread degeneration of the macula is observed by an intensely homogeneous signal on SW-AF, as opposed to darkened NIR-AF signal, which progresses to a pattern of "burning" chorioretinal atrophy within the subsequent decade. Measurement of choroidal thickness reveals a more rapid thinning of Sattler's layer with age as compared to the rate in most other ABCA4 disease (p<0.001). Levels of qAF in the macula prior to atrophy are above both the 95% confidence intervals for healthy individuals and patients with Stargardt disease (>1000 qAF-units). Severe attenuation of cone responses and notable decreases in rod responses are detected by ffERG. Sequencing of the ABCA4 gene revealed exclusively deleterious, null mutations, including stop codons, frameshift deletions, variants in canonical splice sites which completely abolish splicing and known deleterious missense alleles.

Conclusions : The ROC phenotype of ABCA4 disease is caused by deleterious biallelic ABCA4 mutations and is characterized by the adolescent-onset and rapid accumulation of lipofuscin in the macula which deteriorates to atrophy of the outer retina and inner choroid within the first two decades of life.

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