Clinical Characterization of an Extremely Mild, Late-Onset Phenotype of ABCA4 Disease

Abstract

Purpose : To report an unusually mild, parafoveal phenotype in ABCA4 disease.

Methods : Four patients were identified from a large clinically diagnosed and genetically confirmed cohort of patients (n=350) with ABCA4 disease and matching phenotypic characteristics on funduscopy, short-wavelength (SW-AF, 488-nm), and near-infrared (NIR-AF, 787-nm) autofluorescence images. Further clinical characterization included full-field electroretinogram (ffERG) testing and assessment of retinal layer thickness on spectral domain-optical coherence tomography (SD-OCT) scans. Thickness measurements were obtained on horizontal SD-OCT scans out to 3 mm eccentricity along the nasal-temporal axis at 0.5 mm intervals from the fovea.

Results : Mean age at initial presentation was 50.6 years (range, 39-57 years) and mean age of onset was 47.7 years. Best-corrected visual acuity was 20/20 in all patients except P2 who was 20/25. Funduscopic examination was largely unremarkable with the exception of mild RPE mottling around, but not including, the fovea with no discernible abnormalities in periphery in all cases. ffERG testing showed no generalized cone or rod dysfunction. SW-AF and NIR-AF imaging revealed a distinct annular lesion of hypo-autofluorescence, which notably spared a large region of the fovea. A parafoveal disruption of outer retinal layers was observed on SD-OCT although other regions appeared otherwise unaffected. Retinal layer thicknesses compared to respective thicknesses ± 2 SD of healthy individuals/eyes (n = 25,mean age = 47.5 years) varied amongst the cohort. P2, P3 and P4 exhibited generalized thinning (below 2 standard deviations) across the fovea in total retina (TRET) and only a sharp dip in outer segment+ (OS+) and total receptor (TREC+) thickness. P1 only exhibited a sharp dip in TREC+ and OS+ thickness. Retinal pigment epithelium (RPE) thickness was normal in all patients. Disease-causing mutations in ABCA4were detected in all patients. Notably, the hypomorphic c.5603A>T (p.Asn1868Ile) variant was detected in P1 and P4 while P2 and P3 harbored the also mild c.6320G>A (p.Arg2107His) variant.

Conclusions : The current study describes a novel late-onset phenotype of ABCA4 disease characterized by mild parafoveal disruption of outer retinal layers. Although the variants detected in the cohort have been associated with mild ABCA4 disease, the presented cases represent an even milder manifestation.

This is a 2020 ARVO Annual Meeting abstract.