Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies

Abstract

Purpose: We describe a particular form of autosomal recessive generalized choriocapillaris dystrophy phenotype associated with ABCA4 mutations.

Methods: A cohort of 30 patients with identified ABCA4 mutations and a distinct phenotype was studied. A retrospective review of history, fundus photographs, electroretinography, visual field testing, dark adaptometry, and optical coherence tomography was performed. Genetic analyses were performed by ABCA4 microarray analysis, high resolution melting, and/or next generation sequencing of all protein-coding sequences of the ABCA4 gene.

Results: The earliest recorded manifestation of ABCA4-associated disease was a central bull's eye type of macular dystrophy that progressed to chorioretinal atrophy of the macula with coarse rounded hyperpigmentations and expanding involvement of the periphery. The mean age at first presentation was 10.3 years, the longest follow-up was 61 years. All patients had two ABCA4 mutations identified, confirming the molecular genetic diagnosis of an ABCA4-associated disease. Most patients harbored at least one mutation classified as "severe," the most common of which was the p.N965S variant that had been found previously at a high frequency among patients with ABCA4-associated retinal dystrophies in Denmark.

Conclusions: Generalized choriocapillaris dystrophy is a progressive ABCA4-associated phenotype characterized by early-onset macular dystrophy that disperses and expands to widespread end-stage chorioretinal atrophy with profound visual loss. All cases in this study were confirmed as harboring two ABCA4 mutations. Most of the ABCA4 mutations were classified as "severe" explaining the early onset, panretinal degeneration, and fast progression of the disease.

Keywords: ABCA4; chorioretinal dystrophy; phenotype–genotype.

Figure 1

Three stages of generalized choriocapillaris dystrophy in 5 patients. Stage 1: Bull's-eye maculopathy. Stage 2: Expanding maculopathy with indistinct margins, central pigmentations, and early peripheral atrophy. Stage 3: End-stage disease with central atrophy and coarse round pigmentations plus widespread peripheral chorioretinal atrophy. The dark spot in the maculae of patients D514 and D116 at Stage 2 is a camera artifact.

Figure 2

Peripheral/mid peripheral atrophy in the initial/middle stages of generalized choriocapillaris dystrophy. (A) Patient D117 at the age of 18, with small, partially confluent, round and oblong patches of unpigmented atrophy, and (B) patient D112 at the age of 14, with less confluent peripheral round patches of atrophy, some of which have a small, round central pigmentation (white circle).

Figure 3

Goldman visual fields for object IV of patient D112 (10 years old) in stage 1 (1A), and patient D514 in stage 2 ([1B], 20 years old) and stage 3 ([1C], 36 years old). Dark adaptations for patient D107 in stage 1 ([2A], 15 years old), patient D514 in stage 2 ([2B], 20 years of age), and patient D804 in stage 3 ([2C], 58 years of age).

Figure 4

Fundus photographs in color (A), autofluorescence (B, C), and infrared ([D], left), and OCTs ([D], right) from two patients (upper block No. 1, D116 at the age of 47; lower block No. 2, D023 at the age of 39) with end-stage generalized choriocapillaris dystrophy characterized by semiconfluent multifocal areolar outer retinal atrophy, the severity of which decreases with increasing eccentricity. Central patches of visible sclera are surrounded by coarse confluent hyperpigmentation. The periphery shows isolated or clustered hyperpigmentation. In and around the fovea there is pronounced atrophy of the retinal pigment epithelium, the photoreceptor layer, and the outer nuclear layer and intraretinal hyperreflective material corresponding to the hyperpigmentation ([D2], white arrow).

Figure 5

Family GCCD0801 with ABCA4 mutations and fundus photographs of affected family members from two generations.