Abstract
Purpose::
Broad phenotypic variation exists among patients with retinal dystrophy due to mutation in the ABCA4 gene, the only gene known to cause autosomal recessive macular dystrophy. The purpose of this study is to analyze fundus autofluorescence (FAF) patterns and explore the existence of distinct phenotypic subgroups in a group of patients with suspected ABCA4-retinopathy.
Methods::
Autofluorescence images were collected from a cohort of 108 patients attending the clinics at Moorfields Eye Hospital, fitting the following criteria: retinal disease confined to, or severely affecting the macula, a genetic segregation pattern compatible with autosomal recessive inheritance, and an absence of signs or history suggesting an acquired etiology. Images were characterized based on the pattern of FAF and other distinguishing features, such as the presence or absence of posterior pole flecks. Areas of FAF atrophy were digitally quantified using a retinal mapping program. Distinct phenotypic subgroups were observed and concordance in retinal atrophic area between a patient's two eyes was investigated. All patients underwent screening for 487 specific ABCA4 DNA sequence variants using the Apex chip (AsperBiotech), and correlation was sought based on all likely-pathologic ABCA4 variants.
Results::
Six phenotypic subgroups were established using FAF data: (1) small central relative hypofluoresence, (2) central relative hypofluoresence, (3) central patchy atrophy, (4) central regular solid atrophy, (5) central irregular solid atrophy, (6) widespread multiple areas of atrophy. A Spearman's rank correlation coefficient of .923, indicated high concordance between a patient's two eyes. The ABCA4 DNA chip revealed 27 patients with 0 potentially pathologic changes, 39 with 1, 35 with 2, 5 with 3, and 2 patients with 4 changes. No correlation was observed for the number of ABCA4 disease alleles detected and the phenotypic subtype, nor did two patients sharing the same two deleterious mutations have the same phenotype.
Conclusions::
Phenotypic subgroups of ABCA4-related retinal disease based on FAF are not related to the number or type of ABCA4 base variants detected. This does not exclude a correlation with other pathogenic changes such as intragenic rearrangements. Modifying factors may influence the fundal appearance. These data will prove useful in interpreting the effect of future potential therapeutics.
Keywords: degenerations/dystrophies • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound) • gene/expression