Abstract
Purpose :
To detail the clinical features, genetic findings and genotype-phenotype correlations of patients with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD) harboring biallelic AIPL1 pathogenic variants.
Methods :
This case-series study enrolled 51 Chinese participants from 47 families with a clinical diagnosis of LCA/EOSRD and harboring disease-causing variants in the AIPL1 gene. Clinical records on symptoms, medical history, and results of molecular genetic testing, best-corrected visual acuity (BCVA), retinal imaging (color fundus photography, fundus auto-fluorescence imaging, SD-OCT, and full-field electroretinography (ffERG) were reviewed.
Results :
Nineteen patients with EOSRD and 32 patients with LCA were identified as harboring 28 disease-causing AIPL1 variants, with 18 being novel. In patients with EOSRD, the mean BCVA was both 1.25 logMAR for the right and left eyes, which showed an average annual decline of 0.031 logMAR (P < 0.01). OCT imaging showed a preservation of the foveal outer retinal structure in the 5 youngest (3.3-7.6 years) of 14 patients. The majority (11/12) showed severe cone-rod patterns of ffERG characterized by undetectable photopic responses and significantly reduced scotopic responses. For patients with LCA, the BCVA ranged from light perception to counting fingers. Preserved foveal ellipsoid zone (EZ) was observed in 9 children (1.7–5.7 years), 5 of whom showed island-like EZ remnants (4.5–5.7 years). All patients with EOSRD carried at least one missense mutation with c.152A>G identified in 13 of 19 and c.572T>C identified in 5 of 19, while 26 patients with LCA harbored 2 null AIPL1 variants, 18 of whom were homozygous for c.421C>T and 6 of whom were heterozygous for c.421C>T and another loss-of-function variant.
Conclusions :
This study provides comprehensive analysis of the clinical and genetic findings of a large AIPL1 cohort, allowing precise distinction between LCA and EOSRD and establishing genotype-phenotype correlation. The fact that residual foveal outer retinal structure is observed in the youngest proportion of patients suggests an early window of opportunity for gene augmentation therapy. These results are critical for the understanding of natural progression of the disease and the design of future randomized clinical trial.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.