Frequency of mutations and genotype-phenotype correlation of patients with Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is the most severe and earliest form of inherited retinal disease representing approximately 5% of all retinal dystrophies and 20% of childhood blindness. The purpose of this study is to evaluate the frequency of gene mutations among LCA patients in the Southwest Eye Registry (SER) and determine possible genotype-phenotype correlations. 

The SER database (Retina Foundation, Dallas TX) of 7680 individuals was tabulated by disease category.  Data from 90 LCA patients was assessed. The probands from each family were identified and their clinical and molecular data analyzed. The prevalence of LCA was estimated for the Dallas Metroplex region.

Of the probands (n=77), 54 had genetic evaluation. Disease-causing mutations were determined in 36 cases (66.7%). Mutations were distributed in 12 different genes: CEP290(18.5%), AIPL1(13.0%), RPE65(11.1%), CRB1(5.6%), RPGRIP1(3.7%), RDH12(3.7%), CRX(1.9%), GUCY2D(1.9%), SPATA7(1.9%), TULP1(1.9%), IQCB1(1.9%), PRPH2(1.9%). No mutations were found in 18 patients (33.3%). Clinically, all the cases presented congenital nystagmus, ERG abnormalities, and variable levels of visual loss. CEP290-LCA10 patients showed severe visual loss in the first year, hyperopia, widespread retinal atrophy, fovea lamellar structure preservation. AIPL1-LCA4 patients presented progressive visual loss, night-blindness, bone spicules, bullseye maculopathy. RPE65-LCA2 patients presented progressive visual loss until third decade, color-blindness, night-blindness, bone spicules, macula preservation. The estimated prevalence of LCA in Dallas Metroplex was 1.02/130,000.

A precise molecular diagnosis and genotype-phenotype characterization leads to better prognostic information, improved patient management, and targeted treatment options for LCA patients. Ongoing gene therapy trials and similar emerging therapies underscore the molecular diagnosis importance.