Molecular Analysis and Detailed Phenotypic Study
Abstract
Purpose: To report novel variants and characterize the phenotype associated with the autosomal recessive retinal dystrophy caused by mutations in the lecithin retinol acyltransferase (LRAT) gene.
Methods: A total of 149 patients with Leber's congenital amaurosis (LCA) or early onset retinal dystrophy were screened for mutations in LCA-associated genes using an arrayed-primer extension (APEX) genotyping microarray (Asper Ophthalmics). LRAT sequencing was subsequently performed in this 148-patient panel. Patients identified with mutations underwent further detailed phenotyping.
Results: APEX analysis identified one patient with a previously reported homozygous LRAT mutation. Sequencing of the panel identified three additional patients with novel homozygous LRAT mutations in exon 2. All four patients had severe progressive nyctalopia, visual field constriction, and photophilia in childhood. Visual acuity ranged from 0.22 logMAR to hand motion. Funduscopy revealed severe retinal pigment epithelial atrophy and minimal retinal pigmentation. Asteroid hyalosis and macular epiretinal fibrosis were frequent. All demonstrated reduced fundus autofluorescence. Optical coherence tomography identified disrupted retinal lamination, outer-retinal debris, and an unidentifiable photoreceptor layer in two cases. Full-field electroretinograms were undetectable or showed severe rod-cone dysfunction. Photopic perimetry revealed severe visual field constriction. Dark-adapted perimetry demonstrated markedly reduced photoreceptor sensitivity. Dark-adapted spectral sensitivity measurements identified functioning rods in two of three patients. All three had severely reduced L- and M-cone sensitivity and poor color discrimination.
Conclusions: LRAT mutations cause a severe, early childhood onset, progressive retinal dystrophy. Phenotypic similarities to the retinal dysfunction associated with RPE-specific protein 65 kDa mutations, another visual cycle gene, suggest that LRAT deficiency may show a good response to novel therapies.
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Investigative Ophthalmology & Visual Science June 2012, Vol.53, 3927-3938. doi:https://doi.org/10.1167/iovs.12-9548