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Valentina Di lorio, Ada Orrico, Paolo Melillo, Francesco Testa, Michele Della Corte, Francesca Simonelli; A natural history study to explore genotype / phenotype correlations in Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4646. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Genotype/phenotype correlation data in Stargardt disease due to ABCA4 mutations (STGD1) are still needed, particularly for gene therapy clinical trials, since previous studies reported data from small size cohorts, often with uncomplete genotype definition and focusing on few clinical parameters. We performed a retrospective longitudinal study on a large cohort of patients with two mutations in ABCA4 gene to explore genotype - phenotype correlations.
We reviewed medical charts of STGD1 patients who underwent best-corrected visual acuity (BCVA), fundus photography, optical coherence tomography (OCT) and full-field electroretinography (ERG). Mutations were classified as "likely-null" (i.e., stop codon mutations, frameshift, deletions and insertions), and missense mutations, therefore, the genotype was classified in three groups. Survival analysis was performed to compare the age distribution for legal blindness and advanced disease stages according to fundus photography, ERG and OCT.
The study cohort consisted of 156 STGD1 patients with a mean age of 30.4 ± 1.1 years. Based on genotype, 68 patients (43.6%) had missense mutations in both alleles (Group 1), 74 patients (47.4%) a missense mutation and a "likely-null" mutation (Group 2), 14 patients (9.0%) had "likely-null" mutations in both alleles (Group 3). The survival analysis (mean follow-up: 3 years) showed that Group 3 reached legal blindness, based on loss of BCVA, at a significantly younger age (27.4 ± 2.3 years) than Group 1 (36.2 ± 1.5 years) and Group 2 (38.1 ± 1.4 years), and a clinically significant lesion area assessed by OCT (i.e, ≥ 2.5 mm2) at a mean age of 33.1 ± 2.5 years, about 11 years earlier than Group 1 (43.4 ± 1.6 years) and Group 2 (45.5 ± 1.4 years). Similarly, they reached the most advanced disease stages according to fundus photography (i.e., extensive macular atrophy) and electroretinography (i.e., alterations in both scotopic and photopic responses) about 10 years earlier than the other two groups.
The current study, for the first time in literature, reports in a large Italian cohort that STGD1 patients with “likely-null” mutations in both alleles showed a fast disease progression in terms of the main morphological and functional parameters. These findings could be useful to improve prognostic evaluations and the choice of the most amenable candidates for gene therapy clinical studies.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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