Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies

Leo Sheck,Wayne I.L Davies,Phillip Moradi,Anthony G Robson,Neruban Kumaran,Alki C Liasis,Andrew R Webster,Anthony T Moore,Michel Michaelides

doi:10.1016/j.ophtha.2017.12.013

Abstract

PurposeTo investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children.DesignRetrospective case series.ParticipantsPatients with mutations in CEP290 identified at a single UK referral center.MethodsReview of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing.Main Outcome MeasuresMolecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment.ResultsForty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features.ConclusionsDetailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches.

Highlights

The current study provides a detailed characterization of the clinical phenotype and natural history in a large number of patients with CEP290 Leber congenital amaurosis (LCA)/EOSRD seen at a single institution, which will help to provide improved genetic counseling and advice on prognosis, and to assist in the preparation and design of anticipated clinical trials of novel therapies
The majority of patients had 2 CEP290 variants identified (n 1⁄4 36, 90%), with the rest having 1 mutation identified to date (n 1⁄4 4, 10%)
The majority (75%) of variants encoded for premature stop codons, which would lead to protein truncation and dysfunction due to the loss of critical

Summary

Methods

Patients harboring likely disease-causing variants in CEP290 were identified from the Moorfields Eye Hospital Inherited Eye Disease database. Patients were included in this database after obtaining informed consent. This retrospective study adhered to the tenets of the Declaration of Helsinki and was approved by the Moorfields Eye Hospital ethics committee. Clinical notes, imaging, and electrophysiologic testing were reviewed. OCT, fundus autofluorescence (FAF) imaging, and color fundus photography were reviewed when available. Fundus autofluorescence images were obtained with Spectralis HRA OCT (Heidelberg Engineering, Heidelberg, Germany) or Optos widefield camera. Termination Substitution (missense) In-frame amino acid deletion Second mutation unknown. Given that all 3 substitutions constitute changes in the net charge of the amino acid side changes, they are likely to induce significant effects on CEP290 function

Results

Clinical Findings

Discussion