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

Abstract

Purpose: To 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.

Design: Retrospective case series.

Participants: Patients with mutations in CEP290 identified at a single UK referral center.

Methods: Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing.

Main outcome measures: Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment.

Results: Forty 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.

Conclusions: Detailed 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.

Figure 1

Schematic diagram showing the CEP290 gene and the location of the mutations identified in our cohort. LCA = Leber congenital amaurosis.

Figure 2

Optos (Optos Panoramic 200; Optos PLC., Scotland, UK) color fundal image of the right eye of patient 31a (A) showing the typical white flecks found in CEP290 Leber congenital amaurosis (LCA). Very mild pigmentary changes were also observed. This is compared with the Optos color fundal image of the right eye of patient 5e (B) showing severe peripheral retinal atrophy and pigment formation.

Figure 3

Color fundus photograph showing mild pigmentary changes in the right retina in patient 5c at 23 years of age (A) and increased pigmentary change 4 years later (B).

Figure 4

Optos fundus autofluorescence (FAF) of the left eye of patient 25 (A) showing central hyperautofluorescent ring with peripheral loss of autofluorescence compared with Optos FAF of patient 22a (B) showing loss of autofluorescence in the far periphery and in the paramacula region.

Figure 5

The OCT images of patient 22a showing preservation of left foveal outer retinal architecture at 36 years of age (A) and progression over 6 years (B). Triangles denote termination of inner/outer segment line.

Figure 6

The OCT images of the right eye of patient 25 at 14 (A) and 18 years of age (B) showing progressive loss of the inner segment/outer segment line (triangle).

Figure 7

Handheld Bioptigen (Morrisville, NC) OCT imaging of the left eye of patient 33 (22 months old) that revealed relatively intact outer retinal structure.