Leber Congenital Amaurosis Associated with AIPL1: Challenges in Ascribing Disease Causation, Clinical Findings, and Implications for Gene Therapy

Mei Hong Tan,Robin R Ali,Dorothy A Thompson,Donna S Mackay,Jill Cowing,Hoai Viet Tran,Isabelle Russell-Eggitt,Phillip Moradi,Michael E Cheetham,Michel Michaelides,Genevieve A Wright,Anthony T Moore,Anthony G Robson,Andrew R Webster,Alexander J Smith,Robert H Henderson,Arundhati Dev-Borman,Robert E Maclaren

doi:10.1371/journal.pone.0032330

Abstract

Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced. The assessment of disease-causation of identified AIPL1 variants included segregation testing, assessing evolutionary conservation and in silico predictions of pathogenicity. The chip identified AIPL1 variants in 12 patients. Sequencing of AIPL1 in 153 patients and 96 controls found a total of 46 variants, with 29 being novel. In silico analysis suggested that only 6 of these variants are likely to be disease-causing, indicating a previously unrecognized high degree of polymorphism. Seven patients were identified with biallelic changes in AIPL1 likely to be disease-causing. In the youngest subject, electroretinography revealed reduced cone photoreceptor function, but rod responses were within normal limits, with no measurable ERG in other patients. An increasing degree and extent of peripheral retinal pigmentation and degree of maculopathy was noted with increasing age in our series. AIPL1 is significantly polymorphic in both controls and patients, thereby complicating the establishment of disease-causation of identified variants. Despite the associated phenotype being characterised by early-onset severe visual loss in our patient series, there was some evidence of a degree of retinal structural and functional preservation, which was most marked in the youngest patient in our cohort. This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood.

Highlights

Leber Congenital Amaurosis (LCA) is an inherited retinal dystrophy characterised by visual impairment and nystagmus from birth or early infancy [1,2]
The safety and efficacy demonstrated by the on-going clinical trials of gene therapy for LCA associated with RPE65 deficiency have provided proof-of-principle for other forms of LCA; thereby establishing a greater need for making timely and accurate molecular diagnoses [3,4,5]
Mutations in AIPL1 are associated with a form of LCA that is characterised by maculopathy and a pigmentary retinopathy which is evident from a young age [9,10,11,12,13]

Summary

Introduction

Leber Congenital Amaurosis (LCA) is an inherited retinal dystrophy characterised by visual impairment and nystagmus from birth or early infancy [1,2] AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1) is expressed in rod and cone photoreceptors, and has a critical role in cell viability [7,8]. Retinal imaging studies have demonstrated significant loss of outer retinal structure at the central macula, with areas of relative preservation peripherally [9,11,13] These findings principally relate to adult patients, and the finding that the presumed loss of photoreceptors on the basis of optical coherence tomography, is more severe with age, suggests that younger patients may have a greater degree of retained photoreceptors, which could be targeted by gene-supplementation therapy. Retained rod function on darkadapted perimetry and pupillometry has been observed in patients, some of whom were in the third and fourth decades of life [11]

Methods

Results

Conclusion