Natural history study of RPE65 associated autosomal recessive retinal dystrophies.

Abstract

Purpose : Gene augmentation therapy and pharmacological substitution therapy for RPE65 associated autosomal recessive retinal dystrophies (LCA2 and RP20) seem to be within reach for patients. It is currently unclear whether the RPE65 genotype correlates with phenotype and visual course, and if this knowledge would influence the timing and type of therapy that needs to be considered. We performed a longitudinal cohort study to gain insight into the natural course of disease as a function of RPE65 genotype.

Methods : We collected retrospective and prospective data from 43 subjects with biallelic homozygous or compound heterozygous RPE65 mutations, 30 originating from a genetic isolate. We studied the course of visual acuity over time.

Results : The median age of patients in our cohort at recent examination was 26.5 years, ranging from 8 months to 58 years. The majority of subjects were diagnosed with RPE65 associated retinal dystrophy within the first year of life, based on nystagmus, lack of eye contact, night blindness, adoration to bright light, and severely reduced electrographic responses. Visual acuity in early childhood ranged from 1.3 to 0.1 logMAR at the age of 5, and remained relatively stable the first three decades of life. In a subset of patients perifoveal atrophy seemed the precursor of loss of central vision during in the fourth decade.

Mutation analysis revealed 12 different disease causing variants (Table). We found missense, nonsense, frame shift mutations and mutations that altered splicing. The Y368H founder mutation was the most observed mutation in our cohort, 20 patients (47%) carried this mutation on both alleles.

We observed large differences in visual function between individuals carrying the same RPE65 mutations, even in siblings from the same genetic pool and exposed to similar environmental factors.

Conclusions : Genotype-phenotype correlations were not present in our cohort of 43 subjects with retinal dystrophies caused by RPE65 mutations. Central visual function as measured in childhood varied widely, subsequently remained stable for the first three decades of life, but inevitable progressed towards blindness.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Frequency of RPE65 mutations