Phenotypic Survey of Patients and Families With Retinitis Pigmentosa Due to Mutations in the RP1 Gene

Abstract

Purpose: : To determine the spectrum of RP1 mutations in families with autosomal dominant retinitis pigmentosa (ADRP) and to survey the effects on retinal structure and function.

Methods: : All families with a diagnosis of ADRP, who had given informed consent, were included in the study. Mutations were sought in RP1 through Sanger sequencing of the mutational hotspot c.617-c.1081 in leukocyte DNA. Affected members from each family underwent full ophthalmic examination, fundus photography, autofluorescence imaging, perimetry, optical coherence tomography and electrophysiology.

Results: : 54 patients from 37 Caucasian families were ascertained for the study. Evaluation of RP1 in the 37 families showed 11 specific alleles all of which would be expected to produce a truncated protein, 3 of which are previously unreported. No patient noted symptoms in the first decade of life, but 50% of the patients were symptomatic before 30 years of age. All patients younger than 40 (n=22) maintained visual acuity (VA) of better than 6/12 in their better seeing eye. Between 40 and 60 years of age (n=81), more than 78% retained VA better than 6/12 and none were worse than 6/24. Of 37 patients examined in their sixties, 86.5% had VA better than 6/12 while the rest had VA between 6/12 and 6/24. Affected retinas showed attenuated blood vessels and pale discs but little bone spicule pigmentation. 8/54 (15%) patients developed macular oedema. Full-field electroretinograms (ERG) were consistent with rod-cone dystrophy. Pattern ERG P50 was normal in 10 individuals and mildly subnormal in 4, in keeping with mild macular involvement. There was negative correlation between pattern ERG P50 and age (r=0.75, p<0.001). 2 patients had a sectorial distribution of retinal degeneration. One patient age 61, with a confirmed germline mutation had completely unilateral disease, with a normal ERG in the unaffected eye. No association between the specific allele and the severity of phenotype was evident.

Conclusions: : Heterozygosity for RP1 mutations generally causes a mild adult onset retinal degeneration affecting rods first. Macular function is retained until late. One patient had unilateral disease both clinically and electrophysiologically.

Keywords: retinal degenerations: hereditary • electrophysiology: clinical • genetics