The clinical features of retinal disease due to a dominant mutation in RPE65

PURPOSE To present a detailed phenotypic and molecular study of two families with autosomal dominant RPE65-related retinal dystrophy. METHODS Five patients from two families were ascertained from the retinal clinics of a tertiary referral center. Phenotyping included retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of exon 13 of RPE65 and its intron-exon boundaries was performed on all reported patients and segregation confirmed in available relatives. The main outcome measures were the results of an ophthalmic examination and investigation and molecular genetic analysis. RESULTS Four affected patients from two families presented with nyctalopia and central visual disturbance in adulthood progressing to severe visual loss by the fifth to eighth decades. The patients had extensive chorioretinal atrophy with a relatively preserved anterior retina. In the second family, one patient had bilateral, vitelliform-like foveal lesions consistent with adult onset vitelliform macular dystrophy and no peripheral retinal changes. These unrelated families were both heterozygous for c.1430A>G (p.Asp477Gly). One unaffected family member also tested positive for this mutation but had good vision at age 80 years. CONCLUSIONS Autosomal dominant retinal dystrophy resembling choroideremia can arise from a heterozygous mutation in RPE65. It may manifest with mild disease or be non-penetrant. Awareness of these unusual presentations can facilitate targeted molecular investigation.