Background/aims To present detailed phenotypic and molecular findings in four patients from four families with atypical, mild, recessive RPE65-related retinal dystrophy and discuss potential implications for gene replacement therapy.

Methods Four patients from four families with early onset retinal dystrophy underwent clinical examination, retinal imaging and electrophysiological testing. Bidirectional Sanger sequencing of all exons and intron–exon boundaries of RPE65 was performed.

Results All patients presented with nyctalopia in early childhood but demonstrated a mild phenotype with good visual acuity until at least 19 years of age. All had generalised retinal dysfunction on electroretinography. Central macular thickness on optical coherence tomography was preserved in those patients with good visual acuity. One patient had extensive white dots throughout the retina reminiscent of fundus albipunctatus with electrophysiological evidence of partial recovery of rod function after prolonged dark adaptation. Sanger sequencing identified RPE65 mutations in all patients including three missense variants likely to represent hypomorphic alleles.

Conclusions Hypomorphic mutations of RPE65 are associated with mild disease in childhood with preservation of good visual acuity into adulthood; they may in rare cases be associated with a flecked retina appearance similar to fundus albipunctatus. The presence of normal visual acuity in patients with hypomorphic mutations in RPE65 suggests that efficiency of transduction may not be the limiting factor in improving visual acuity in trials of gene replacement therapy. Rather, it suggests that for optimal recovery of visual acuity gene replacement therapy may need to be given much earlier in childhood.