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.
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Oral presentation at the International Society for Genetic Eye Diseases and Retinoblastoma biannual meeting, Halifax, Canada, August 2015.
Contributors SH, ARW and ATM designed the study; SH, RM and ARW acquired data; all authors analysed data and critically reviewed the manuscript; all authors approved the final manuscript.
Funding The National Institute for Health Research (UK) and Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology (BRC2_003), Fight For Sight (1318 and 1801), Moorfields Eye Hospital Special Trustees (ST1109B). Michel Michaelides is supported by an FFB Career Development Award.
Competing interests ATM is the Chairman of Data safety and on the Management Board of gene therapy trials for retinal disease sponsored by Sanofi and Oxford Biomedica and has served on an Advisory Board for Sucampo Pharmaceuticals and Sanofi. He has also participated in a clinical trial of oral retinoid therapy for RPE65 deficiency sponsored by QLT.
Ethics approval NRES Committee London – Camden amp; Islington, Research Management Committee, Moorfields.
Provenance and peer review Not commissioned; externally peer reviewed.