title: Preserved visual function in retinal dystrophy due to hypomorphicRPE65mutations.
abstract: OBJECTIVE
  To present detailed phenotypic and molecular findings in four patients from four families with atypical, mild, recessiveRPE65-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 ofRPE65was 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 identifiedRPE65mutations in all patients including three missense variants likely to represent hypomorphic alleles.
  
  
  CONCLUSIONS
  Hypomorphic mutations ofRPE65are 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 inRPE65suggests 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.
authors.affiliation: UCL Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: UCL Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.affiliation: UCL Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.affiliation: UCL Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: UCL Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: UCL Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: UCL Institute of Ophthalmology, London, UK.|Moorfields Eye Hospital, London, UK.|Department of Ophthalmology, University of California, San Francisco Medical Centre, California, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult; D019745:cis-trans-Isomerases / Q000235:genetics* / Q000378:metabolism; D000099178:Retinoid Isomerohydrolase
chemical_list: D004247:DNA; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
keywords: Dystrophy; Electrophysiology; Genetics; Imaging; Vision