title: Fundus albipunctatus associated with compound heterozygous mutations in RPE65.
abstract: OBJECTIVE
  To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations.
  
  
  METHODS
  Observational study.
  
  
  METHODS
  Four family members.
  
  
  METHODS
  Clinical examinations included full-field electroretinogram (ffERG) after standard (30-minute) and prolonged (17-hour) dark adaptation, multifocal electroretinogram (mfERG), optical coherence tomography (OCT), and fundus autofluorescence (FAF). Molecular genetic testing included sequencing of RDH5 and RLBP1 and screening for known autosomal-recessive retinitis pigmentosa mutations by a commercially available microarray technique. RPE65 sequencing was performed after the identification of a known heterozygous splice-site mutation by array screening.
  
  
  METHODS
  We recorded ffERG and mfERG amplitudes, OCT characteristics, the FAF intensity index, and the outcomes of DNA sequencing regarding RPE65 mutations.
  
  
  RESULTS
  Uniform, yellow-white dots typical of fundus albipunctatus were demonstrated in the proband. These dots corresponded with discrete, hyperreflective formations extending from the Bruch's membrane and retinal pigment epithelium (RPE) into the level of the external limiting membrane, thus spanning along the entire RPE and photoreceptor outer and inner segments. A reduced thickness of the central retina and the RPE-outer segment complex was demonstrated. The intensity of the FAF was severely reduced in the entire fundus. At age 18, ffERG-including prolonged dark adaptation-demonstrated a barely recordable rod response after standard dark adaptation and normalization (increase by more than 700%) of the response after prolonged dark adaptation. The cone 30-Hz flicker response was reduced after standard dark adaptation and increased by >50% after prolonged dark adaptation. In addition, mfERG demonstrated reduced central and peripheral responses. Molecular genetic analysis demonstrated compound heterozygous mutations (IVS1+5G>A and c.344T>C) in RPE65. No mutations were found in RDH5 or RLBP1. No significant abnormalities of retinal structure or function were detected in the parents and sister carrying single heterozygous mutations in RPE65.
  
  
  CONCLUSIONS
  This is the first reported association between compound heterozygous RPE65 mutations and fundus albipunctatus, indicative of a mutation-specific phenotypic effect in this gene. This finding, together with the reduced FAF, supports that disruption of retinoid recycling in the RPE is essential for the development of fundus albipunctatus.
authors.affiliation: Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark. patrik.schatz@med.lu.se
authors.forename: Patrik
authors.initials: P
authors.lastname: Schatz
authors.forename: Markus
authors.initials: M
authors.lastname: Preising
authors.forename: Birgit
authors.initials: B
authors.lastname: Lorenz
authors.forename: Birgit
authors.initials: B
authors.lastname: Sander
authors.forename: Michael
authors.initials: M
authors.lastname: Larsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
mesh_terms: D000293:Adolescent; D000429:Alcohol Oxidoreductases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D003623:Dark Adaptation; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009755:Night Blindness / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics*; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D055815:Young Adult; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D000429:Alcohol Oxidoreductases; D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C020932:11-cis-retinal-binding protein; C105846:retinol dehydrogenase 5