title: Phenotype and Progression of Retinal Degeneration Associated With Nullizigosity of ABCA4.
abstract: We describe the phenotypes associated with nullizigosity and nine splicing mutations in the ABCA4 gene.
  
  
  
  The study included 19 patients with biallelic null mutations (Group A, nullizygous), 27 with splicing mutations in the homozygous state or in trans with a null mutation (Group B), and 20 with p.G1961E in trans with a null mutation (Group C, control). Ages at onset and visual acuities were determined from medical histories. Area of decreased autofluorescence within a 30° × 30° fundus autofluorescence (FAF) image was measured with the Region Finder (N = 58). Full-field electroretinography (ERG) was performed incorporating the International Society for Clinical Electrophysiology of Vision (ISCEV) standard (N = 40).
  
  
  
  For groups A to C, the median ages of onset were 6, 8, and 17, respectively. Kaplan Meier survival analysis estimated that 50% of patients reached visual acuity below 20/400 at the ages of 29, 48, and 66 years, respectively. The area of reduced FAF was estimated to increase by 1.5, 1.2, and 0.03 mm2 per year, respectively, and cone-rod dystrophy was present in 10/12, 13/15, and 0/13 of cases, respectively. Splicing mutation c.5714+5G>A was associated with a significantly milder phenotype in comparison with nullizygous patients for all parameters.
  
  
  
  Nullizygosity for ABCA4 is associated with early onset cone-rod dysfunction with rapid progression shown by enlargement of central atrophy on FAF, decline of ERG amplitudes with age, and a high risk of reaching legal blindness by the fourth decade. Most studied splicing mutations were associated with a similarly severe phenotype. Estimated rates of progression may facilitate further genotype-phenotype correlations and inform the design of treatment trials.
authors: UCL Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors: Ana
authors: A
authors: Fakin
authors: UCL Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors: Anthony G
authors: AG
authors: Robson
authors: UCL Institute of Ophthalmology, London, United Kingdom 3National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan 4Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan.
authors: Kaoru
authors: K
authors: Fujinami
authors: UCL Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom 5Department of Ophthalmology, University of California, San Francisco School of Medicine, San Francisco, California, United States.
authors: Anthony T
authors: AT
authors: Moore
authors: UCL Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors: Michel
authors: M
authors: Michaelides
authors: Casey Molecular Diagnostic laboratory, Portland, Oregon, United States.
authors: John
authors: J
authors: Pei-Wen Chiang
authors: UCL Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors: Graham
authors: G
authors: E Holder
authors: UCL Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
authors: Andrew R
authors: AR
authors: Webster
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009887:Ophthalmoscopy; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D004247:DNA