title: Clinical and molecular characteristics of childhood-onset Stargardt disease.
abstract: OBJECTIVE
  To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD).
  
  
  METHODS
  Retrospective case series.
  
  
  METHODS
  Forty-two patients who were diagnosed with STGD in childhood at a single institution between January 2001 and January 2012.
  
  
  METHODS
  A detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next-generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients.
  
  
  METHODS
  Clinical, imaging, electrophysiologic, and molecular genetic findings.
  
  
  RESULTS
  The median ages of onset and the median age at baseline examination were 8.5 (range, 3-16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD.
  
  
  CONCLUSIONS
  Childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease.
authors.affiliation: Laboratory of Visual Physiology, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan; Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan; UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, City Road, London, UK.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Fujinami
authors.affiliation: Department of Ophthalmology, Columbia University, New York, New York.
authors.forename: Jana
authors.initials: J
authors.lastname: Zernant
authors.affiliation: UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, City Road, London, UK.
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Chana
authors.affiliation: UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, City Road, London, UK.
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Wright
authors.affiliation: Laboratory of Visual Physiology, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Tsunoda
authors.affiliation: Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.affiliation: UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, City Road, London, UK.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.affiliation: UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, City Road, London, UK.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.affiliation: Department of Ophthalmology, Columbia University, New York, New York; Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.affiliation: UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, City Road, London, UK. Electronic address: michel.michaelides@ucl.ac.uk.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, City Road, London, UK. Electronic address: tony.moore@ucl.ac.uk.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D008297:Male; D025202:Molecular Diagnostic Techniques; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D000080362:Stargardt Disease; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters