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The Phenotype of Leber Congenital Amaurosis in Patients With AIPL1 Mutations
Sharola Dharmaraj, MD, FRCS;
Bart P. Leroy, MD;
Melanie M. Sohocki, PhD;
Robert K. Koenekoop, MD, PhD;
Isabelle Perrault, PhD;
Khalid Anwar, MD;
Shagufta Khaliq, PhD;
R. Summathi Devi, MD;
David G. Birch, PhD;
Elaine De Pool, MD;
Natalio Izquierdo, MD;
Lionel Van Maldergem, MD;
Mohammad Ismail, MD;
Annette M. Payne, PhD;
Graham E. Holder, PhD;
Shomi S. Bhattacharya, PhD;
Alan C. Bird, MD, FRCOphth;
Josseline Kaplan, MD, PhD;
Irene H. Maumenee, MD
Arch Ophthalmol. 2004;122:1029-1037.
Objectives To describe the phenotype of Leber congenital amaurosis (LCA) in 26 probands with mutations in aryl hydrocarbon receptor interacting protein-like 1 protein (AIPL1) and compare it with phenotypes of other LCA-related genes. To describe the electroretinogram (ERG) in heterozygote carriers.
Methods Patients with AIPL1-related LCA were identified in a cohort of 303 patients with LCA by polymerase chain reaction single-strand confirmational polymorphism mutation screening and/or direct sequencing. Phenotypic characterization included clinical and ERG evaluation. Seven heterozygous carrier parents also underwent ERG testing.
Results Seventeen homozygotes and 9 compound heterozygotes were identified. The W278X mutation was most frequent (48% of alleles). Visual acuities ranged from light perception to 20/400. Variable retinal appearances, ranging from near normal to varying degrees of chorioretinal atrophy and intraretinal pigment migration, were noted. Atrophic and/or pigmentary macular changes were present in 16 (80%) of 20 probands. Keratoconus and cataracts were identified in 5 (26%) of 19 patients, all of whom were homozygotes. The ERG of a parent heterozygote carrier revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal.
Conclusions The phenotype of LCA in patients with AIPL1 mutations is relatively severe, with a maculopathy in most patients and keratoconus and cataract in a large subset. Rod ERG abnormalities may be present in heterozygous carriers of AIPL1 mutations.
Clinical Relevance Understanding and recognizing the phenotype of LCA may help in defining the course and severity of the disease. Identifying the gene defect is the first step in preparation for therapy since molecular diagnosis in LCA will mandate the choice of treatment.
From the Johns Hopkins Center for Hereditary Eye Diseases, Baltimore, Md (Drs Dharmaraj, De Pool, and Maumenee); the Departments of Molecular Genetics (Drs Leroy, Payne, and Bhattacharya) and Clinical Ophthalmology (Drs Bird and Leroy), Institute of Ophthalmology, University College of London, London, England; the Department of Ophthalmology and Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium (Dr Leroy); the Departments of Ophthalmology and Pathology, Columbia University, New York, NY (Dr Sohocki); McGill Ocular Genetics Lab, Montreal Children's Hospital, Montreal, Quebec (Dr Koenekoop); Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Inserm U393, Hôpital des Enfants Malades, Paris, France (Drs Perrault and Kaplan); the Biomedical and Genetic Engineering Division, Dr AQ Khan Research Laboratories, Islamabad, Pakistan (Drs Anwar, Khaliq, and Ismail); Stanley Medical College, University of Madras, Madras, India (Dr Devi); The Retinal Foundation of the Southwest Dallas, Tex (Dr Birch); Instituto de Glaucoma y Genetic a Ocular, Rio Piedras, Puerto Rico (Dr Izquierdo); Centre de Génétique Humaine Institut de Pathologie et de Génétique, Loverval, Belgium (Dr Van Maldergem); the Department of Biological Sciences, Brunel University, London (Dr Payne); the Electrophysiology Department, Moorfields Eye Hospital, London (Dr Holder). The authors have no relevant financial interest in this article.
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