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J.A. Galvin, G.A. Fishman, E.M. Stone, J.L. Secrist, B.R. Roos, I. Lopez, R.K. Koenekoop; Clinical Phenotypes Associated with Specific Genotypes in Leber Congenital Amaurosis (LCA). . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4063.
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© ARVO (1962-2015); The Authors (2016-present)
Objectives: To describe the clinical phenotypes associated with sequence variations in six genes known to cause LCA. Methods: Medical records of 110 patients with LCA were reviewed and 34 patients (31%) were identified with probable disease–causing sequence variations in one of six genes known to cause this disease. Evaluation included the assessment of visual acuity as well as slit–lamp biomicroscopy and dilated fundus examination. Additionally, twenty–seven obligate heterozygotes were assessed for fundus and ERG abnormalities. Results: Eighteen female (53%) and 16 male (47%) patients were identified as having at least one disease causing sequence variation. Their ages ranged from 7 to 72 years, with a mean of 30.5 years. Three patients (8.8%) had an AIPL1 variation, 8 (23.5%) CRB1, 2 (5.8%) CRX, 4 (11.7%) GUCY2D, 11 (32.4%) RPE65, and 6 (17.6%) a RPGRIP1 variation. Ocular findings included keratoconus in 2/2 with CRX, 1/3 with AIPL1, 1/8 with CRB1, 0/4 with GUCY2D, 0/6 with RPGRIP1, and 0/11 with RPE65; drusen–like lesions in 10/11 with RPE65, 5/6 with RPGRIP1, 6/8 with CRB1, 1/3 with AIPL1, 0/2 with CRX, 0/4 with GUCY2D; and chorioretinal atrophy in 7/11 with a RPE65 mutation exclusively. In the heterozygote parents, drusen–like changes were identified in at least one eye in 5/6 RPE65 carriers, 3/4 CRB1, 3/8 RPGRIP1, 0/1 CRX, 0/5 AIPL1, and 0/5 GUCY2D carriers. Reduced rod and/or cone ERG amplitudes were recorded in at least one eye in 3/5 GUCY2D carriers, 2/4 CRB1, 1/1 CRX, 2/8 RPGRIP1, 0/5 AIPL1, and 0/6 RPE65 carriers. Conclusions: Phenotypic similarities and differences were observed in the various genotypes for chorioretinal atrophy, drusen–like lesions, and keratoconus. Also of note, RPE65 obligate heterozygotes showed only drusen–like changes whereas CRB1 and RPGRIP1 heterozygotes had both drusen–like changes and abnormal ERG amplitudes. Carriers of AIPL1 changes had normal fundus findings and ERG amplitudes. Recognizing these phenotypic patterns in both patients and heterozygotes will facilitate a more focused approach in the screening of LCA patients for various mutations.
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