Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (LCA), whereas the less aggressive forms are usually considered juvenile retinitis ... Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (LCA), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Various intermediate phenotypes between LCA and retinitis pigmentosa are known and are sometimes described as 'early-onset severe rod-cone dystrophy' or 'early-onset retinal degeneration' (Booij et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000; for cone-rod dystrophy, see 120970.
Hameed et al. (2000) studied a consanguineous Pakistani family in which 3 sibs and their cousin had Leber congenital amaurosis and keratoconus. All affected individuals were blind from birth, with absence of rod and cone function as demonstrated ... Hameed et al. (2000) studied a consanguineous Pakistani family in which 3 sibs and their cousin had Leber congenital amaurosis and keratoconus. All affected individuals were blind from birth, with absence of rod and cone function as demonstrated by electroretinography (ERG), and the patients also showed bone spicule pigmentation of the retina. In addition, patients developed bilateral ectasia with central thinning of the cornea before age 20 years. On examination, the central cornea had a pronounced cone shape with severe corneal clouding. Sohocki et al. (2000) examined affected members of 4 unrelated LCA families in whom mutations in the AIPL1 gene (604392) were found (see MOLECULAR GENETICS). Affected individuals from a Pakistani family were blind from birth with absence of rod and cone function as demonstrated by ERG, but without keratoconus. Fundus examination indicated pigmentary retinopathy, attenuated blood vessels, and macular degeneration. In 3 unrelated European families, patients had poor central vision from birth, severe night blindness, and pendular nystagmus. ERG testing revealed borderline or nondetectable cone and rod responses by the second decade of life. Fundus examination showed widespread retinal pigment epithelium changes with pigment clumping, attenuated retinal vessels, macular atrophy, and a pale optic disc.
In affected members of a consanguineous Pakistani family with Leber congenital amaurosis and keratoconus mapping to chromosome 17p13.1, originally studied by Hameed et al. (2000) and found to be negative for mutation in the GUC2D gene (600179), Sohocki ... In affected members of a consanguineous Pakistani family with Leber congenital amaurosis and keratoconus mapping to chromosome 17p13.1, originally studied by Hameed et al. (2000) and found to be negative for mutation in the GUC2D gene (600179), Sohocki et al. (2000) demonstrated homozygosity for a nonsense mutation in the AIPL1 gene (W278X; 604392.0001). Analysis of the AIPL1 gene in 14 additional LCA families revealed 4 more families that were homozygous or compound heterozygous for W278X and/or other mutations in AIPL1 (see 604392.0002-604392.0003), and Sohocki et al. (2000) concluded that mutations in the AIPL1 gene might account for approximately 20% of recessive LCA. Noting that AIPL1 is not expressed in the cornea and that affected members of 2 unrelated families who had LCA without keratoconus were homozygous for the W278X mutation, the authors suggested that the keratoconus present in affected members of the original LCA4 family, who were also homozygous for W278X, was possibly secondary to eye rubbing due to the LCA. To determine more generally the prevalence of AIPL1 mutations in inherited retinal degenerative disease, Sohocki et al. (2000) screened for mutations in 512 unrelated probands with a range of retinal degenerative diseases. They identified 11 LCA families whose retinal disorder was caused by homozygosity or compound heterozygosity for AIPL1 mutations. They also identified affected individuals in 2 apparently dominant families, diagnosed with juvenile retinitis pigmentosa or dominant cone-rod dystrophy, respectively, who were heterozygous for a 12-bp deletion (604392.0004) in the AIPL1 gene. The results suggested that AIPL1 mutations cause approximately 7% of LCA worldwide and may cause dominant retinopathy.