Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. ... Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). - Genetic Heterogeneity of Leber Congenital Amaurosis LCA2 (204100) is caused by mutation in the RPE65 gene (RPE65; 180069) on chromosome 1p31. LCA3 (604232) is caused by mutation in the SPATA7 gene (609868) on chromosome 14q31.3. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13.1. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14.1. LCA6 (613826) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. LCA7 (613829) is caused by mutation in the CRX gene (602225) on chromosome 19q13.3. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31-q32. LCA9 (608553) is a locus that has been mapped to chromosome 1p36. LCA10 (611755) is caused by mutation in the CEP290 gene (610142) on chromosome 12q21 and may account for as many as 21% of cases of LCA. LCA11 (613837) is caused by mutation in the IMPDH1 gene (146690) on chromosome 7q31.3-q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32.3. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24.1. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q31. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21.3. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. Perrault et al. (1999) provided a review of Leber congenital amaurosis, with emphasis on genetic heterogeneity. Wiszniewski et al. (2011) analyzed 13 known LCA genes in 60 LCA probands, and identified homozygous or compound heterozygous mutations in 42 (70%). In addition, a third disease-associated mutant allele at a second locus was identified in 7 (12%) of the 60 patients. Wiszniewski et al. (2011) stated that the significance of the third mutated allele was unknown, but suggested that mutational load might be important to penetrance of the LCA phenotype. Because LCA manifests very early in life and results in profound vision loss, patients with mutations in other syndromic or nonsyndromic eye disease genes may receive an initial diagnosis of LCA, prior to development of syndromic features or before more thorough phenotyping can be performed (see, e.g., Senior-Loken syndrome-5, 609254).
Leber (1869), pronounced LAY-ber (see also 535000 and 204100), described this condition as pigmentary retinopathy with congenital amaurosis. Leber (1871) recognized the familial nature of the condition and the role of consanguinity.
Alstrom (1957) found that ... Leber (1869), pronounced LAY-ber (see also 535000 and 204100), described this condition as pigmentary retinopathy with congenital amaurosis. Leber (1871) recognized the familial nature of the condition and the role of consanguinity. Alstrom (1957) found that a single disorder inherited as an autosomal recessive was responsible for 10% of blindness in Sweden. Total blindness or greatly impaired vision with loss of central vision was present. Early in life fundus changes were lacking, but by age 50 years widespread atrophy exposed white areas of sclera. Cataract and keratoconus were associated. Keratoconus was of diagnostic usefulness. No manifestations except those in the eye were discovered. Alstrom (1957) stated: 'It was not until combined genealogic and genetico-statistical studies had been made, and clinical data collected over a long period that the congenital development and affinity of these apparently heterogeneous cases could be established with some degree of probability.' Striking pedigrees were presented. There is a wide variety of fundus characteristics in the various forms of LCA (Chung and Traboulsi, 2009).
Cremers et al. (2002) reviewed the molecular genetics of Leber congenital amaurosis, including the structures and roles of the 6 known gene products.
Hanein et al. (2004) reported a comprehensive mutation analysis of all known LCA-related ... Cremers et al. (2002) reviewed the molecular genetics of Leber congenital amaurosis, including the structures and roles of the 6 known gene products. Hanein et al. (2004) reported a comprehensive mutation analysis of all known LCA-related genes in 179 unrelated LCA patients, of whom 52 were familial cases and 127 sporadic. Twenty-seven of the sporadic cases were from consanguineous families. Mutations were identified in 47.5% of patients. The most frequent cause of LCA was mutation in the GUCY2D gene, accounting for 21.2%, followed by CRB1 at 10%, RPE65 at 6.1%, RPGRIP1 at 4.5%, AIPL1 at 3.4%, TULP1 at 1.7%, and CRX at 0.6%. Genotype/phenotype correlations were found that allowed the division of patients into 2 main groups: the first group included patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, whereas the second group included patients affected with severe yet progressive rod-cone dystrophy. Furthermore, objective ophthalmologic data allowed the subdivision of each group into 2 subtypes. Based on these findings, Hanein et al. (2004) drew decisional flowcharts directing the molecular analysis of LCA genes in a given case. If the most precise clinical history beginning at birth is available, these flowcharts can lighten the heavy task of genotyping new patients. - Modifier Genes Zernant et al. (2005) evaluated 298 LCA patients using a microarray disease chip that included all known disease-associated variants from coding regions and adjacent intronic sequences of 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and 2 early-onset retinitis pigmentosa (RP; 268000) genes (MERTK; 604705 and LRAT, 604863). The microarray was more than 99% effective in determining existing genetic variation in the 93 patients with known mutations, and yielded at least 1 disease-associated allele in approximately one-third of the 205 novel patients. More than 2 variants were discovered in 22 (7.3%) of the 298 patients, suggesting a modifier effect from more than 1 gene. In support of the latter hypothesis, Zernant et al. (2005) found that the third allele segregated with a more severe disease phenotype in at least 5 families. Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations, including LCA.
Because the clinical presentation of Leber congenital amaurosis in humans is similar to the phenotype of the rd mouse, in which a nonsense mutation in the beta subunit of the cGMP phosphodiesterase gene (Pdeb) has been defined as ... Because the clinical presentation of Leber congenital amaurosis in humans is similar to the phenotype of the rd mouse, in which a nonsense mutation in the beta subunit of the cGMP phosphodiesterase gene (Pdeb) has been defined as the cause, Riess et al. (1992) studied the possible involvement of mutations in the PDEB gene (180072) in LCA. The PDEB gene had been mapped to 4p16.3. In 6 of 23 LCA families of various ethnic backgrounds, they excluded PDEB as the cause on the basis of linkage analysis using highly polymorphic (CA)n microsatellites. In the remaining 17 families, they used single-strand gel electrophoresis (SSGE) to search for mutations in the 22 exons of the PDEB gene. Although multiple exonic polymorphisms were determined, no changes were identified that could be causative for the LCA phenotype. Studying the same group of French families, Perrault et al. (1996) demonstrated mutations in the GUC2D gene as the cause of type I Leber congenital amaurosis in some but not all families. They identified 2 missense mutations (600179.0001; 600179.0004) and 2 frameshift mutations (600179.0002; 600179.0003) in GUC2D. As specific guanylate cyclase activating proteins (GCAPs) are required for activity of the retina-specific guanylate cyclase, Perrault et al. (1996) raised the question of whether some LCA cases unlinked to 17p13 could be accounted for by mutations in the gene encoding guanylate cyclase activator-1 (600364) on 6p21.1. Sohocki et al. (2000) identified mutations in the AIPL1 gene (604392), which, like GUCY2D, maps to 17p13, as the cause of type IV Leber congenital amaurosis (604393). Milam et al. (2003) studied the retinal degeneration in an 11.5-year-old patient with Leber congenital amaurosis caused by mutation in GUCY2D. Visual acuity prior to death was light perception only. Postmortem histopathologic study of the retina revealed substantial numbers of retained cones and rods in the macula and far periphery. The authors concluded that the finding of numerous photoreceptors at this age might portend well for therapies designed to restore vision at the photoreceptor level. Of families with GUCY2D mutations as the basis of Leber congenital amaurosis, 70% originate from Mediterranean countries, the remaining families originating from various countries around the world. Hanein et al. (2002) identified a homozygous 2943G deletion in the GUCY2D gene in 3 unrelated and nonconsanguineous Leber congenital amaurosis (600179.0009) families of Finnish origin, suggesting a founder effect. No linkage disequilibrium was found using polymorphic markers flanking the GUCY2D gene, supporting the view that the mutation is very ancient. Haplotype studies and Bayesian calculation pointed the founder mutation to 150 generations (i.e., 3,000 years ago). - Associations Pending Confirmation See 606844.0009, 600053, and 276903 for discussion of a possible association of LCA with mutation in the ALMS1, CNGA3, and MYO7A genes, respectively.
Leber congenital amaurosis is estimated to affect 1 in 81,000 to 1 in 30,000 live births, although it may be more common in communities that are relatively genetically isolated or in countries with common consanguineous pairings. LCA accounts ... Leber congenital amaurosis is estimated to affect 1 in 81,000 to 1 in 30,000 live births, although it may be more common in communities that are relatively genetically isolated or in countries with common consanguineous pairings. LCA accounts for over 5% of all inherited retinopathies and 20% of children attending schools for the visually impaired (summary by Chung and Traboulsi, 2009).