Leber Congenital Amaurosis 1

A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-1 (LCA1) is caused by homozygous mutation in the gene encoding retinal guanylate cyclase (GUCY2D; 600179) on chromosome 17p13.

Heterozygous mutation in the GUCY2D gene causes an allelic disorder, cone-rod dystrophy-6 (CORD6; 601777), and homozygous mutation in the same gene has also been found to cause autosomal recessive CORD (see 610777).

Description

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. LCA4 (604393) is caused by mutation in the AIPL1 gene (604392) on chromosome 17p13. LCA5 (604537) is caused by mutation in the LCA5 gene (611408) on chromosome 6q14. 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. LCA8 (613835) is caused by mutation in the CRB1 gene (604210) on chromosome 1q31. LCA9 (608553) is caused by mutation in the NMNAT1 gene (608700) on 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 7q32. LCA12 (610612) is caused by mutation in the RD3 gene (180040) on chromosome 1q32. LCA13 (612712) is caused by mutation in the RDH12 gene (608830) on chromosome 14q24. LCA14 (613341) is caused by mutation in the LRAT gene (604863) on chromosome 4q32. LCA15 (613843) is caused by mutation in the TULP1 gene (602280) on chromosome 6p21. LCA16 (614186) is caused by mutation in the KCNJ13 gene (603208) on chromosome 2q37. LCA17 (615360) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22. LCA18 (see 608133) is caused by mutation in the PRPH2 gene (179605) on chromosome 6p21. LCA19 (618513) is caused by mutation in the USP45 gene (618439) on chromosome 6q16.

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).

Clinical Features

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).

Other Features

The association of mental retardation and various neuropsychiatric disorders with LCA has been reported in some patients. In a classic study in Sweden, Alstrom (1957) found no association with neurologic disorders but their patients were drawn from a school for mentally normal blind children. Schappert-Kimmijser et al. (1959), on the other hand, found major neuropsychiatric problems in 25% of the children of their Dutch series. Nickel and Hoyt (1982), who examined this question, found abnormality of the CT scan in only 3 of 31 patients; in each of the 3, hypoplasia of the cerebellar vermis was found. The cerebellar vermis begins to appear as a distinct structure at the same stage of embryogenesis (12 weeks) that active differentiation of the photoreceptor layer of the retina is taking place. All of the patients of Nickel and Hoyt (1982) had vision no better than light perception. However, some authors have reported a small group of children with reasonably good central vision when old enough to be tested, despite apparent blindness and reduced or absent ERG in infancy.

Schuil et al. (1998) investigated a group of 229 patients with Leber congenital amaurosis for associated defects. They focused particularly on the occurrence of mental retardation, which was found in 19.8% of the patients. They also paid special attention to the frequency of sib pairs in which one was mentally retarded and the other functioned normally. They found 11 discordant sib pairs, suggesting that mental retardation is a variable expression of Leber congenital amaurosis.

To investigate whether neurodevelopmental delay is a feature of strictly defined LCA, i.e., otherwise nonsyndromic with documentation of a nonrecordable ERG between 1 and 3 years of life, Khan et al. (2014) performed targeted next-generation sequencing with a panel of 14 LCA genes in 23 affected children from 19 endogamous and/or consanguineous Saudi Arabian families from a retrospective case series. Five (22%) of the 23 children had concomitant neurodevelopmental delay, 2 with mutations in the RPGRIP1 gene and 3 with mutations in the GUCY2D gene.

Congenital retinal blindness indistinguishable from Leber congenital amaurosis occurs with renal dysplasia as a clearly distinct entity (266900). In a family reported by Rahn et al. (1968), there were cigarette-paper scars and stretchable skin suggesting Ehlers-Danlos syndrome. Hayasaka et al. (1986) found hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation in a brother and sister with Leber congenital amaurosis. The sister died at age 4 months of massive pericardial effusion. Hyperthreoninemia as an independent defect has been described (273770). In the patients of Hayasaka et al. (1986), serum threonine levels were increased 3- to 6-fold. Moore and Taylor (1984) described 3 boys, including 2 brothers, who had association of congenital retinal blindness with an ocular motor disorder similar to ocular motor apraxia.

Ek et al. (1986) described a boy with psychomotor retardation and Leber congenital amaurosis, sensory hearing loss, and hepatomegaly, who had biochemical findings suggesting a peroxisomal disorder. The virtual lack of peroxisomes in a liver biopsy specimen lent further support to the suggestion that some patients with Leber congenital amaurosis have a peroxisomal disorder.

Ehara et al. (1997) reported a previously undescribed autosomal recessive syndrome in 4 Japanese children from 2 unrelated families. All 4 children had Leber congenital amaurosis, short stature, developmental delay, hepatic dysfunction, and metabolic acidosis. Three of the 4 children had decreased growth hormone secretion. The karyotype was normal in all 3 children in which it was tested. One of the children died without growth hormone secretion or karyotype having been assessed. Two of the 4 patients were monozygotic twins. One patient underwent a muscle biopsy at age 11 years to look for evidence of a mitochondrial disorder. Mild variation in fiber size and type 2 fiber atrophy were seen on histopathologic examination, but no ragged-red fibers were observed. No mitochondrial DNA alterations were found. Autosomal recessive inheritance was suggested on the basis of 2 sibs born to healthy parents. In neither family were the parents consanguineous.

Yano et al. (1998) reported 2 sisters, born of first-cousin parents, with Leber congenital amaurosis, cerebellar vermis hypoplasia, and facial dysmorphism including hypertelorism, short philtrum, thin upper lip, and prominent jaw. Both were severely mentally retarded with abnormal behavior. Mild skeletal abnormalities consisted of limited extension of elbows and fingers and talipes equinovalgus. One sister had a scalp skin defect and renal anomalies. The authors postulated that their report may represent a distinct clinical entity or a severe manifestation of one of the described LCAs.

Pathogenesis

Jacobson et al. (2013) characterized a cohort of 11 patients with LCA and mutations in the GUCY2D gene (see MOLECULAR GENETICS) In vivo analyses of retinal architecture indicated intact rod photoreceptors in all patients, but abnormalities in foveal cones. Functional phenotyping revealed some patients with and some without detectable cone vision. Rod vision was retained in some patients, and did not correlate with the extent of cone vision or age. In patients without cone vision, rod vision functioned unsaturated under bright ambient illumination. In vitro analyses of the mutant alleles showed that in addition to the major truncation of the essential catalytic domain in GC1, some missense mutations in LCA1 patients result in a severe loss of function by inactivating GC1 catalytic activity and/or ability to interact with the activator proteins, GCAPs. The differences in rod sensitivities among patients were not explained by the biochemical properties of the mutants. However, GC1 mutant alleles with residual biochemical activity in vitro were associated with retained cone vision in vivo. The authors suggested that the degree of cone vision abnormality is related to the level of GC1 activity, and suggested that cone function should be the efficacy outcome in clinical trials of gene augmentation therapy in LCA1.

Nomenclature

Congenital nystagmus and cerebral (or cortical) blindness were terms often assigned to these cases before the chorioretinal site of abnormality was appreciated. Sometimes it is confused with retinitis pigmentosa. Retinal aplasia is the term frequently used in England. Congenital absence of the rods and cones is a designation often used in the United States. Congenital retinal blindness (CRB) is an alternative designation.

Inheritance

Riess et al. (1992) confirmed that LCA1 is an autosomal recessive disorder.

In Holland, Schappert-Kimmijser et al. (1959) studied 227 cases of LCA and presented pedigrees typical of autosomal recessive inheritance.

An autosomal dominant mode of inheritance was suggested in a total of 4 pedigrees reported by Sorsby and Williams (1960) and Francois (1968).

In a study of 43 patients with LCA, Lambert et al. (1993) found that all of the pedigrees were consistent with autosomal recessive inheritance and that the segregation frequency using classic segregation analysis was 0.24 +/- 0.07. In 6 of 7 affected sib pairs, concordance in regard to systemic abnormalities was found. Five of the sib pairs had normal intelligence and 4 of the 5 had no systemic abnormalities. In the fifth, cardiomyopathy was associated (Russell-Eggitt et al., 1989).

Population Genetics

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).

Mapping

Camuzat et al. (1995) mapped a gene for Leber congenital amaurosis to the distal short arm of chromosome 17 by linkage analysis in 15 multiplex families; maximum lod = 5.14 at theta = 0.15 for a probe at the D17S1353 locus. When they split the collection of families into 2 groups according to the ethnic origin of the patients, they were able to confirm the presence of a gene for LCA on 17p by both homozygosity mapping and linkage analysis in 5 families of Maghrebian origin; (maximum lod = 7.21 at theta = 0.01 at the D17S1353 locus), while negative results were found in 10 families of French ancestry. Haplotype analyses supported the placement of the gene, which they designated LCA1, between loci D17S796 and D17S786. From the location of the markers, Camuzat et al. (1995) concluded that the LCA1 gene in the North African families is located at 17p13. The linkage demonstration of genetic heterogeneity in LCA confirmed the conclusion of Waardenburg and Schappert-Kimmijser (1963) based on the observation of normal children born to 2 affected parents. Camuzat et al. (1995) stated that the genes on distal 17p that are good candidate genes for LCA1 include recoverin (179618), beta-arrestin 2 (107941), retinal guanylate cyclase (GUC2D; 600179), and phosphatidylinositol transfer protein (600174). Camuzat et al. (1996) further refined the LCA1 locus to a 1-cM region on chromosome 17p between markers D17S938 and D17S1353.

Molecular Genetics

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).

In a cohort of 58 patients with LCA, Yzer et al. (2006) screened for mutations in 6 known LCA-associated genes and identified 6 patients who were homozygous or compound heterozygous for mutations in the GUCY2D gene (see, e.g., 600179.0001, 600179.0012, and 600179.0015). Within the cohort, the patients with GUCY2D mutations had the most severe form of LCA, compared to patients with mutations in the CRB1, AIPL1, or RPE65 genes. The authors noted that 8 of the 12 alleles carried the R768W mutation (600179.0012) and that all 8 were Dutch or Belgian in origin, suggestive of a founder effect in the northwestern region of Europe.

Jacobson et al. (2013) reported 10 patients with LCA who carried the R768W mutation in the GUCY2D gene, including 2 homozygotes and 8 compound heterozygotes. The patients were all of British/Irish or Scandinavian ancestry, except for 1 Greek patient, who was homozygous for R768W.

Associations Pending Confirmation

See 606844.0009, 600053, 276903, and 616787.0001 for discussion of a possible association of LCA with mutation in the ALMS1, CNGA3, MYO7A, and CLUAP1 genes, respectively.

Genotype/Phenotype Correlations

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.