A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-9 (LCA9) is caused by homozygous or compound heterozygous mutation in the NMNAT1 gene (608700) on chromosome 1p36.

A syndromic form of LCA (SHILCA; 619260) is also caused by mutation in the NMNAT1 gene.

Early-onset neurodegeneration in the human retina can lead to Leber congenital amaurosis (LCA), the most severe human form of inherited photoreceptor-neuron degeneration resulting in congenital blindness, with an incidence of approximately 1 in 80,000 (summary by Koenekoop et al., 2012). NMNAT1 mutations have been observed to cause severe and rapidly progressive macular degeneration, leading to severe central atrophy with an appearance of congenital macular coloboma in the neonatal period, as well as an unusual early-onset atrophy of the optic nerve (Perrault et al., 2012). Some patients present with later onset and milder phenotype than typical LCA (Kumaran et al., 2021).

For a general discussion of the phenotypic and genetic heterogeneity in Leber congenital amaurosis, see LCA1 (204000).

Koenekoop et al. (2012) reexamined affected individuals from 8 families with Leber congenital amaurosis in whom they had identified mutations in the NMNAT1 gene (608700), which is ubiquitously expressed (see MOLECULAR GENETICS). All individuals with biallelic NMNAT1 mutations had severe LCA but otherwise normal physical and mental health. However, in addition to the typical LCA phenotype of nystagmus, severe loss of vision, and abnormal electroretinogram (ERG), all patients were found to have a peculiar, prominent retinal feature termed 'macular coloboma,' which consists of an atrophic lesion in the central retina with a pigmented border, signifying complete loss of neural tissue in the fovea, including photoreceptors, bipolar cells, and ganglion cells. The remainder of the retina was abnormal as well, with pigmentary changes, attenuated retinal blood vessels, and optic disc pallor. In addition, other layers of the retina, such as the ganglion cell layer, were also severely affected. Based on these findings, Koenekoop et al. (2012) suggested that NMNAT1 mutations are associated with severe and rapid foveal degeneration.

Chiang et al. (2012) reported an 8-year-old Canadian boy of western European ancestry with compound heterozygous mutations in the NMNAT1 gene (see 608700.0003) that were inherited from his unaffected mother and father, respectively. Both parents had normal ERGs; 1 parent had midperiphery pigmentary mottling of uncertain significance. In the proband, horizontal nystagmus and poor vision were noted at 2 months of age; examination at 6 months showed hypopigmented macular lesions and he was diagnosed as having a variant of LCA. At 5 years of age, a chin-down head position was adopted, and colors were seen well. Bilateral atrophic macular lesions (colobomas) with outer hyperpigmented borders were noted. By 7 years of age, night vision had become poor. Examination revealed that the atrophic hyperpigmented macular lesion had increased in size, and retinal vasculature had become attenuated; the visual field was approximately 145 degrees. ERG showed primarily dysfunction of the cone system, with slightly delayed rod-cone b-wave implicit times. All photopic responses were reduced in amplitude and isolated cone b-waves and 30-Hz flicker responses were delayed. At 8 years of age, distance visual acuity was 20/200 and 20/400 in the right and left eyes, respectively, with near vision of 20/100 bilaterally; the visual field had decreased to 95 degrees, and colors were still perceived. His diagnosis was revised to 'cone-rod dystrophy' rather than LCA. Ten additional patients with mutations in NMNAT1 who were studied by Chiang et al. (2012) had severe LCA, with a mottled appearance in the peripheral retina and atrophic macular coloboma-like lesions.

Perrault et al. (2012) studied affected individuals from 22 LCA families with homozygous or compound heterozygous mutations in the NMNAT1 gene and observed a consistent phenotype, characterized by severe and rapidly progressive macular degeneration leading to severe central atrophy with an appearance of congenital macular coloboma in the neonatal period. In addition, there was an unusual early-onset atrophy of the optic nerve. Perrault et al. (2012) noted that pseudocoloboma and optic atrophy were not present at birth in patients with NMNAT1 mutations, but rather arose through the progressive yet rapid degeneration of central photoreceptors and retinal ganglion cells. Because studies in Drosophila with retina-specific nmnat knock-out demonstrated that light exposure triggered the loss of photoreceptor cells (Zhai et al., 2006), and the central retina receives most of the photons entering the eye, Perrault et al. (2012) suggested that strict protection against light at birth in patients with NMNAT1-associated LCA might slow the retinal lesions.

Clinical Variability

Khan et al. (2018) reported a 13-year-old girl and her 10-year-old brother from a consanguineous Arab family who had early-onset retinal dystrophy with central nummular macular atrophy. The girl was first noted to have poor daytime vision and nystagmus around age 3 years, and at age 13 had visual acuity of 4/200 vision bilaterally. Her brother showed impaired vision around 1 year of age, with progressive worsening; on examination at age 10 he had visual acuity of 2/200 bilaterally. Both sibs exhibited eccentric fixation, moderate exotropia, and small-amplitude high-frequency pendular nystagmus, and funduscopy revealed a large central macular nummular atrophic lesion bilaterally, with fine mottling of the posterior pole. An ERG in the sister showed depressed and delayed responses affecting cones more than rods, consistent with a cone-rod dystrophy.

Nash et al. (2018) reported 2 unrelated female patients with early-onset retinal dystrophy and mutations in the NMNAT1 gene. Case 1 was a 26-year-old Indian woman who was given a 'provisional' diagnosis of cone disease on the basis of 'bull's eye' macular lesions at age 4 years. At age 25 years, her diagnosis was changed to LCA. Examination at age 26 showed reduced visual acuity of 20/150 and 20/400 in the right and left eyes. Funduscopy revealed bilateral coloboma-like macular atrophy that extended nasal to the optic disc. Fundus autofluorescence (FAF) demonstrated macular hypoautofluorescence at the macular lesions, surrounded by a ring of hyperautofluorescence. Full-field ERG showed mildly reduced scotopic responses and decreased photopic responses. The authors considered the loss of central vision and ERG findings to be consistent with cone dystrophy. Case 2 was a 14-year-old Caucasian girl who at age 7 years had visual acuity of approximately 20/300 bilaterally, which deteriorated to 20/400 by age 14. Granular atrophic macular lesions were 'strikingly similar' to those observed in case 1, and ERG revealed reduced photopic and scotopic responses consistent with cone-rod dystrophy. In both patients, ocular coherence tomography (OCT) showed loss of the photoreceptor layer in the region of macular atrophy. The authors noted that the macular atrophy in both cases was very similar to that seen in previously reported patients with NMNAT1-associated LCA, and that the patient described with LCA by Chiang et al. (2012) also had an ERG suggestive of cone disease.

Bedoukian et al. (2020) studied a 4-year-old Egyptian boy (P1) and his 7-year-old sister (P2) who had onset of reduced vision and nystagmus at around 3 years of age. Visual acuity was 20/100 at age 3 and remained approximately 20/125 at age 4 in the boy, whereas in the sister, visual acuity was 20/70 and 20/80 at age 4 and declined to 20/200 and 20/300 at age 7. Both had reduced color vision. Fundus examination showed foveal and parafoveal depigmentation, and near-infrared FAF showed deep foveal hypoautofluorescence surrounded by a halo of greater signal. Spectral-domain OCT revealed hypoplastic foveas, with a thin outer nuclear layer centrally but normal thickness beyond the vascular arcades. At the foveal center, cone outer segments were absent and the outer nuclear layer was further hyporeflective. ERGs in P1 showed low-normal rod responses with severely reduced cone responses, consistent with cone-rod dystrophy.

Kumaran et al. (2021) reported a sister (patient 1) and brother (patient 2) who had good visual acuity until the ages of 6 and 11 years, respectively, with subsequent gradual worsening into their twenties. ERGs at age 10 and 16 years showed generalized rod and cone system dysfunction of moderate severity, with pattern ERG evidence of severe macular involvement. Repeat testing at the ages of 26 and 33 years revealed only mild worsening of rod photoreceptor function in both.

Keen et al. (2003) reported a large consanguineous Pakistani family in which 11 members had Leber congenital amaurosis that did not show linkage to known LCA loci. By a whole genome linkage analysis, they found significant positive lod scores (multipoint lod = 3.5) at chromosome 1p36, between markers D1S1612 and D1S3669. When consanguineous loops within the pedigree were included in the analysis, they obtained a 3-point lod score of 4.4 between markers D1S2667 and D1S1597. The novel LCA locus, designated LCA9, was located approximately 7 to 14 Mb from the telomere. By direct sequencing and SSCP analysis, Keen et al. (2003) found no mutations in the RBP7 gene (608604).

The transmission pattern of LCA9 in the patients reported by Koenekoop et al. (2012) was consistent with autosomal recessive inheritance.

In 50 individuals with Leber congenital amaurosis who did not have mutations in the known LCA-associated genes, Koenekoop et al. (2012) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the NMNAT1 gene in 3 patients, all of whom carried an E257K mutation (608700.0002) in combination with another missense mutation (see, e.g., 608700.0003-608700.0005). Analysis of NMNAT1 in another 150 LCA patients revealed homozygous or compound heterozygous mutations in 4 more patients (see, e.g., 608700.0006 and 608700.0007), 2 of whom also had at least 1 E257K allele. In addition, Koenekoop et al. (2012) sequenced the NMNAT1 gene in the large Pakistani family with LCA mapping to 1p36 that was originally reported by Keen et al. (2003), and identified a homozygous read-through mutation (X280Q; 608700.0001). The mutations segregated with disease in each of the families, and none were found in 200 controls. Genotyping of surrounding SNPs and haplotype analysis confirmed that all individuals of European descent carrying E257K shared the same haplotype, strongly suggesting that this represents a founder mutation.

In a patient with LCA who was negative for mutation in 17 known LCA-associated genes, Chiang et al. (2012) performed whole-exome sequencing and identified compound heterozygosity for a missense and a nonsense mutation in the NMNAT1 gene (E257K, 608700.0002; W169X, 608700.0006). The mutations were confirmed by Sanger sequencing and found to segregate with disease in the patient's family. Sequencing NMNAT1 in 50 additional unrelated LCA cases with no mutations in known LCA genes revealed 10 more cases with compound heterozygous mutations in NMNAT1 (see, e.g., 608700.0002-608700.0004 and 608700.0006). All 11 patients carried the E257K mutation as 1 of their 2 variant alleles. Chiang et al. (2012) noted that 4 patients who also carried the nonsense allele W169X were blind at birth, whereas in the 5 patients who carried only missense variants, vision decreased within a few years after birth. The retinas of all affected individuals had a mottled aspect in the periphery and atrophic macular coloboma-like lesions; the macular lesions were observed to enlarge over time in 2 patients.

By exome sequencing in a consanguineous Pakistani pedigree in which 3 sibs and 2 cousins had LCA, Falk et al. (2012) identified a homozygous missense mutation in the NMNAT1 gene (V9M; 608700.0009) that segregated with disease. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 mutations in 13 additional probands, including 6 who carried the E257K mutation on 1 allele. Review of available clinical information in mutation-positive LCA patients indicated that the majority had atrophic macular lesions.

Perrault et al. (2012) performed whole-exome resequencing in 5 French index LCA cases without mutations in known LCA genes and identified compound heterozygosity for mutations in the NMNAT1 gene that segregated with disease in each family and were not found in 200 controls. Sanger sequencing of NMNAT1 coding exon and intron-exon boundaries in 256 additional index cases without mutations in known LCA genes revealed another 20 cases with homozygous (608700.0006) or compound heterozygous mutations (see, e.g., 608700.0002 and 608700.0005). Seven probands in whom only a single heterozygous NMNAT1 mutation was found presented an identical phenotype to that of patients in whom 2 mutations were identified, suggesting that the former harbored a second undetected NMNAT1 mutant allele. The most common mutation identified was the E257K variant, which was present on 1 allele in 23 of the 29 index cases with mutation in NMNAT1.

Bedoni et al. (2020) analyzed a Spanish cohort of 76 patients with LCA or early-onset retinal dystrophy and identified a 6-year-old boy with LCA who was compound heterozygous for the common E257K variant and a large duplication within the NMNAT1 gene (608700.0010). The boy presented at 3 years of age with light perception-only in both eyes, moderate exotropia, nystagmus, central macular atrophy with fine peripheral mottling on funduscopy, and nonrecordable full-field ERG. The authors stated that the boy's phenotype was 'fully compatible' with typical NMNAT1-associated LCA.

In an Arab sister and brother with early-onset retinal dystrophy with central nummular macular atrophy, who had ERG findings consistent with a cone-rod dystrophy, Khan et al. (2018) performed targeted next-generation sequencing using a retinal dystrophy gene panel and identified homozygosity for a missense mutation in the NMNAT1 gene (N167S; 608700.0012) that segregated with disease in the family and was not found in public variant databases. The authors stated that nummular macular atrophy in the context of early-onset retinal dystrophy should raise suspicion for mutations in the NMNAT1 gene.

In a 26-year-old Indian woman (case 1) who had early-onset retinal dystrophy and coloboma-like macular atrophy, with loss of central vision and ERG findings consistent with cone dystrophy, Nash et al. (2018) performed Sanger sequencing and identified homozygosity for a missense mutation in the NMNAT1 gene (E91K; 608700.0013). In a similarly affected 14-year-old Caucasian girl (case 2), who had ERG findings more consistent with cone-rod dystrophy, Nash et al. (2018) performed whole-genome analysis of genes known to be associated with cone or cone-rod dystrophy or other inherited retinal dystrophies, and identified compound heterozygosity for the common E257K variant and another missense mutation in the NMNAT1 gene (N18S; 608700.0014). The authors noted that these variants had previously been reported in patients with LCA.

In an Egyptian brother and sister who had early-onset progressive retinal dysfunction and foveal hypoplasia, consistent with cone-rod dystrophy, Bedoukian et al. (2020) identified compound heterozygosity for the E257K variant and another missense mutation in the NMNAT1 gene (V82L; 608700.0015). The authors concluded that NMNAT1 mutations cause a consistent phenotype characterized by early-onset progressive retina-wide dysfunction, affecting cones more than rods, with predominantly central abnormalities ranging from hypoplasia to atrophy of the fovea (pseudocoloboma), supporting a critical role for NMNAT1 in central retinal development and maintenance.

In a sister and brother with childhood-onset rod-cone dystrophy, Kumaran et al. (2021) identified compound heterozygosity for the E257K and N18S mutations in NMNAT1, noting that these cases extended the phenotypic spectrum associated with the NMNAT1 gene.