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., ...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 (608700) mutations consistently 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)
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 ...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
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 ...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