Leber's congenital amaurosis (LCA) is a rare inherited retinal dystrophy characterized by vision loss, often from birth. LCA is the most severe form of all inherited retinal dystrophies, accounting for at least 5% of all such cases. It is also one of the main causes of blindness in children. The estimated birth prevalence of LCA is two to three per 100,000 births. There are at least 13 types of Leber congenital amaurosis. These types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.
Clinical diagnosis is based on clinical history of failure to develop reactions to visual stimuli, roving eye movements or nystagmus, sluggish pupillary responses and a normal, or less frequently an abnormal fundus on dilated fundoscopy. To date, no definitive treatment or cure for LCA exists.
Leber's congenital amaurosis is generally inherited in an autosomal recessive pattern, although some autosomal dominant families have been reported. At least 20 different genes involved in LCA have been identified. LCA type I is caused by mutations in the GUCY2D gene, located on chromosome 17p13.1. This gene is expressed in the photoreceptor cells, where it plays an essential role in normal vision.
Perrault et al. (1996) conducted genetic analysis for all sibs with Leber congenital amaurosis in two consanguineous Arab-Algerian families and found homozygosity for a T>C transition in exon 8 at nucleotide 1767 of the GUC2D gene.
Li et al. (2009) studied 37 multigenerational consanguineous families from Saudi Arabia with Leber congenital amaurosis. Of the 417 individuals from these families, 117 were affected. All affected patients had early loss of vision, with variations in the clinical phenotypes. One family was found to carry a mutation in the GUCY2D gene, indicating the presence of LCA1 in the patients from this family. This family had three affected siblings born to healthy consanguineous parents. The patients showed a relatively normal retinal appearance with no or minimal vascular attenuation. One of them showed navigational vision, while another had 'fix and follow' vision. All affected members were found to be homozygous for the respective mutations.
Wang et al. (2011) performed homozygosity mapping, whole-exome sequencing and direct sequencing to identify mutations affecting a collection of six consanguineous Saudi families with Leber congenital amaurosis (LCA). There were 14 affected members who had vision defects since birth or as early as two years of age. A total of five disease-causing mutations located on four genes (ALMS1, IQCB, CNGA3, and MYO7A) were identified in the six families. The novel variants were rare and were absent in all 200 normal matching controls. In addition, they have been not recorded in the dbSNP 130 database and the 1,000 Genome database. Patients with IQCB1 gene mutations had typical LCA phenotypes including; nystagmus, nonrecordable electroretinograms (ERGs), and other visual defects. Patients with CNGA3 mutation showed early-onset nystagmus (at 5-months old), sluggish pupils, no visual response, and nonrecordable ERG at 10 months of age. All patients with MYO7A mutation have had poor vision since birth, nystagmus, neuroepithelial atrophy, and nonrecordable ERGs.
Khan et al. (2014) conducted a retrospective case series analysis for a consecutive cohort of Saudi children diagnosed with LCA between 2012 and 2014. A total of 23 patients from 19 consanguineous or endogamous families were screened for mutations in a panel of 14 known LCA genes. Five of these families were found to have recessive mutations in the GUCY2D gene. All five affected patients from these families with LCA3 tended to prefer darkness. Three of these children showed obvious neurorodevelopmental delay.
Soens et al. (2016) reported on a 5-year-old Saudi boy with LCA. At 6-months of age, the child’s vision was found to be limited to light perception. He also suffered from nystagmus, the oculo-digit sign and an absent electroretinogram. Whole exome sequencing found that the patient’s CLUAP1 gene contained a homozygous non-synonymous mutation c.817C>T (c.319C>T in the short isoform), resulting in a p.L273F substitution at a highly conserved residue within the coiled-coil domain (p.L107F in the short isoform). Functional studies found that the mutation was highly hypomorphic and resulted in a CLUAP1 protein with only 5% of the activity of the wildtype.
Safieh et al., (2016) described a 6-month old Saudi girl with Leber congenital amaurosis. She was born to consanguineous parents and was noticed to have rapid synchronous eye movements of both eyes at 40-days of age. Clinical examination after 18-months showed classical oculodigital sign, moderate bilateral enophthalmos, irregular nystagmus, mild neuro-epithelial atrophy, and mild retinal vascular attenuation. A novel pathogenic missense mutation in the GUCY2D gene was identified in the patient. The authors concluded that this mutation expanded the genotypic spectrum of congenital retinal dystrophies in the Saudi population.
Perrault et al. (1996) conducted a genetic analysis for three families from Tunisia with Leber congenital amaurosis. The first family was a Jewish Sephardi family in which affected members were homozygous for a 1-bp deletion (c.460delC) in exon 2 at nucleotide 460 of GUC2D. The second family was of Arab Tunisian origin. Affected members were homozygous for a 1-bp deletion in exon 2 at nucleotide 693 (693delC) of GUC2D. In the third family, a consanguineous Arab Tunisian family, all sibs had homozygosity for a G>T transversion at nucleotide 227 of GUC2D.