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, and accounts for at least 5% of these and is 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. All these genes are necessary for normal vision, and play a variety of roles in the development and function of the retina. Mutations in the RPE65 gene are the cause of LCA type 2. This gene is located on the chromosome 1p31.3-p31.2, and expressed in the retinal pigment epithelium. The RPE65 protein converts all-trans retinal back to 11-cis retinal in the visual cycle. Patients with RPE65 mutations defects have no photophobia and may transiently acquire the ability to fix and follow large objects in a well-lit environment.
[See: Yemen > Jakobsson et al., 2014].
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. Two of the families were found to carry mutations in RPE65, indicating the presence of LCA2 in the patients from these families. The first family had two affected siblings born to consanguineous parents. The second family had six affected patients in three different sibships, all having consanguineous parents. In addition, the second family also had an additional affected member in the grandparental generation. All affected members were found to be homozygous of the respective mutations.
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. Two of these families were found to have mutations in the RPE65 gene. All three affected patients with LCA3 tended to prefer daylight. There was no evidence of any neurodevelopment delay in these patients.
El Matri et al. (2006) studied three consanguineous Tunisian families presenting with early onset retinal degeneration. A total of 53 members from these families were evaluated; 11 of them being affected with the condition. Sequencing of the RPE65 gene within this locus identified a homozygous mutation (p.R91W) that co-segregated with the condition in all affected members. The homozygotes were found to have nystagmus and visual acuities. They had no detectable full-field Erg and had an abnormal papillary light reflex. The heterozygous members had a normal visual function.
Jacobsson et al. (2014) analyzed a family from Yemen with three members affected with a severe phenotype of Leber Congenital Amaurosis. The patients showed severe visual impairment and night blindness, starting from infancy. The youngest patient had bilateral hyperopia of +3,50 and visual acuity of 1/60. In the oldest patient, visual acuity was restricted to hand movement in the right eye and counting fingers in the right eye. For the third patients, acuity was 5/60 and 6/60. The patients showed disc pallor, attenuated vessels, white flecks in the retina mid-periphery, and bull's eye maculopathy. Analysis indentified a novel homozygous missense mutation (IVS2-3C>G) in the RPE65 gene in all three affected patients.
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