Leber congenital amaurosis (LCA) accounts for around 5% of all inherited retinal dystrophies and is the earliest and most severe form of inherited retinal disease (1, 2, 3, 4). LCA is clinically and genetically heterogeneous, although most forms show autosomal recessive inheritance. Patients with nonsyndromic LCA typically have an onset of poor vision and nystagmus before 6 months of age, sluggish pupillary reactions, and undetectable electroretinogram (ERG) (5). Their vision, when they are old enough for formal assessment, is usually less than 20/400. Children with LCA are usually hyperopic and may demonstrate the oculodigital sign (repetitive pushing of the knuckle or finger into the eye). The appearance of the fundus is highly variable (6, 7, 8). A normal-appearing fundus may be encountered in infancy (6,8,9), although later in childhood a variety of fundus abnormalities may be present (6,7). These include typical retinitis pigmentosa (RP) (6,7,10), salt-and-pepper appearance of the fundus (10, 11, 12, 13, 14, 15), increased granularity of the retinal pigment epithelium (RPE) (10,13,15), white spots or fundus flecks (6,10,16), macular coloboma (6, 7, 8,10,17), marbled fundus (6,7,10,18,19), peripheral nummular pigmentation (6,10,20), attenuation of the retinal vessels (14,15), and optic atrophy (11). Macular changes, peripapillary hypopigmentation, and lack of pigment migration into the retina (bone spicules) are common features observed in adult patients (15,21).

The clinical heterogeneity of the disease is reflected by the genetic heterogeneity. To date, 14 causative genes have been found to be mutated in patients with LCA and juvenile retinal degeneration, and explain approximately 70% of LCA cases (22). These genes are expressed preferentially in the retina or the RPE. Their putative functions are diverse and include vitamin A metabolism (RPE65) (23,24), phototransduction (RetGC1/GUCY2D) (25,26), retinal embryonic development (CRX) (27), protein trafficking (AIPL1 and RPGRIP1) (28, 29, 30), photoreceptor cell structure (CRB1) (31), and G protein trafficking (CEP290) (32,33).

Compound heterozygous or homozygous mutations in RPE65 result in a number of different retinal degenerations, including LCA and early onset severe retinal dystrophy (EOSRD) (15,23,24,34, 35, 36). In various series, mutations in RPE65 accounted for 3% to 16% of cases of LCA/EOSRD (34,37, 38, 39, 40, 41, 42). Very recently, RPE65 has gained particular interest because of the initiation of small pilot studies in which patients with retinal dystrophies due to mutations in this gene received treatment with subretinal injections of recombinant adeno-associated virus vector expressing RPE65 complementary DNA (43, 44, 45). These studies represent the first attempt to use gene therapy to treat an eye disease. The results of similar treatments in animals have been very promising, and investigators were able to restore vision in a naturally occurring animal model (46, 47, 48, 49). Patients with RPE65 mutations have better visual function than is typically seen in LCA, especially in childhood (15,21,35). Although severe visual impairment is
noted in infancy, with visual responses elicited only in bright surroundings, children with LCA and RPE65 mutations generally have poor but useful vision in early life. Visual performance often improves during the first years of life, allowing the children to attend regular schools, but then gradually declines during the school-age years. A number of patients retain residual islands of peripheral vision, although it is considerably compromised in the third decade of life (39). In higher-age groups, progressive visual field loss and severe visual loss is the norm (50). Nystagmus is often present; however, the roving eye movements commonly seen in LCA are rarely seen in LCA caused by mutations in RPE65 (5).