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Leber congenital amaurosis (LCA) (MIM 204000) is characterized by severe or complete loss of visual function apparent early in infancy with failure to follow visual stimuli, nystagmus, and roving eye movements. Affected individuals have an extinguished electroretinogram and eventually develop abnormalities of the ocular fundus including a pigmentary retinopathy. Although many LCA patients have no additional abnormalities, in some there is associated mental retardation. LCA is inherited as an autosomal recessive trait. Aside from helping the patient adapt to life with no visual function, there is no treatment.
The LCA phenotype is genetically heterogeneous, with mutations in at least three genes causing the disorder. LCA1 maps to 17p13 and encodes retGC-1, a photoreceptor-specific guanylate cyclase. LCA2 maps to 1p31 and encodes RPE65, a 61-kDa retinal pigment epithelium (RPE)-specific microsomal protein. Mutations at this locus also have been shown to cause childhood-onset severe retinal dystrophy (CSRD). LCA3 maps to 19q13.3 and encodes CRX, a homeodomain transcription factor that is a positive activator of several photoreceptor-specific genes.
Animal models of LCA include the rd/rd chick, in which blindness precedes photoreceptor degeneration. The responsible gene (GC1) encodes a guanylate cyclase with 61 percent amino acid identity to mammalian guanylate cyclase 1, and a deletion/insertion mutant allele has been identified in the rd/rd chick. Additionally, a mouse model with targeted disruption of the murine guanylate cyclase gene (GCE) has been produced. These mice exhibit an early loss of the cone ERG followed later by loss of the rod ERG. Finally, a mouse model with targeted disruption of the RPE65 gene has been produced. These animals have a severely abnormal dark-adapted ERG and subtle morphologic abnormalities of the photoreceptor outer segments.
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Originally described by Leber in 1869, Leber congenital amaurosis (LCA) is an autosomal recessive disease distinct from other retinal dystrophies and responsible for congenital blindness.1 The diagnosis is usually made at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus, and an extinguished electroretinogram (ERG)2. This condition, the most early and severe of all inherited retinopathies, was largely unrecognized until two population studies from Sweden3 and Holland4 revealed that it is not uncommon. Indeed, LCA accounts for at least 5 percent of all retinal dystrophies and probably much more in countries with a high rate of consanguinity.5,6 Genetic heterogeneity in LCA has long been suspected since the report by Waardenburg of normal children born to affected parents.7 LCA is either isolated or associated with various extraocular abnormalities, including renal dysplasia (Senior-Loken syndrome, MIM 266900), vermis agenesia (Joubert syndrome, MIM 213300), and inherited metabolic diseases, i.e., hyperthreoninemia8 and peroxisomal disorders.9 These latter associations most likely represent distinct clinical and genetic entities and will not be covered in this chapter.
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Until 1996, little was known regarding the pathophysiology of LCA, but ...