Leber congenital amaurosis (LCA), a severe dystrophy of the retina, typically becomes evident in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Visual acuity is rarely better than 20/400. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. The electroretinogram (ERG) is characteristically "nondetectable" or severely subnormal.
The diagnosis of LCA is established by clinical findings. Molecular genetic testing is clinically available for the 12 genes currently known to be associated with LCA: GUCY2D (locus name: LCA1), RPE65 (LCA2), SPATA7 (LCA3), AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX (LCA7), CRB1 (LCA8), CEP290 (LCA10), IMPDH1 (LCA11), RD3 (LCA12), and RDH12 (LCA13). Together, mutation in these genes is estimated to account for, depending on the survey, about 40%-50% of all LCA. At least one other disease locus for LCA has been reported, but the gene is not known.
Most often LCA is inherited in an autosomal recessive manner. At conception, each sib of an individual with recessively inherited LCA has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk may be possible if the disease-causing mutations in the family are known. Rarely, LCA is inherited in an autosomal dominant manner as a result of mutations within CRX; the possibility of autosomal dominant inheritance resulting from a de novo CRX mutation should be considered in individuals with LCA and no family history of the disease.