Leber Congenital Amaurosis – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE. SEE LEBER CONGENITAL AMAUROSIS / EARLY-ONSET SEVERE RETINAL DYSTROPHY OVERVIEW.

Clinical characteristics: 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.

Diagnosis/testing: The diagnosis of LCA is established by clinical findings. Pathogenic variants in 17 genes are known to cause LCA: GUCY2D (locus name: LCA1), RPE65 (LCA2), SPATA7 (LCA3), AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX (LCA7), CRB1 (LCA8), NMNAT1 (LCA9), CEP290 (LCA10), IMPDH1 (LCA11), RD3 (LCA12), RDH12 (LCA13), LRAT (LCA14), TULP1 (LCA15), KCNJ13 (LCA16), and IQCB1. Together, pathogenic variants in these genes are estimated to account for more than half of all LCA diagnoses. At least one other disease locus for LCA has been reported, but the gene is not known.

Management: Treatment of manifestations: Treatment is supportive. Children and their parents should be referred to programs for the visually impaired child within their state or locality. Affected individuals benefit from correction of refractive error, use of low-vision aids when possible, and optimal access to educational and work-related opportunities.

Prevention of secondary complications: When possible children should be discouraged from repeatedly poking and pressing on their eyes.

Surveillance: Periodic ophthalmic evaluation for assessment of vision, trials of correction for refractive error, and, in those with residual vision, assessment of the presence of amblyopia, glaucoma, or cataract.

Genetic counseling: 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 is possible if the pathogenic variants in the family are known. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing. Rarely, LCA is inherited in an autosomal dominant manner as a result of a pathogenic variant in CRX; the possibility of autosomal dominant inheritance resulting from a de novo CRX pathogenic variant should be considered in individuals with LCA and no family history of the disease.