LCA2

LCA2, or Leber congenital amaurosis type 2, is a genetic form of early-onset retinal dystrophy caused by biallelic mutations in the RPE65 gene. It is inherited in an autosomal recessive pattern and is one of several genetic subtypes of Leber congenital amaurosis. The condition leads to severe visual impairment that is present from infancy and may be accompanied by nystagmus and reduced light perception.

The underlying pathophysiology involves a defect in the retinal pigment epithelium’s RPE65 enzyme, which is required for the visual cycle to convert all-trans-retinal to 11-cis-retinal. Without functional RPE65, the supply of 11-cis-retinal is limited, impairing photoreceptor signaling and contributing to progressive retinal degeneration. Over time, this can result in reduced central and peripheral vision, with variable progression among individuals.

Clinical features typically include poor or absent light perception in infancy, nystagmus, and severely reduced or nonrecordable electroretinography. Fundus appearance may be normal in early stages but can show peripheral constraints, atrophy, or pigmentation changes as the disease progresses. Diagnosis is established through genetic testing confirming biallelic RPE65 mutations, often supported by electrophysiological testing and retinal imaging.

Treatment options for LCA2 have expanded with the approval of gene therapy using voretigene neparvovec-rzyl, intended for individuals with confirmed biallelic RPE65 mutations. The therapy is delivered by subretinal injection and has demonstrated improvements in functional vision and navigation in several studies. Management also includes visual rehabilitation, regular ophthalmic monitoring, and supportive care, as disease progression and access to treatment vary.

Epidemiologically, LCA2 is rare, representing a subset of Leber congenital amaurosis cases, with prevalence influenced by population genetics and carrier frequency.