Leber congenital amaurosis 2

Leber congenital amaurosis 2 (LCA2) is an inherited eye disorder that causes severe visual impairment from infancy. The condition results from harmful changes in the RPE65 gene, which encodes a protein essential for the visual cycle in the retinal pigment epithelium. Because symptoms begin in the first months of life, most affected individuals are identified as infants or young children; males and females are affected equally. Precise prevalence figures are not well established, but LCA2 is considered uncommon worldwide. Severity and symptoms vary widely between individuals, and modern genetic testing now allows many families to obtain a clear diagnosis early in life.

The earliest clues are usually rapid, side-to-side eye movements (nystagmus) and poor visual tracking noted in the first months of life. Nearly all children have severely reduced vision in daylight as well as night blindness (nyctalopia), and electroretinography typically shows no detectable retinal response under either light- or dark-adapted conditions. Ophthalmologic examination often reveals narrowed retinal blood vessels and, in many cases, a pale or absent foveal reflex. As children grow, some develop optic disc pallor or patchy retinal atrophy that can slowly worsen. A minority experience additional neurological challenges such as mild intellectual or cognitive impairment, highlighting that the condition can extend beyond the eyes. Not all individuals experience all features, and the extent of vision loss—while usually profound—can differ from person to person.

LCA2 is caused by pathogenic variants in the RPE65 gene. The RPE65 protein converts vitamin A derivatives into 11-cis-retinal, the light-sensitive molecule required for photoreceptor function. When both copies of the gene carry harmful changes, the visual cycle is disrupted and photoreceptors cannot respond properly to light, leading to early-onset visual impairment. The condition follows an autosomal recessive inheritance pattern: an individual must inherit one altered RPE65 gene from each parent to be affected. Parents who each carry one pathogenic variant are typically unaffected carriers, and with every pregnancy they have a 25 percent chance of having an affected child, a 50 percent chance of having a carrier child, and a 25 percent chance of having a child who inherited neither variant. The condition can be more common in families where parents share a common ancestor, because both may carry the same rare variant. Even within the same family, specific symptoms and progression can vary considerably, a phenomenon known as variable expressivity. Genetic counseling is strongly recommended for families to discuss testing and reproductive options.

Currently, management focuses on supportive care and symptom management. Early referral to a multidisciplinary team that includes pediatric ophthalmology, low-vision specialists, orientation and mobility instructors, and educational professionals helps children reach their developmental potential. Vision aids such as high-contrast materials, magnifiers, and tactile learning tools can improve daily functioning. Regular ophthalmologic surveillance is important to monitor retinal health and identify treatable complications such as refractive errors or cataracts. Because a small proportion of individuals have cognitive or developmental challenges, coordination with developmental therapists and educational specialists may be beneficial. Genetic counseling provides families with information about inheritance and emerging therapeutic research. Patients should discuss management strategies with their healthcare team to determine which interventions are most appropriate for their specific situation.

LCA2 generally causes lifelong, severe visual impairment beginning in infancy, but the rate of retinal degeneration and the degree of residual vision differ among individuals. Some children retain limited light perception or hand-motion vision for many years, whereas others experience gradual decline. Intellectual development is usually typical, though a minority of individuals require additional educational or behavioral support. Assistive technology, early intervention services, and accessible educational environments can significantly enhance quality of life. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialist centers familiar with inherited retinal diseases and to participate in patient registries that support natural-history studies and access to emerging therapies.

Several clinical trials are currently investigating gene-based and other novel treatments aimed at improving or stabilizing vision in individuals with RPE65-related disease. These studies explore approaches such as enhanced gene delivery methods and pharmacologic agents that may boost the visual cycle. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.