Leber congenital amaurosis (LCA) is an inherited eye disorder appearing at birth or within the first few months of life. The condition affects the retina, the light-sensitive tissue at the back of the eye. LCA is a rare disease, found in two to three of every 100,000 newborns, and is a cause of inherited blindness in childhood. It results from the malfunction of the retina’s photoreceptor cells, causing severe vision loss.
Genetic Origins of LCA
LCA is a genetic condition caused by mutations in genes integral to retinal development and function. These genes provide instructions for proteins active in photoreceptor cells, which convert light into electrical signals the brain interprets as images. When a gene mutation disrupts this process, photoreceptor cells cannot function properly, leading to vision loss. More than 25 genes have been linked to LCA.
The inheritance pattern for LCA is almost always autosomal recessive. This means a child must inherit one mutated gene from each parent. The parents are considered carriers, each having one normal and one mutated gene, and do not show signs of the disorder. Carrier parents have a 25 percent chance of having a child with LCA with each pregnancy.
Mutations in the CEP290 and GUCY2D genes are the most frequent, each accounting for up to 20% of cases. The RPE65 gene is responsible for about 6 to 10 percent of cases. The RPE65 gene provides instructions for an enzyme necessary for the visual cycle, which regenerates the molecule photoreceptors need to detect light. Identifying the specific genetic cause is important for understanding an individual’s condition.
Recognizing the Early Signs
The initial signs of LCA in an infant appear within the first few months of life. A common symptom is nystagmus, which involves involuntary, rapid, and repetitive eye movements. This is often accompanied by a lack of visual responsiveness, as an infant with LCA may not track objects or make eye contact.
Another sign is extreme light sensitivity, known as photophobia, and pupils that react sluggishly to light. A characteristic behavior is Franceschetti’s oculo-digital sign, the tendency for children to frequently poke, press, and rub their eyes. This pressure is thought to stimulate the retina mechanically, producing the sensation of light flashes called phosphenes.
The Diagnostic Pathway
Diagnosing LCA begins with a clinical eye examination by an ophthalmologist. The doctor assesses the infant’s visual behavior, pupillary light reflexes, and examines the eye’s structures. The retina may appear normal in early stages, though abnormalities can sometimes be observed.
A diagnostic tool is the electroretinogram (ERG), which measures the electrical activity of photoreceptor cells in response to light flashes. In an individual with LCA, the ERG response is severely reduced or absent, indicating retinal cell dysfunction. This finding helps distinguish LCA from other causes of early-life vision loss.
The definitive diagnosis relies on genetic testing, where a blood sample is analyzed to identify mutations in genes known to cause LCA. Pinpointing the specific gene mutation confirms the diagnosis, helps predict the disease’s course, and determines eligibility for gene-targeted therapies.
Current Treatment and Support Strategies
While there is no universal cure for all forms of LCA, supportive care and medical treatments improve quality of life. Supportive strategies begin early and include low-vision aids, like magnifiers and electronic devices, to maximize residual vision. Orientation and mobility training helps children navigate their environment safely.
Specialized educational plans are developed for school settings, incorporating tactile learning methods like braille and auditory resources. These plans facilitate learning and social development. Early intervention helps prevent developmental delays associated with severe visual impairment.
A major medical advance is the development of gene therapy. In 2017, the FDA approved voretigene neparvovec-rzyl (Luxturna), a one-time treatment for LCA caused by RPE65 gene mutations. This therapy uses a modified virus to deliver a functional copy of the RPE65 gene to retinal cells, allowing them to produce the enzyme needed to restore part of the visual cycle.
Patients treated with Luxturna show improvements in seeing in low-light conditions and navigating their surroundings. This treatment is only for patients with RPE65 mutations who have viable retinal cells. Research is ongoing to develop similar gene therapies and other treatments for the other genetic forms of LCA.