Leber Congenital Amaurosis (LCA)

What happens in LCA

The retina contains light-sensing cells called photoreceptors (rods and cones), supported by a layer called the retinal pigment epithelium. In LCA, a gene change disrupts the development or function of these cells, so the retina cannot convert light into signals properly. Vision is severely reduced from early infancy. In some types, retinal cells slowly degenerate over time; in others, the cells survive but do not work, which is important for gene therapy.

LCA is closely related to retinitis pigmentosa, another inherited retinal disease that usually starts later. LCA is usually inherited in an autosomal recessive pattern: both parents carry one copy of the gene change, and each child has a 1 in 4 chance of being affected.

Genes involved

More than 25 genes are linked to LCA. Some of the more common ones are:

• CEP290: one of the most common in North America and Europe
• GUCY2D
• CRB1
• RPE65: the type treatable with approved gene therapy
• AIPL1, RPGRIP1, RDH12, NMNAT1 and others

Each gene type has somewhat different features and course.

Signs and symptoms

• severe vision loss noticed in the first months of life
• nystagmus: involuntary, rhythmic eye movements
• poor visual behavior: not fixing on faces, not following objects
• sluggish or absent pupil responses to light
• oculodigital sign: repeated pressing or poking of the eyes, which can lead to sunken eyes over time
• light sensitivity or, in some types, night blindness
• high farsightedness
• later, keratoconus (cone-shaped cornea) or cataract in some people

Most children with LCA have normal intelligence, although a minority of gene types are associated with developmental delay, kidney disease or other organ involvement.

Diagnosis

• Pediatric eye exam: pupils, eye movements, refraction and the retina, which may look normal early on.
• Electroretinogram (ERG): measures the retina's electrical response to light; in LCA it is typically severely reduced or absent. This is the key test.
• Optical coherence tomography (OCT) and retinal photographs.
• Genetic testing: a panel of inherited retinal disease genes identifies the cause in most cases, which is essential for treatment eligibility and family planning.
• Evaluation for other conditions that can cause infant visual impairment, such as optic nerve hypoplasia, albinism and cortical visual impairment.

Treatment

Gene therapy for RPE65-related LCA

Voretigene neparvovec (Luxturna), approved by the FDA in 2017, delivers a working copy of the RPE65 gene into retinal cells via an injection under the retina during surgery. It is approved for people with confirmed biallelic RPE65 mutations who have enough viable retinal cells. It can improve light sensitivity and navigation in dim light. It does not cure the condition, and results vary.

Clinical trials

Gene therapies, gene editing and RNA-based treatments are being studied for other LCA genes, including CEP290 and GUCY2D. Genetic diagnosis is needed to qualify.

Supportive care for everyone

• early intervention services and vision teachers
• low vision aids: magnifiers, high-contrast materials, screen readers
• orientation and mobility training, braille when appropriate
• glasses for refractive error
• management of keratoconus or cataract if they develop
• discouraging eye poking where possible, to protect the eyes
• genetic counseling for the family

Outlook

Vision in LCA is usually severely limited, and many people meet the definition of legal blindness. Some types gradually worsen. With early support, children with LCA attend school, develop independence and lead full lives. Treatment options are expanding rapidly as gene therapies reach trials.

Frequently asked questions

What is Leber congenital amaurosis?

Leber congenital amaurosis is a group of rare inherited retinal diseases that cause severe vision loss from birth or early infancy. It is caused by changes in more than 25 different genes that affect the retina's light-sensing cells.

What are the first signs of LCA in a baby?

Early signs include not fixing on faces or following objects, wandering or jerky eye movements (nystagmus), sluggish pupils, pressing or poking the eyes, and unusual responses to light. These are usually noticed in the first few months.

Is there a cure for Leber congenital amaurosis?

There is no cure. For LCA caused by RPE65 gene changes, an approved gene therapy, voretigene neparvovec, can improve vision function. Trials are underway for other gene types. Low-vision support helps all children with LCA.

Is LCA inherited?

Yes. Most types are autosomal recessive, meaning both parents carry a gene change and each child has a 1 in 4 chance of being affected. Genetic testing and counseling help families understand the risk.