Leber’s Congenital Amaurosis

Leber’s congenital amaurosis is a rare inherited eye disease that causes severe vision loss or blindness in babies and young children. It affects the retina, the light-sensitive tissue at the back of the eye, and is one of the most common causes of inherited blindness in childhood.

Table of contents

• What is Leber’s congenital amaurosis?
• Other names for this condition
• How common is this condition?
• Signs and symptoms
• What causes this condition?
• How is it inherited?
• Diagnosis and testing
• Treatment options
• Related conditions

What is Leber’s congenital amaurosis?

Leber’s congenital amaurosis, also known as LCA, is a rare disease that affects the retinas in babies’ eyes. The retina is the specialized tissue at the back of the eye that detects light and color, similar to film in a camera. The word “congenital” means the condition is present at birth.^[1]

People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. Some babies with LCA are born with blindness. About one in three babies with Leber’s congenital amaurosis is born blind, while other babies develop symptoms when they’re about 6 months old.^[2] The visual impairment tends to be severe and may worsen over time.^[1]

LCA is a group of inherited retinal diseases characterized by severe impaired vision or blindness at birth. The condition is caused by degeneration and dysfunction of photoreceptors, the cells in the retina that make vision possible. Photoreceptors capture light and convert it to electrical signals which are sent to the back of the brain to create the images we see.^[3]

• Retina
• Eye
• Photoreceptors

Other names for this condition

amaurosis congenita of leber, CRB – congenital retinal blindness, Leber amaurosis, Leber’s amaurosis, Leber’s congenital amaurosis, Leber’s disease

How common is this condition?

Leber congenital amaurosis occurs in 2 to 3 per 100,000 newborns. It is one of the most common causes of blindness in children and is the most common cause of inherited blindness in childhood.^[1][4] LCA accounts for 5 percent of all retinal dystrophies and 20 percent of blindness in school-age children.^[17]

Signs and symptoms

Often within an affected infant’s first few months of life, parents notice a lack of visual responsiveness and roving eye movements, known as nystagmus. Some babies with LCA are born with blindness, while other babies with the condition develop symptoms when they’re about 6 months old.^[2][3]

You may not notice any changes in your baby’s vision right away. For example, babies often rub their eyes when they’re tired. But your baby frequently rubbing or poking at their eyes may be an early symptom of LCA. This specific behavior called Franceschetti’s oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of affected individuals poking, pressing, and rubbing their eyes with a knuckle or finger. Poking their eyes often results in the sensation of flashes of light called phosphenes. Researchers suspect that this behavior may contribute to deep-set eyes in affected children.^[1]

Other common symptoms include:^[2]

• Misaligned eyes (strabismus)
• Sensitivity to light (photophobia)
• Shaking eyes (nystagmus)
• Pupils that don’t adjust to changes in light (slow or missing pupillary response)
• Extreme farsightedness (hyperopia)

Eye examinations of infants with LCA sometimes reveal normal-appearing retinas. In other cases, several abnormalities are observed. Over time, the retina deteriorates; retinal blood vessels can become thin and narrow and undergo pigmentary changes.^[3][4]

Less common symptoms include cataracts (clouding of the lens through which light passes), corneal abnormality (keratoconus, which is when the cornea becomes cone-shaped and abnormally thin), hearing impairment and developmental delays, epilepsy and motor skill impairment.^[4] In some cases, other body systems such as kidneys can be affected by the genetic defects that cause LCA.^[3]

In very rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. Because of the visual loss, affected children may become isolated. Providing children with opportunities to play, hear, touch, understand and other early educational interventions may prevent developmental delays in children with Leber congenital amaurosis.^[1]

What causes this condition?

Leber’s congenital amaurosis happens when your baby inherits certain genetic variations that affect how their retinas develop. The genetic variations affect the process that creates images that your baby sees. Normally, light-detecting cells (photoreceptors) in your baby’s retinas turn light into electrical signals. Your baby’s brain turns the signals into images that they see. Leber’s congenital amaurosis affects that process so there’s less electrical activity (signals). The less electrical activity there is, the less sight your baby has.^[2]

Leber congenital amaurosis can result from variants (also known as mutations) in at least 20 genes, all of which are necessary for function of the retina and normal vision. Variations in almost 30 different genes can cause Leber’s congenital amaurosis.^[1][2] At least 19 to 20 genetic types of Leber congenital amaurosis have been described. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities.^[1]

These genes play a variety of roles in the development and function of the retina. For example, some of the genes associated with this disorder are necessary for the normal development of light-detecting cells called photoreceptors. Other genes are involved in phototransduction, the process by which light entering the eye is converted into electrical signals that are transmitted to the brain. Still other genes play a role in the function of cilia, which are microscopic finger-like projections that stick out from the surface of many types of cells. Cilia are found in the retina’s photoreceptors and are necessary for vision.^[1]

The most common genes associated with Leber congenital amaurosis (LCA) are CEP290, CRB1, GUCY2D, and RPE65.^[1][3] Variants in these genes are the most common causes of Leber congenital amaurosis, while variants in the other genes generally account for a smaller percentage of cases. In about 30 percent of all people with Leber congenital amaurosis, the cause of the disorder is unknown, though research is ongoing.^[1]

How is it inherited?

Leber congenital amaurosis usually has an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have variants. LCA is usually an autosomal recessive condition. That means both biological parents have one or more of the changed genes that can cause Leber’s congenital amaurosis.^[1][2]

The parents of an individual with an autosomal recessive condition each carry only one copy of the altered gene, and therefore they typically do not show any signs and symptoms of the disease. In order to have the disease, the child needs two abnormal genes, one from each parent. Both parents are typically unaware they carry the mutation, as they do not have vision loss.^[1][5]

Each of their children has a 25 percent chance of inheriting the two LCA genes (one from each parent) needed to cause the disorder.^[4]

Diagnosis and testing

An eye care specialist will diagnose Leber’s congenital amaurosis. They’ll perform an eye exam to look at your child’s eyes, including inside them.^[2] On ophthalmic examination, patients with LCA often initially have a relatively normal-looking retina, as the degeneration of the retina occurs later.^[5]

LCA causes an abnormally low electrical response of the retina. An electro-diagnostic test known as an electroretinogram (ERG) may be recommended to investigate how the retina is working. An electroretinogram (ERG) measures retinal function and detects little if any activity in the retina. ERG tests are often essential to establishing a diagnosis of LCA. LCA patients classically have a “flat” ERG, which suggests virtually no retinal function.^[3][4][5]

The electrical activity of the retina is measured under different lighting conditions to determine which part of the retina is not functioning normally. This test requires the eyes to be dilated with special eye drops. A hard contact lens in each eye is also used to measure the eye’s responses to different kinds of light.^[4]

They may do an optical coherence tomography (OCT) scan. This test uses reflected light to create images of the back of your baby’s eyes.^[2]

Genetic testing is important to determine which gene is abnormal. A genetic test can often provide a definitive diagnosis. Genetic counseling can also help parents and patients understand the inheritance and the risk of future children having the condition.^[3][5]

Your child’s eye care specialist may do tests to rule out other conditions that can affect your child’s eyes. You might see this referred to as a differential diagnosis. Some conditions they’ll check for include color blindness, drooping eyelids (ptosis), Joubert syndrome, retinitis pigmentosa, and Zellweger syndrome.^[2]

Treatment options

There’s no cure for Leber’s congenital amaurosis. Your child’s eye specialist will recommend low vision aids if your child can see. Low vision aids include eyeglasses, magnifying glasses and reading prisms.^[2] Some people with LCA may also benefit from low-vision aids, including electronic, computer-based and optical aids. Orientation and mobility training, adaptive training skills, job placement and income assistance are available through community resources.^[4]

Although LCA typically leads to progressive loss of all vision, new advances in gene therapy offer hope for some patients. This new therapy involves implanting new genes into the abnormal retinal cells to correct the defective gene.^[5]

Your child may be a candidate for gene therapy if genetic tests show they have a changed version of the RPE65 gene. Gene therapy replaces diseased or inactive genes with copies of healthy genes. In some cases, gene therapy introduces new genes into your body to treat a specific disease.^[2]

Recently, gene therapy has become available for patients with mutations in both copies of the RPE65 gene. A defect in this gene can cause LCA in some patients as well as retinitis pigmentosa (RP) in others. RP is a disease similar to LCA that occurs later in life.^[5]

Voretigene neparvovec-rzyl (Luxturna™) is the gene therapy product injected underneath the retina, allowing a new, functional copy of the gene to pass into the appropriate cells. It is the first gene therapy approved by the US Food and Drug Administration (FDA) to treat a disease. Luxturna™ requires a common retina surgery procedure called a vitrectomy, and must be done by an ophthalmologist with experience in injecting genes under the retina.^[5]

This treatment has been shown to improve vision in patients who have received it, as tested by their ability to navigate an obstacle course in low light conditions termed “multi-luminance mobility testing” (MLMT). While Luxturna™ does not completely restore vision, the improvement noted in clinical trials can be beneficial for patients with extreme vision loss. The visual improvement is stable over at least a few years.^[5] Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration.^[10]

Gene therapy is currently available for LCA caused by two mutations in a gene called RPE65, which accounts for about six percent of LCA cases. Researchers are working to develop gene therapies to target other LCA-linked mutations.^[4] Recent research advances include gene therapy treatments for other forms of LCA, including LCA5, LCA10, LCA4 (caused by mutations in the gene AIPL1), and LCA1 (GUCY2D).^[11]

Related conditions

Some retinal experts consider LCA to be a severe form of retinitis pigmentosa (RP).^[3]