Leber congenital amaurosis, also known as LCA, is an eye disorder that is present from birth (congenital). This condition primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. The visual impairment tends to be severe and may worsen over time.

Leber congenital amaurosis is also associated with other vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). The pupils, which usually expand and contract in response to the amount of light entering the eye, do not react normally to light. Instead, they expand and contract more slowly than normal, or they may not respond to light at all.

A 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.

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.

At least 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.

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. 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.

Variants in any of the genes associated with Leber congenital amaurosis disrupt the development and function of the retina, resulting in early vision loss. Variants in the CEP290, CRB1, GUCY2D, and RPE65 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.

Normal Function

The CRX gene provides instructions for making a protein called the cone-rod homeobox protein. This protein is found in the eyes, specifically in the light-sensitive tissue at the back of the eye called the retina. The cone-rod homeobox protein attaches (binds) to specific regions of DNA and helps control the activity of particular genes. On the basis of this action, this protein is called a transcription factor.

In the retina, the cone-rod homeobox protein is necessary for the normal development of light-detecting cells called photoreceptors. Through its actions as a transcription factor, the cone-rod homeobox protein helps photoreceptor cells mature into two types: rods and cones. Rods are needed for vision in low light, while cones are needed for vision in bright light, including color vision. The protein also helps maintain these cells and preserve vision.

Health Conditions Related to Genetic Changes

Cone-rod dystrophy

More than 20 mutations in the CRX gene have been found to cause cone-rod dystrophy. The problems associated with this condition include a loss of visual sharpness (acuity), an increased sensitivity to light (photophobia), and impaired color vision. These vision problems worsen over time. Cone-rod dystrophy is caused by mutations that occur in one of the two copies of the CRX gene in each cell. CRX gene mutations are responsible for about one-quarter of the cases of a form of the condition called autosomal dominant cone-rod dystrophy. These mutations lead to a reduction in the amount of functional cone-rod homeobox protein that is available to regulate other genes in the retina. As a result, maintenance of the rod and cone cells is insufficient and these cells deteriorate over time, leading to the vision problems characteristic of cone-rod dystrophy. Researchers believe that there is enough cone-rod homeobox protein function to allow for photoreceptor cell differentiation, but long-term maintenance of the cells cannot be sustained.

Several CRX gene mutations have been found to cause different forms of vision loss in different individuals. It is unclear how mutations in the CRX gene can cause different eye disorders.

Leber congenital amaurosis

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Retinitis pigmentosa

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Other Names for This Gene

• cone-rod homeobox protein
• CORD2
• CRD
• LCA7
• orthodenticle homeobox 3
• OTX3

Genomic Location

Normal Function

The RPE65 gene provides instructions for making a protein that is essential for normal vision. The RPE65 protein is produced in a thin layer of cells at the back of the eye called the retinal pigment epithelium (RPE). This cell layer supports and nourishes the retina, which is the light-sensitive tissue that lines the back of the eye. The RPE layer is essential for capturing light and vision.

The RPE65 protein is involved in a multi-step process called the visual cycle (also called the retinoid or vitamin A cycle), which converts light entering the eye into electrical signals that are transmitted to the brain. When light hits photosensitive pigments in the retina, it changes a molecule called 11-cis retinal (a form of vitamin A) to another molecule called all-trans retinal. This conversion triggers a series of chemical reactions that create electrical signals.

The RPE65 protein is a key enzyme in this cycle as it converts all-trans retinal to 11-cis retinol. Other enzymes then produce 11-cis retinal, so that the visual cycle can begin again and capture light.

Health Conditions Related to Genetic Changes

Leber congenital amaurosis

Many variants (also called mutations) in the RPE65 gene have been found to cause Leber congenital amaurosis. This condition is an eye disorder that primarily affects the retina. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. Variants in the RPE65 gene account for 6 to 16 percent of all cases of this condition.

RPE65 gene variants lead to a partial or total loss of RPE65 protein function. As a result, all-trans retinal cannot be converted back to 11-cis retinal, and excess all-trans retinal builds up in the retinal pigment epithelium. These abnormalities block the visual cycle, which leads to severe visual impairment beginning very early in life in Leber congenital amaurosis.

Fundus albipunctatus

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Retinitis pigmentosa

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Other Names for This Gene

• all-trans-retinyl-palmitate hydrolase
• BCO3
• LCA2
• mRPE65
• p63
• RBP-binding membrane protein
• rd12
• retinal pigment epithelium specific protein 65
• retinal pigment epithelium-specific 65 kDa protein
• retinal pigment epithelium-specific protein 65kDa
• retinitis pigmentosa 20 (autosomal recessive)
• retinoid isomerohydrolase
• retinol isomerase
• RP20
• RPE65_HUMAN
• sRPE65

Genomic Location

Normal Function

The CRB1 gene provides instructions for making a protein that plays an essential role in normal vision. This protein is found in the brain and the retina, which is the specialized tissue at the back of the eye that detects light and color.

In the retina, the CRB1 protein appears to be critical for the normal development of light-sensing cells called photoreceptors. Studies suggest that this protein is part of a group (complex) of proteins that help determine the structure and orientation of photoreceptors. The CRB1 protein may also be involved in forming connections between different types of cells in the retina.

Health Conditions Related to Genetic Changes

Leber congenital amaurosis

Many variants (also called mutations) in the CRB1 gene have been found to cause Leber congenital amaurosis. Leber congenital amaurosis is an eye disorder that primarily affects the retina. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. Variants in the CRB1 gene account for 9 to 13 percent of all cases of this condition.

Most of the CRB1 gene variants responsible for Leber congenital amaurosis lead to an abnormally short, nonfunctional version of the CRB1 protein or significantly reduce the amount of this protein produced in cells. A shortage of the CRB1 protein disrupts the early development of the retina. The retina becomes unusually thick and does not develop the normal layered structure. These changes cause severe visual impairment beginning very early in life.

Cone-rod dystrophy

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Retinitis pigmentosa

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Other Names for This Gene

• CRUM1_HUMAN
• crumbs family member 1, photoreceptor morphogenesis associated
• crumbs homolog 1
• crumbs homolog 1 (Drosophila)
• LCA8
• RP12

Genomic Location

Normal Function

The GUCY2D gene provides instructions for making a protein that plays an essential role in normal vision. This protein is found in the retina, which is the specialized tissue at the back of the eye that detects light and color. Within the retina, the GUCY2D protein is located in light-detecting cells called photoreceptors. The retina contains two types of photoreceptor cells: rods and cones. Rods are needed for vision in low light, while cones are needed for vision in bright light, including color vision.

The GUCY2D protein is involved in a process called phototransduction. When light enters the eye, it stimulates specialized pigments called opsins that "hold" a vitamin A molecule in photoreceptor cells. This stimulation triggers a series of chemical reactions that close the open channel in the cell membranes of rod and cone cells. This closure produces an electrical signal, which is then interpreted by the brain as vision.

Once photoreceptors have been stimulated by light, they must return to their resting (or "dark") state before they can be stimulated again. The GUCY2D protein is involved in a chemical reaction that re-opens the cell membrane channels that helps return photoreceptors to their dark state after light exposure.

Health Conditions Related to Genetic Changes

Cone-rod dystrophy

Some variants (also known as mutations) in the GUCY2D gene have been identified in people with a vision disorder called cone-rod dystrophy. The problems associated with this condition include a loss of visual sharpness (acuity), an increased sensitivity to light (photophobia), and impaired color vision. These vision problems worsen over time.

The variants that cause cone-rod dystrophy occur in one of the two copies of the GUCY2D gene in each cell. These variants are responsible for about one-quarter of the cases of a form of the condition called autosomal dominant cone-rod dystrophy. Most of these variants affect a particular protein building block (amino acid) in the GUCY2D protein, replacing the amino acid arginine at position 838 with one of several other amino acids. These genetic changes impair normal phototransduction, causing the photoreceptor cells to deteriorate over time. The loss of these cells leads to the progressive vision problems characteristic of cone-rod dystrophy.

Leber congenital amaurosis

Many variants in the GUCY2D gene have been found to cause Leber congenital amaurosis. This condition is an eye disorder that primarily affects the retina. People with this disorder typically have severe visual impairment beginning at birth or shortly afterward. Variants in this gene account for 6 to 21 percent of all cases of this condition.

The variants that cause Leber congenital amaurosis occur in both copies of the GUCY2D gene in each cell. Most of these genetic changes lead to an abnormally short, nonfunctional version of the GUCY2D protein. A lack of this protein prevents photoreceptor cells from returning to their dark state after they are exposed to light. As a result, the process of phototransduction is almost totally shut down, leading to severe visual impairment beginning very early in life in Leber congenital amaurosis.

Other Names for This Gene

• CORD6
• CYGD
• guanylate cyclase 2D, membrane (retina-specific)
• GUC1A4
• GUC2D
• GUC2D_HUMAN
• LCA1
• RCD2
• retGC
• RETGC-1
• RETGC1
• retinal guanylyl cyclase 1
• rod outer segment membrane guanylate cyclase
• ROS-GC
• ROS-GC1
• ROSGC

Genomic Location

Normal Function

The CEP290 gene provides instructions for making a protein that is present in many types of cells, including in the eye's light receptor cells (photoreceptors). Although this protein's function is not well understood, studies suggest that it plays an important role in cell structures called centrosomes and cilia. Centrosomes are involved in cell division and the assembly of microtubules, which are proteins that transport materials in cells and help the cell maintain its shape. Cilia are microscopic, finger-like projections that stick out from the surface of cells. Cilia are involved in cell movement and many different chemical signaling pathways. They are also necessary for the perception of sensory input (such as vision, hearing, and smell). The CEP290 protein is likely necessary for vision by playing a role in transporting proteins within photoreceptors.

Health Conditions Related to Genetic Changes

Leber congenital amaurosis

Many variants (also known as mutations) in the CEP290 gene have been found to cause Leber congenital amaurosis. Leber congenital amaurosis is an eye disorder that primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. People with this disorder typically have severe visual impairment beginning near birth or shortly afterward. Variants in the CEP290 gene account for 15 to 22 percent of all cases of Leber congenital amaurosis.

A particular genetic change, written as 2991+1655A>G, is the most common CEP290 gene variant associated with Leber congenital amaurosis. This variant creates a premature stop signal in the instructions for making the CEP290 protein, which reduces the production of functional protein to low levels in cells. Other CEP290 gene changes responsible for this disorder result in the production of abnormally short, completely nonfunctional versions of the CEP290 protein.

It is unclear how variants in the CEP290 gene cause the characteristic features of Leber congenital amaurosis. A shortage of the CEP290 protein clearly affects the development of the retina. Photoreceptors in the retina contain cilia, which are essential for normal vision. Abnormalities involving these cilia may lead to the severe, early visual impairment characteristic of Leber congenital amaurosis.

Bardet-Biedl syndrome

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Joubert syndrome

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Meckel syndrome

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Senior-Løken syndrome

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Other disorders

Several dozen variants in the CEP290 gene have also been identified in other syndromes associated with abnormal cilia. These conditions, which are known as ciliopathies, affect many body systems and include Joubert syndrome, Meckel syndrome, Senior-Løken syndrome, and Bardet-Biedl syndrome (mentioned above). The features of these disorders overlap significantly. They each affect multiple organ systems, most commonly the brain and spinal cord (central nervous system), retina, and kidneys. Meckel syndrome is typically the most severe of the CEP290-associated ciliopathies; affected individuals usually die before or shortly after birth.

The CEP290 gene variants responsible for these disorders lead to the production of an abnormally short version of the CEP290 protein. The abnormal protein likely disrupts cilia function in many different parts of the body. However, it is unclear how variants in this single gene can cause multiple disorders. Researchers speculate that changes in other genes, particularly genes involved in cilia function, may contribute to the varied signs and symptoms of these conditions.

Other Names for This Gene

• 3H11Ag
• BBS14
• cancer/testis antigen 87
• CE290_HUMAN
• centrosomal protein 290kDa
• centrosomal protein of 290 kDa
• CT87
• CTCL tumor antigen se2-2
• FLJ13615
• FLJ21979
• JBTS5
• JBTS6
• KIAA0373
• LCA10
• MKS4
• monoclonal antibody 3H11 antigen
• nephrocytsin-6
• NPHP6
• POC3
• POC3 centriolar protein homolog
• prostate cancer antigen T21
• rd16
• SLSN6
• tumor antigen se2-2

Genomic Location

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. 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.

When Leber congenital amaurosis is caused by varaints in the CRX or IMPDH1 genes, the disorder has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. In most of these cases, an affected person inherits a gene mutation from one affected parent. Other cases result from new variants and occur in people with no history of the disorder in their family.

Leber congenital amaurosis (LCA) primarily affects the retina, the specialized tissue at the back of the eye that detects light and color. Beginning in infancy, people with LCA typically have severe visual impairment. This is most often non-progressive, but sometimes it very slowly worsens over time. Other vision problems associated with LCA include:

• Photophobia
• Nystagmus
• Clouding of the lens of the eyes (cataract)
• Crossed eyes (strabismus)
• Enophthalmos (eye balls are dislocated backward)
• Abnormal retinal pigment
• Extreme farsightedness (hyperopia)
• Pupils that may not react normally to light; they may expand and contract more slowly than normal, or they may not respond to light at all
• Keratoconus, a condition in which the cornea is cone-shaped and abnormally thin, may also be present

A specific behavior called Franceschetti's oculodigital sign is characteristic of LCA. This behavior consists of poking, pressing, and rubbing the eyes with a knuckle or finger. It may possibly contribute to deep-set eyes and keratoconus in affected children.

In rare cases, delayed development, hearing loss, and intellectual disability have been reported in people with the features of LCA. However, it is unclear whether these people actually have LCA or another syndrome with similar signs and symptoms.

Leber congenital amaurosis occurs in 2 to 3 per 100,000 newborns. It is one of the most common causes of blindness in children.