Leber congenital amaurosis

Synonyms

5

Overview

Leber congenital amaurosis (LCA) 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 condition typically have severe visual impairment beginning in infancy. The visual impairment tends to be stable, although it may worsen very slowly over time.

Other features include photophobia, involuntary movements of the eyes (nystagmus), and extreme farsightedness. The pupils also do not react normally 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. Additionally, the clear front covering of the eye (the cornea) may be cone-shaped and abnormally thin, a condition known as keratoconus.

A specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of poking, pressing, and rubbing the eyes with a knuckle or finger. Researchers suspect that this behavior may contribute to deep-set eyes and keratoconus in affected children.

In rare cases, delayed development and intellectual disability have been reported in people with the features of Leber congenital amaurosis. However, researchers are uncertain whether these individuals actually have Leber congenital amaurosis or another syndrome with similar signs and symptoms.

At least 13 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 mutations in at least 14 genes, all of which are necessary for 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 necessary for the perception of several types of sensory input, including vision.

Mutations in any of the genes associated with Leber congenital amaurosis disrupt the development and function of the retina, resulting in early vision loss. Mutations in the CEP290, CRB1, GUCY2D, and RPE65 genes are the most common causes of the disorder, while mutations 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.

Symptoms

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, affected individuals 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, and extreme farsightedness (hyperopia). Additionally, the pupils 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 oculo-digital 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 and intellectual disability have been reported in people with the features of LCA. However, it is unclear whether these individuals actually have LCA or another syndrome with similar signs and symptoms.

  • Abnormality of retinal pigmentation
  • Optic atrophy
  • Visual impairment
  • Crossed eyes
  • Blindness
  • Rapid involuntary eye movements
  • Sensitivity to light
  • Clouding of eye lenses
  • Protruding cone-shaped cornea
  • Psychomotor retardation

Causes

Mutations in twelve genes are thought to be responsible for 40-50% of all LCA. LCA is usually inherited as an autosomal recessive genetic condition. Mutations in 11 genes are associated with this type of LCA: GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRB1, CEP290, IMPDH1, RD3 and RDH12.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Rarely, LCA is inherited as an autosomal dominant genetic disorder. Mutations in the CRX gene are associated with this type of LCA.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Diagnosis

Electroretinography (ERG) is used to assess visual function by measuring activity in the retina. Infants with LCA have absent or reduced electrical activity of the retina. Molecular genetic testing is available for the 12 genes associated with LCA. Clinical signs and symptoms can be helpful in determining which genes to test for, and in what order..

Treatment

One form of LCA, patients with LCA2 bearing a mutation in the RPE65 gene, has been successfully treated by gene therapy in clinical trials. The results of three early clinical trials were published in 2008 demonstrating the safety and efficacy of adeno-associated virus to restore vision in LCA patients. In all three clinical trials, patients recovered functional vision without apparent side-effects. These studies, which used adeno-associated virus, have spawned a number of new studies investigating gene therapy for human retinal disease.

The results of a phase 1 trial conducted, by the University of Pennsylvania and Children's Hospital of Philadelphia and published in 2009, showed sustained improvement in 12 subjects (ages 8 to 44) with RPE65-associated LCA after treatment with AAV2-hRPE65v2, a gene replacement therapy. Early intervention was associated with better results. In that study patients were excluded based on the presence of particular antibodies to the vector AAV2 and treatment was only administered to one eye as a precaution. A 2010 study testing the effect of administration of AAV2-hRPE65v2 in both eyes in animals with antibodies present suggested that immune responses may not complicate use of the treatment in both eyes.

Eye Surgeon Dr. Al Maguire and gene therapy expert Dr. Jean Bennett developed the technique used by the Children's Hospital.

Dr. Sue Semple-Rowland at the University of Florida has recently restored sight in an avian model using gene therapy.