Leber congenital amaurosis

Definition

Leber congenital amaurosis (LCA) is a group of autosomal recessive-inherited eye disorders which lead to blindness at birth or within the first few years of life. Other manifestations of the disease may include hearing loss, mental retardation, and decreased physical coordination.

Description

Vision is an important and complex sense by which the qualities of an object, such as color, shape, and size, are perceived through the detection of light. For proper vision, a critical series of biological steps must occur; if any of the steps in the process is abnormal, visual impairment or blindness may occur.

The process of vision begins with light that bounces off an object and passes through the outer coverings and lens of the eye and projects onto a layer of cells at the back of the eye called the retina. The retina contains two kinds of specialized cells types, called the rods and cones, that are responsible for sensing visual stimuli. When rods and cones are stimulated by light, impulses are conducted through the optic nerve to a region in the back of the brain known as the occipital lobe. The occipital lobe contains the visual cortex, the area of the brain that processes visual stimuli and integrates signals sent by the retina to obtain a composite image of an object.

Leber congenital amaurosis (LCA) is term for a group of inherited conditions in which the rod and cone receptors in the retina are defective or missing. Without the proper function of these specialized cells, light cannot be sensed normally.

LCA is often referred to by other names, such as: congenital absence of the rods and cones, congenital retinal blindness, congenital retinitis pigmentosa , Leber's congenital tapetoretinal degeneration, or Leber's congenital tapetoretinal dysplasia . The disorder was first described by the German ophthalmologist, Theodor Leber, in 1869, who subsequently showed that it was an inherited defect. Although similarly named, LCA should not be confused with another disorder of sight, Leber optic atrophy , that was also discovered by Theodor Leber.

Genetic profile

Mutations in any one of at least six different gene groups may result in LCA. Each of the known genes produce proteins, which are located within the retinal rod and cone cells. These proteins participate in the detection of an incoming stimulus of light and the subsequent transmission of signals out of the retinal cells to the visual cortex of the brain. The different types of LCA and the corresponding genetic abnormality is described in the table below. These six identified mutations likely account for less than half of all diagnosed cases of LCA, and thus, there are additional mutations resulting in LCA that remain to be discovered.

LCA is a genetic condition and can be inherited or passed on in a family. The genetic defects for the disorder are all inherited as autosomal recessive traits, meaning that two mutant genes of the same group are needed to display the disease. A person who carries one mutant gene does not display the disease and is called a carrier. A carrier has a 50% chance of transmitting the gene to their children, who must inherit the same defective gene from each parent to display the disease. Since there are different genes that are responsible for causing LCA, two individuals with different types of LCA will have an unaffected child, as it is impossible for the child to inherit two of the same type of defective genes from the parents.

Demographics

LCA has been reported to account for at least 5% of all cases of inborn blindness, but several reports suggest that is an underestimation. In 1957, scientific investigators reported that one form of LCA was responsible for 10% of blindness in Sweden. Several years later, similar rates of LCA were found in people living in the Netherlands. While this suggests that the geographical distribution of LCA is not uniform and may be higher in certain ethnic groups, a comprehensive study has never been performed.

Signs and symptoms

Because there are different types of LCA, there is considerable variation in the symptoms experienced by an affected infant. Most infants with LCA are often blind at birth or lose their sight within the first few years of life, however some people with LCA may have residual vision. In these patients, visual acuity is usually limited to the level of counting fingers or detecting hand motions or bright lights, and patients are extremely farsighted. There may be some small improvement in vision during the first decade of life as the visual system reaches maturity, but it is uncommon for children to be able to navigate without assistance or to be able to read print.

Other symptoms of LCA may include crossed eyes, sluggish pupils, rapid involuntary eye movements, unusual sensitivity to light, and the clouding of the lenses of the eyes. Many children with LCA habitually press on their eyes with their fists or fingers. This habitual pressing on the eyes is known as an oculo-digital reflex and may represent an instinctual attempt to provide the eveloping visual cortex of the brain with a stimulus to replace the loss of normal visual stimuli. As a result of this behavior, the eyes may become thin and conical in shape and appear sunken or deep. In some cases, LCA is associated with hearing loss, epilepsy , decreased coordination, kidney problems, or heart abnormalities. Mental retardation may be present in approximately 20% of individuals affected with LCA.

Diagnosis

Infants are usually brought to medical attention within the first six months of life when parents note a lack of visual responsiveness and the unusual roving eye movements characteristic of the disease. As with any evidence of loss of vision, a prompt and thorough evaluation is initiated to determine the cause of the visual defect, and steps may include physical tests designed to measure brain and eye function, CT scans (a method using x rays controlled by a sophisticated computer) of the brain and eye, and even tests to look for genetic and metabolic causes of blindness.

Eye examinations of infants with LCA usually reveal a normal appearing retina. By early adolescence, however, various changes in the retinas of patients with LCA become readily apparent; blood vessels often become narrow and constricted, and a variety of color changes can also occur in the retina and its supportive tissue.

One of the most important tests in diagnosing LCA is called electroretinography (ERG). This test measures electrical impulses which are produced in the retina when light is sensed by the rod and cone cells. It is useful in distinguishing whether blindness is due to a problem in the retina versus a problem in the visual cortex of the brain. When ERG tests are performed on people with LCA, there is no recordable electrical activity arising from the eye, indicating the problem is based in the retina rather than in the brain.

Thus, an absence of activity on ERG, combined with the absence of diagnostic signs of other conditions which result in blindness, point to a diagnosis of LCA. Although several abnormal genes have been identified which are responsible for LCA, genetic analysis and prenatal diagnosis is rarely performed outside of research studies.

Treatment and management

Currently, there is no treatment for LCA, and thus, patient and family education and adaptive assistance is critical. Some people with remaining vision may benefit from vision-assistance technology such as electronic, computer-based, and optical aids, but severely visually-impaired

individuals often utilize traditional resources such as canes and companion-guide dogs. Orientation and mobility training, adaptive training skills, job placement and income assistance are available through hospital physical and occupation therapy programs and various community resources. It should be noted that up to 20% of patients with LCA may have associated mental retardation and will require additional adaptive and vocational assistance.

Most people with LCA are unable to read print and instead utilize braille, an alphabet represented by raised dots that can be felt with the fingertips. People with LCA often attend schools specially designed to meet the needs of visually-impaired students and may require modifications to their home and work environments in order to accommodate their low or absent vision. As almost all patients with LCA are legally blind, they will not be able to drive or operate heavy machinery. Genetic counseling may assist affected individuals with family planning.

Scientists have isolated several mutant genes that can each cause LCA. Ongoing scientific research is directed toward understanding how these genes function in the retina and toward locating the remaining genes that cause LCA. With this information, scientists can better develop a means of prevention and treatment. A dramatic example of this principle was provided in 2000, when researchers were able to restore vision in mice with LCA2. By giving oral doses of a chemical compound derived from vitamin A, the scientists were able to restore the animals' visual functions to almost normal levels after just two days. The researchers report that they will attempt the same experiments in dogs with LCA2 before trying the treatment in humans. It should be noted that LCA2 causes only 10% of the known cases of LCA, and the treatment in this experimental study does not work for other types of LCA.

Prognosis

While children born with LCA may have variable symptoms and differing levels of visual acuity, they can lead productive and healthy lives with adaptive training and assistance. In those patients who do not have associated problems with their brain, heart, or kidney, lifespan is approximately the same as the general population, otherwise the prognosis is variable and depends on the extent of the complication.

Resources

BOOKS

"Disorders of Vision" In Nelson Textbook of Pediatrics, edited by R. E. Behrman. Philadelphia: W. B. Saunders, 2000, pp. 1900-1928.

PERIODICALS

Dharmaraj, S. R., et al. "Mutational Analysis and Clinical Correlation in Leber Congenital Amaurosis." Ophthalmic Genetics 21 (September 2000): 135-150.

Gamm, D. M., and A.T. Thliveris. "Implications of Genetic Analysis in Leber Congenital Amaurosis." Archives of Ophthalmology 119 (March 2001): 426-427.

Lambert, S. R., A. Kriss, and D. Taylor. "Vision in Patients with Leber Congenital Amaurosis." Archives of Ophthalmology 11 (February 1997): 293-294.

Perrault, I. "Leber Congenital Amaurosis." Molecular Genetics and Metabolism 68 (October 1999): 200-208.

ORGANIZATIONS

Foundation Fighting Blindness. Executive Plaza 1, Suite 800, 11350 McCormick Rd., Hunt Valley, MD 21031-1014. (888) 394-3937. <http://www.blindness.org>.

WEBSITES

"Entry 20400: Leber Congenital Amaurosis, Type 1." OMIM—Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=20400>.

Leber's Links: Leber's Congenital Amaurosis.<http://www.freeyellow.com/members4/leberslinks/index.html>.

Oren Traub, MD, PhD