Leber Congenital Amaurosis (LCA) | Strive For Good Health

Leber congenital amaurosis (LCA) is an eye disorder that primarily affects the retina. LCA is most typically passed through families by the autosomal recessive pattern of inheritance. In this type of inheritance, both parents, called carriers, have one gene for the disease paired with one normal gene. Each of their children has a 25 percent chance (or 1 chance in 4) of inheriting the two LCA genes (one from each parent) needed to cause the disorder. Carriers are unaffected because they have only one copy of the gene. At this time, it is impossible to determine who is a carrier for LCA until after the birth of an affected child.People with this condition typically have severe visual impairment beginning in infancy.

Signs or symptoms with this disease include:

Photophobia, involuntary movements of the eyes (nystagmus), and extreme farsightedness. The pupils also do not react normally to light. Additionally, the cornea may be cone-shaped and abnormally thin (keratoconus). 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. Different subtypes have been described. The different subtypes are caused by genetic changes in different genes. Some of these subtypes are also distinguished by their patterns of vision loss and related eye abnormalities.

Leber congenital amaurosis (LCA) is a rare genetic eye disorder. Affected infants are often blind at birth. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or a cone shape to the front of the eye (keratoconus). LCA is usually inherited as an autosomal recessive genetic condition. In addition, some infants may exhibit hearing loss, intellectual disability, and/or developmental delay.

Specific types of LCA have been defined based on the causative gene. Some types are associated with little change in vision over time (stationary disease) while others become more severe over time (progressive disease).

Causes

LCA is a monogenic disease and at least 27 genes are implicated. Changes (mutations) in these genes can account for about 80-90% of diagnosed cases of LCA. The genes responsible for the remaining 10-20% of diagnoses are not known. LCA is usually inherited as an autosomal recessive genetic condition. Twenty-four of the genes associated with LCA cause only recessive disease. Two genes (IMPDH1 and OTX2) are known to cause dominant disease. One gene (CRX) is known to cause either dominant or recessive disease, depending on the specific mutation.

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.

There are about 20,000 different genes in a human and all individuals carry one copy of several 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.

In rare cases, LCA is inherited as an autosomal dominant genetic disorder. Mutations in three genes, CRX, IMPDH1, and OTX2 are currently known to be 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 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.

Those affected populations with LCA:

The prevalence of LCA has been estimated to be 1-2/100,000 births. This disorder affects males and females in equal numbers.

Related Disorders

Symptoms of the following disorders can be similar to those of Leber congenital amaurosis. Comparisons may be useful for a differential diagnosis:

Loken-Senior syndrome is a rare autosomal recessive genetic disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. (For more information on this disorder, choose “Loken-Senior” as your search term in the Rare Disease Database.)

Joubert syndrome is an autosomal recessive genetic disorder that affects the area of the brain that controls balance and coordination. This condition is characterized by a specific finding on an MRI called a “molar tooth sign” in which the cerebellar vermis of the brain is absent or underdeveloped and the brain stem is abnormal. The most common features of Joubert syndrome are lack of muscle control (ataxia), abnormal breathing patterns (hyperpnea), sleep apnea, abnormal eye and tongue movements and low muscle tone. (For more information on this disorder, choose “Joubert” as your search term in the Rare Disease Database.)

Zellweger spectrum disorders are a group of rare, autosomal recessive genetic, multisystem disorders that were once thought to be separate entities. These disorders are also known as peroxisome biogenesis disorders (PBDs), a group of disorders characterized by the failure of the body to produce peroxisomes that function properly. Zellweger syndrome is the most severe form; neonatal adrenoleukodystrophy is the intermediate form; and infantile Refsum disease is the mildest form. Zellweger spectrum disorders can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. (For more information on this disorder, choose “Zellweger” as your search term in the Rare Disease Database.)

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 mutations in the genes associated with LCA. Clinical signs and symptoms can be helpful in determining which genes to test for, and in what order.

Standard Therapies

Treatment
Treatment for LCA is symptomatic and supportive. Genetic counseling is recommended for families of affected children.

In 2017, the gene therapy Luxturna (voretigene neparvovec-rzyl) was approved by the U.S. Food and Drug Administration (FDA) to treat children and adults with two mutations in the RPE65 gene which includes a type of LCA called LCA2. Luxturna is manufactured by Spark Therapeutics, Inc.

Causes

Related Disorders

Diagnosis

Standard Therapies

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