Leber's congenital amaurosis: what is this disease, symptoms, treatment, prognosis

What is Leber's amaurosis?

Leber's congenital amaurosis (abbr. SHAFT) Is a rare genetic eye disease. Affected children are often blind at birth. Other symptoms may include strabismus; rapid involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lens of the eyes (cataract); and / or in the form of a cone in the front of the eye (keratoconus).

Leber's congenital amaurosis begins earlier and can have the most serious consequences. The rate of vision loss with VAL varies from case to case, but remains stable in 75% of cases. About 15% of children have progressive vision loss, and 10% may have some mild, often temporary, improvement.

Leber's amaurosis is characterized by the absence of any pathological changes in the eye that could be seen visually, but this disease arises due to a dysfunction of the optic nerve along with the rest of the departments responsible for vision. This is why with VAL the eyes usually appear normal before the initial examination.

Leber's amaurosis is usually inherited as an autosomal recessive genetic disorder.

Signs and symptoms

Decreased visual response at birth is the first sign of illness. Often, the child pokes, presses, and rubs his eyes to stimulate the retina to receive light. This activity can cause the eyes to become sunken or deep-set (enophthalmos).

Other symptoms may include:

• strabismus;
• nystagmus;
• photophobia;
• cataract;
• keratoconus.

In addition, some children may have hearing loss, mental retardation, and / or developmental delays.

Causes

Leber's congenital amaurosis is a monogenic disease with at least 27 genes implicated in the disease. Changes (mutations) in these genes can account for about 80-90% of diagnosed cases of VAL. The genes responsible for the remaining 10-20% of diagnoses are unknown. VAL is usually inherited as an autosomal recessive genetic disorder. Twenty-four of the genes associated with VAL cause only recessive disease. It is known that two genes (IMPDH1 and OTX2) cause the dominant disease. It is known that one gene (CRX) causes a dominant or recessive disease, depending on the specific mutation.

Recessive genetic disorders occur when a person inherits two copies of an abnormal gene for the same trait, one from each parent. If a person receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually asymptomatic. The risk for two carrier parents who both pass on the defective gene and infect the baby is 25% with each pregnancy. The risk of having a child who will be a carrier, like a parent, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for this particular trait is 25%. The risk is the same for men and women.

There are about 20,000 different genes in humans, and all humans have one copy of several abnormal genes. Parents who are close relatives (brother and sister) are more likely than unrelated parents who have the same abnormal gene, which increases the risk of having children with recessive genetic disorder.

In rare cases, Leber's amaurosis is inherited as an autosomal dominant genetic disorder. It is now known that mutations in three genes, CRX, IMPDH1 and OTX2are associated with this type of SHAFT.

Dominant genetic disorders occur when only one copy of an abnormal gene is needed to cause a specific disorder. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation in the affected person. The risk of passing the abnormal gene from the affected parent to the offspring is 50% with every pregnancy. The risk is the same for men and women.

Affected populations

The estimated prevalence of VAL is 1–2 per 100,000 births. This disorder affects men and women equally.

Symptomatic disorders

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

• Senior-Loken Syndrome is a rare autosomal recessive genetic disorder characterized by progressive depletion of the filter element of the kidney (nephronophthisis), with or without medullary cystic kidney disease, and progressive eye disease. This disorder usually appears during the first year of life.
• Joubert's syndrome Is an autosomal recessive genetic disorder that affects the areas of the brain that control balance and coordination. This condition is characterized by a specific MRI picture, called the sign of a "molar", when in which the cerebellar worms (bundles of nerve fibers) are absent or underdeveloped, and the brain stem has anomalies. The most common signs of Joubert's syndrome are lack of muscle control (ataxia), abnormal breathing (hyperpnea), sleep apnea, abnormal eye and tongue movements, and low muscle tone.
• Violations of the biogenesis of peroxisome spectrum of Zelweger syndrome are a group of rare, autosomal recessive genetic, multisystem disorders that were once considered separate diseases. These disorders are also known as disorders of peroxisome biogenesis (NBP), a group of disorders characterized by the inability of the body to produce peroxisomes. Zellweger's syndrome is the most severe form; neonatal adrenoleukodystrophy is an intermediate form; and Refsum childhood disease is the mildest form. Peroxisome biogenesis disorders of the spectrum of Zellweger syndrome can affect most organs of the body. Neurological disorders, loss of muscle tone (hypotension), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common signs of this disorder.

Diagnostics

Genetic testing can be done to help determine if there is a damaged gene that causes VAL. This helps to assess the risk of transmission of the disease from parents to children. Testing can also help you get a more accurate diagnosis, which will allow you to keep track of new discoveries in the area of ​​interest, research developments and new treatments in the future.

Standard treatments

VAL treatment is symptomatic and supportive. Genetic counseling is recommended for families of affected children.

In 2017, the US Food and Drug Administration (FDA) approved Luxturna gene therapy for the treatment of children and adults with two mutations in gene RPE65. Looksturna is manufactured by Spark Therapeutics, Inc.

Forecast

With age, vision usually decreases, and by the third or fourth decade of life, complete blindness is observed.

Lilia Khabibulina/ article author