ataxia-telangiectasia


Ataxia-Telangiectasia

 

Definition

Ataxia-telangiectasia (A-T), also called Louis-Bar syndrome, is a rare, genetic neurological disorder of childhood that progressively destroys part of the motor control area of the brain, leading to a lack of balance and coordination. A-T also affects the immune system and increases the risk of leukemia and lymphoma in affected individuals.

Description

The disorder first appeared in the medical literature in the mid-1920s, but was not named specifically until 1957. The name is a combination of two recognized abnormalities: ataxia (lack of muscle control) and telangiectasia (abnormal dilatation of capillary vessels that often result in tumors and red skin lesions). However, A-T involves more than just the sum of these two findings. Other associated A-T problems include immune system deficiencies, extreme sensitivity to radiation, and blood cancers.Medical researchers initially suspected that multiple genes (the units responsible for inherited features) were involved. However, in 1995, mutations in a single large gene were identified as causing A-T. Researchers named the gene ATM for A-T, mutated. Subsequent research revealed that ATM has a significant role in regulating cell division. The symptoms associated with A-T reflect the main role of the AT gene, which is to induce several cellular responses to DNA damage, such as preventing damaged DNA from being reproduced. When the AT gene is mutated into ATM, the signaling networks are affected and the cell no longer responds correctly to minimize the damage.A-T is very rare, but it occurs in every population world wide, with an estimated frequency of between 1/40,000 and 1/100,000 live births. But it is believed that many A-T cases, particularly those who die at a young age, are never properly diagnosed. Therefore, this disease may actually be much more prevalent. According to the A-T Project Foundation, an estimated 1% (2.5 million in the United States) of the general population carries defective A-T genes. Carriers of one copy of this gene do not develop A-T, but have a significantly increased risk of cancer. This makes the A-T gene one of the most important cancer-related genes identified to date.

Causes and symptoms

The ATM gene is autosomal recessive, meaning the disease occurs only if a defective gene is inherited from both parents. Infants with A-T initially often appear very healthy. At around age two, ataxia and nervous system abnormalities becomes apparent. The root cause of A-T-associated ataxia is cell death in the brain, specifically the large branching cells of the nervous system (Purkinje's cells) which are located in the cerebellum. A toddler becomes clumsy, loses balance easily and lacks muscle control. Speech becomes slurred and more difficult, and the symptoms progressively worsen. Between ages two and eight, telangiectases, or tiny, red "spider" veins, appear on the cheeks and ears and in the eyes.

Key terms

Angioma — A tumor (such as a hemangioma or lymphangioma) that mainly consists of blood vessels or lymphatic vessels.Antibody — Any of a large number of proteins produced by specialized blood cells after stimulation by an antigen and that act specifically against the antigen in an immune response.Antigen — Any substance (such as a toxin or enzyme) capable of stimulating an immune response in the body.Ataxia — The inability to control voluntary muscle movement, most frequently resulting from disorders in the brain or spinal cord.Autosomal — Relating to any of the chromosomes except for X and Y, the sex chromosomes.Cerebellum — The part of the brain responsible for coordination of voluntary movements.Gamma-globulin — An extract of human blood that contains antibodies.Immune response — A response from the body to an antigen that occurs when the antigen is identified as foreign and that induces the production of antibodies and lymphocytes capable of destroying the antigen or making it harmless.Immunoglobulin — A protein in the blood that is the component part of an antibody.Leukemia — A cancer of blood cells characterized by the abnormal increase in the number of white blood cells in the tissues. There are many types of leukemias and they are classified according to the type of white blood cell involved.Lymphoma — A blood cancer in which lymphocytes, a variety of white blood cells, grow at an unusually rapid rate.Mutation — Any change in the hereditary material of genes.Purkinje's cells — Large branching cells of the nervous system.Recessive — Producing little or no phenotypic effect when occurring in heterozygous condition with a contrasting allele.Telangiectases — Spidery red skin lesions caused by dilated blood vessels.Telangiectasia — Abnormal dilation of capillary blood vessels leading to the formation of telangiectases or angiomas.Thymus — A gland located in the front of the neck that coordinates the development of the immune system.By age 10-12, children with A-T can no longer control their muscles. Immune system deficiencies become common, and affected individuals are extremely sensitive to radiation. Immune system deficiencies vary between individuals but include lower-than-normal levels of proteins that function as antibodies (immunoglobulins) and white blood cells (blood cells not containing "iron" proteins). The thymus gland, which aids in development of the body's immune system, is either missing or has developed abnormally. Intelligence is normal, but growth may be retarded owing to immune system or hormonal deficiencies. Individuals with A-T are also sometimes afflicted with diabetes, prematurely graying hair, and difficulty swallowing. As the children grow older, the immune system becomes weaker and less capable of fighting infection. In the later stages, recurrent respiratory infections and blood cancers, such as leukemia or lymphoma, are common.

Diagnosis

Diagnosis relies on recognizing the hallmarks of A-T: progressive ataxia and telangiectasia. However, this may be difficult as ataxia symptoms do appear prior to telangiectasia symptoms by several years. Other symptoms can vary between individuals; for example, 70% of individuals with A-T have a high incidence of respiratory infection, 30% do not. The identification of the ATM gene raises hopes that screening, and perhaps treatment, may be possible.

Treatment

There is currently no cure for A-T, and treatment focuses on managing the individual's multiple symptoms. Physical therapy and speech therapy can help the patient adjust to ataxia. Injections of gamma globulin, or extracts of human blood that contain antibodies, are used to strengthen the weakened immune system. High-dose vitamin administrations may also be prescribed. Research continues in many countries to find effective treatments. Individuals and families living with this disorder may benefit from attending support groups.

Prognosis

A-T is a fatal condition. Children with A-T become physically disabled by their early teens and typically die by their early 20s, usually from the associated blood cancers and malignancies. In very rare cases, individuals with A-T may experience slower progression and a slightly longer life span, surviving into their 30s. A-T carriers have a five-fold higher risk than non-carriers of developing certain cancers, especially breast cancer.

Prevention

Medical researchers are investigating methods for screening individuals who may be carriers of the defective gene. Prenatal testing for A-T is possible but not done routinely, because commercial screening tests have yet to be developed.

ataxia

 [ah-tak´se-ah] failure of muscular coordination; irregularity of muscular action. adj., adj atac´tic, atax´ic.cerebellar ataxia ataxia due to disease of the cerebellum.Friedreich's ataxia see friedreich's ataxia.frontal ataxia disturbance of equilibrium associated with tumor of the frontal lobe.hereditary ataxia Friedreich's ataxia.hysterical ataxia ataxia recognizable as a conversion symptom; see also astasia-abasia.locomotor ataxia tabes dorsalis.sensory ataxia ataxia due to loss of proprioception (joint position sense), resulting in poorly judged movements and becoming aggravated when the eyes are closed.ataxia-telangiectasia a severe, autosomal recessive, progressive ataxia, associated with telangiectasias (dilation of small blood vessels) in the skin and eyes; immunodeficiency with frequent infections of the respiratory tract from sinuses to lungs; and abnormal eye movements. Called also Louis-Bar's syndrome.

a·tax·i·a tel·an·gi·ec·ta·si·a

, ataxia-telangiectasia [MIM*208900] an autosomal recessive multisystem disorder consisting of ataxia, ocular apraxia, hypotonia, proprioceptive sensory loss, areflexia, and choreoathetosis; onset typically in early childhood; systemic features include increased susceptibility to malignancies, conjunctival and cutaneous telangiectasia, and recurrent pulmonary infections due to immunodeficiencies. Caused by breaks on chromosome 11q at q22-q23, producing failure of DNA repair. Synonym(s): ataxia telangiectasia syndrome, Boder-Sedgewick syndrome, Louis-Bar syndrome

ataxia-telangiectasia

An autosomal recessive condition (OMIM:208900) characterised by sinopulmonary infections, choreoathetosis (wobbly gait), slurring of speech, muscular atrophy and “red eyes”.
 
Clinical findings
Progressive cerebellar ataxia, oculocutaneous telangiectasia, thymic aplasia or hypoplasia (cellular defect), immune deficiency, autoimmune phenomena.
Lab
Decreased IgG4 and IgA2, ± decreased IgE, increased AFP.
Genetics
Increased susceptibility to radiation-induced chromosomal damage (breakage and rearrangement due to defective DNA repair); increase in lymphoid, breast and other cancers.
Immunity
Immune complex (IC) deposits in glomeruli, choroid plexus, heart valves and synovium; increase in vasoactive amines (histamine), serotonin, IgE and platelets; presence of macrophages; antigen and antibody valences; class of antibody; antibody:antigen ratio; affinity of antibody:antigen; types of vasculature involved depend on the tissue through which the ICs pass and response of the reticuloendothelial system to the ICs.
Diagnosis
Clinical findings, cell culture for radiosensitivity and atypical radioresistant DNA synthesis; cell culture for prenatal diagnosis of ATM mutation.
Management
Symptomatic, supportive; aggressive treatment of infections and surveillance for malignancy.

ataxia-telangiectasia

Louis-Bar syndrome Neurology An AR condition associated with sinopulmonary infections, choreoathetosis—wobbly gait, slurring of speech, muscular atrophy, 'red eyes' Lab ↓ IgG4 and IgA2, ±↓ IgE, ↑ AFP Clinical Progressive cerebellar ataxia, oculocutaneous telangiectasia, thymic aplasia or hypoplasia–cellular defect, immune deficiency, autoimmune phenomena, ↑ susceptibility to radiation-induced chromosomal damage–breakage and rearrangement, and ↑ in lymphoid, breast, and other CA, and rearrangements due to defective DNA repair; immune complex deposits in glomeruli, choroid plexus, heart valves, synovium; ↑ in vasoactive amines–histamine, serotonin, IgE, platelets; presence of macrophages; antigen and antibody valences Diagnosis Clinical findings, ↑ AFP, cell culture assay for radiosensitivity and atypical radioresistant DNA synthesis; cell culture methods can be used for prenatal diagnosis. See Phakomatosis.