Diagnosis: Ataxia-Telangiectasia

Ataxia telangiectasia (AT) is a complex genetic neurodegenerative disorder that may manifest in childhood or early childhood. The disorder is characterized by progressively impaired coordination of voluntary movements (ataxia), the development of reddish lesions on the skin and mucous membranes due to persistent dilation of groups of blood vessels (telangiectasia), and impaired function of the immune system (i.e., humoral immunodeficiency), resulting in increased susceptibility to upper and lower respiratory tract infections (sinopulmonary infections). Individuals with AT also have an increased risk of developing certain malignancies, especially of the lymphatic system (lymphomas), hematopoietic organs (e.g., leukemias), and the brain.

In patients with AT, progressive ataxia typically develops in childhood and may initially be characterized by abnormal swaying of the head and trunk. As the disease progresses, the condition leads to an inability to walk (loss of ambulation) in late childhood or adolescence. Ataxia is often accompanied by difficulties with speech (dysarthria), drooling, and impaired ability to coordinate certain eye movements (oculomotor apraxia), including the occurrence of involuntary, rapid, rhythmic oscillatory eye movements when attempting to fixate on objects (fixation nystagmus). Affected children may also develop an unusually stooped posture and irregular, rapid, jerky movements that may occur together with relatively slow, writhing movements (choreoathetosis. By mid‑childhood, telangiectasia may also develop, often appearing on sun‑exposed areas of the skin, such as the nasal bridge, ears, and certain regions of the limbs, as well as on the ocular mucous membranes (conjunctiva).

AT is inherited as an autosomal recessive trait. The disorder is caused by changes (mutations) in a gene known as ATM (“ataxia‑telangiectasia mutated”), which has been mapped to the long arm (q) of chromosome 11 (11q22.3). The ATM gene regulates (encodes) the production of an enzyme that plays a role in controlling cell division after DNA damage.

Diagnosis

Ataxia telangiectasia is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one inherited from the father and the other from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. Individuals who receive one normal gene and one gene for the disorder are carriers but usually do not show symptoms. The risk that two carrier parents will pass the defective gene to their child and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance that a child will inherit normal genes from both parents and be genetically unaffected for this trait is 25%.

The ATM gene responsible for ataxia telangiectasia is located on the long arm (q) of chromosome 11 (11q22.3). Chromosomes are located in the nucleus of every body cell and carry the genetic characteristics of each individual. Human chromosome pairs are numbered 1 through 22, with the 23rd pair consisting of X and Y chromosomes in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further subdivided into numbered bands.

Researchers have found that the ATM gene encodes a protein that plays a role in regulating cell division after DNA damage. The protein known as ATM (“AT‑mutated”) is an enzyme (a protein kinase) that normally responds to DNA damage by triggering the accumulation of the protein p53, which prevents cell division (tumor suppressor protein). In individuals with ataxia telangiectasia, abnormal mutations in the ATM gene cause the absence or defect of the ATM protein and delayed accumulation of p53. As a result, cells with DNA damage continue to divide without proper DNA repair, leading to an increased risk of cancer. It is believed that approximately half of all human cancers involve abnormalities affecting the p53 tumor‑suppressor pathway. Exposure to ionizing radiation (such as X‑rays) normally increases ATM protein activity directed toward p53; however, in individuals with AT, deficient ATM activity results in extreme sensitivity to such radiation.

Ataxia telangiectasia typically begins in childhood (between ages one and three) and often affects more than one child in a family. Males and females are affected in equal numbers. In the United States, prevalence is estimated at approximately one in 40,000–100,000 live births.

Diagnosis is based on a detailed patient anamnesis, thorough clinical evaluation, identification of characteristic symptoms, and a variety of specialized tests including blood tests, magnetic resonance imaging (MRI), and karyotyping.

Blood tests may reveal elevated levels of serum alpha‑fetoprotein, present in approximately 85% of cases; however, in unaffected infants, this protein may remain elevated until age 2. Blood tests may also show elevated liver enzymes. MRI can show progressive cerebellar atrophy. Karyotyping detects chromosomal abnormalities, which are increased in affected individuals.

Therapy

Treatment of AT is aimed at controlling symptoms. In cases of respiratory infections, therapy may include antibiotics, postural drainage (with the head lower than the rest of the body) of the bronchi and lungs, and injections of gamma globulin.

Avoiding excessive sun exposure may help reduce the spread and severity of telangiectasias. Vitamin E therapy has been reported to temporarily relieve some symptoms but should only be attempted under strict medical supervision to avoid toxicity. Diazepam (Valium) may be useful in some cases for slurred speech and involuntary muscle contractions. Physical therapy can help maintain muscle strength and prevent limb contractures. Care must be taken to protect the patient from infections.

Additional treatment is symptomatic and supportive. Genetic counseling may be beneficial for individuals with AT and their families.

Ataxia-Telangiectasia

General

Diagnosis

Therapy

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