Ataxia-telangiectasia (A-T) is an autosomal recessive, complex, multisystem disorder characterized by progressive neurologic impairment, cerebellar ataxia, and variable immunodeficiency with susceptibility to sinopulmonary infections, impaired organ maturation, x-ray hypersensitivity, ocular and cutaneous telangiectasia, and a predisposition to malignancy.

Causes

• The responsible gene (ATM gene) has been mapped to band 11q22-23.
• The ATM gene encodes the protein kinase ATM, which is the key regulator of cellular response to double-strand breaks (DSB) in DNA.
• Abnormal sensitivity of ataxia-telangiectasia cells to x-rays and certain radiomimetic chemicals but not to ultraviolet irradiation, which leads to chromosome and chromatid breaks.
• ATM mutations are poor prognostic factor in patients with lung cancer
• ATM gene targets include well-known tumor suppressor genes such as TP53 and BRCA1, both of which play an important role in the predisposition to breast cancer.
• Studies of ataxia-telangiectasia families have consistently reported an increased risk of breast cancer in women with one mutated ATM gene.

Clinical types

• Pure A-T where patients present with all/most of the diagnostic symptoms
• Attenuated A-T where sufferers do not possess all of the diagnostic symptoms.
• Carrier A-T where individuals with a single ATM mutation show an increased risk of cancer 

These are sometimes classified into ‘types’ from I to IV.

• Type I is the classic syndrome with all manifestations.
• Type II lacks some of the typical findings but shows radio sensitivity.
• Type III has the classic clinical findings but is not radiosensitive.
• Type IV shows only some clinical features and is not radiosensitive.

Signs and symptoms

Ataxia

• Ataxia has its onset in infancy, becoming apparent when the child begins to walk (usually from 12-14 month).
• From this early stage, ataxia is associated with abnormal head movements and is slowly and steadily progressive.
• Ataxia is relentlessly progressive, but the pace is variable
• At a typical rate of progression, the child requires a wheelchair by age 10 or 11 years, even when muscular strength continues to be good. 

Other neurologic symptoms

• Dyssynergia and intention tremor of the extremities become prominent features with age.
• Myoclonic jerks of the trunk and the extremities
• Choreoathetosis is the most prominent extra pyramidal feature in ataxia-telangiectasia.
• The facies is usually relaxed, dull, sad, and seemingly inattentive, which is in sharp contrast to the cheerful, alert appearance when the patient is smiling.
• Dystonic posturing of the fingers is characteristic.
• About 30% of patients have mild mental retardation

Telangiectasias

• Telangiectasias are a second major clinical manifestation (nonneurologic) of the disease
• Dilated conjunctivae vessels, first noticed in the angles of both eyes, spread horizontally in the equatorial region of the conjunctivae toward the corneal limb.
• Ocular telangiectasias may be mistaken for conjunctivitis
• Telangiectatic vessels of ataxia-telangiectasia very rarely hemorrhage 

Skin changes

• Progeric changes of hair and skin are a cardinal feature of ataxia-telangiectasia.
• Some gray hairs are usually found, even in young children if carefully looked for.
• The facial skin tends to become atrophic and sclerodermoid in adolescence.
• The ears tend to become inelastic.
• Café au lait spots, usually single rather than multiple
• Frequent hyperpigmented macules resembling large freckles.
• Seborrheic dermatitis; keratosis pilaris; common warts; and, in female patients, hirsutism of the arms and the legs are also frequently found. 

Malignancy

• In children, more than 85% of neoplasm cases are acute lymphocytic leukemia or lymphoma. In adults with ataxia-telangiectasia, solid tumors are more frequent.
• Solid tumors include lung cancer, stomach cancer, breast cancer, medulloblastoma, basal-cell carcinoma, ovarian dysgerminoma, hepatoma, uterine leiomyoma, parotid gland cancer, and thyroid cancer. 
• The stunting of growth is not well understood.Chronic sinopulmonary disease may be a contributing factor, but stunting of growth also occurs in its absence.

Tests and diagnosis

• Laboratory markers are important for both diagnosis and prognosis. The most constant markers are elevated levels of AFP and carcinoembryonic antigen
• Chromosomal abnormalities, especially inversions and translocations involving chromosomes 7 and 14, though neither of these abnormalities is always found
• The dysgammaglobulinemia of ataxia-telangiectasia includes an absent or low level of IgA, including secretory IgA, a normal or low level of IgG, and an elevated or normal level of IgM.
• IgA deficiency is found in about 70% of patients with ataxia-telangiectasia syndrome.
• MRI and sporadically made CT scan often show evidence of nonspecific cerebellar atrophy with widened cerebellar sulci and enlargement of the fourth ventricle.
• Chest radiographs may show a small or absent thymic shadow, decreased mediastinal lymphoid tissue, and pulmonary changes similar to those seen in cystic fibrosis. 

Treatment

• The life span of patients with ataxia-telangiectasia clearly has been prolonged by antibiotic treatment.
• Prevention of infections by regular injection of immunoglobulins is considered useful.
• Fetal thymus implants and stimulants of the immunologic system have given inconclusive results.
• Treatment of neurologic manifestations is disappointing. Beta-adrenergic blockers may improve fine motor coordination in some cases.
• Desferrioxamine has been shown to increase genomic stability of ataxia-telangiectasia cells and, therefore, may present a promising tool in ataxia-telangiectasia treatment.
• Antioxidants in ataxia-telangiectasia patients have been constructed and are currently underway.