eMedicine Specialties > Ophthalmology > Phakomatoses

Ataxia-telangiectasia

Author: Andrew A Dahl, MD, Director of Ophthalmology Teaching, Mid-Hudson Family Practice Institute, The Institute for Family Health; Assistant Professor of Surgery (Ophthalmology), New York College of Medicine
Coauthor(s): Diego Calonje, MD, Consulting Staff, Department of Ophthalmology, Private Practice; Sherif M El-Harazi, MD, MPH, Consulting Staff, Department of Ophthalmology, Sherif El-Harazi, MD
Contributor Information and Disclosures

Updated: Nov 18, 2008

Introduction

Background

Ataxia-telangiectasia (AT) is a genetic disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, and recurrent respiratory and sinus infections.

The first case described in the literature was a 9-year-old child with progressive cerebellar ataxia and bilateral oculocutaneous telangiectasia reported in 1941 by Madame Louis-Bar. Initially known as the Louis-Bar syndrome, the term ataxia-telangiectasia was introduced in 1958 by Boder et al, who recorded the clinical features and recognized the familial incidence proposing an autosomal recessive mode of inheritance for the disease.¹ The disease is sometimes referred to as Boder-Sedgwick syndrome.

Progressive cerebellar ataxia usually becomes clinically apparent when the child begins to walk. The ataxia affects station, gait, and intention. Telangiectasia of the bulbar conjunctiva first appears at age 3-7 years and, subsequently, involves the malar areas, palate, ears, and antecubital and popliteal spaces. Other features of this syndrome include retardation of growth, dysarthric speech, dry coarse hair and skin, and mental retardation after age 10 years. The complete syndrome includes hypoplasia of the thymus associated with defective T-cell function and decreased levels of circulating immunoglobulin. Recurrent respiratory tract and sinus infections are common, frequently causing death in adolescence or young adulthood. A high incidence of malignancies occurs, particularly leukemia and Hodgkins lymphoma.

Ataxia-telangiectasia combines central nervous system disease with an oculocutaneous anomaly, fulfilling the criteria for classification within the phakomatoses group of diseases.

Pathophysiology

Ataxia-telangiectasia mainly is due to a defect in a DNA processing or repair protein. The cerebellar and extrapyramidal systems are the most severely affected. This syndrome is characterized by a severe loss of Purkinje cells and, to a lesser degree, the basket and granular cells of the cerebellar cortex. Other pathological changes include cerebellar cortical atrophy, diffuse fibrillary gliosis, and degeneration of the anterior horn cells of the spinal cord. Studies have revealed reduced levels of cerebellar neurotransmitters, including phosphoethanolamine, gamma-aminobutyric acid (GABA), and glutamic acid.

Frequency

United States

The true incidence of ataxia-telangiectasia is unknown. Although ataxia-telangiectasia is rare, the prevalence has been estimated at about 1 in 40,000-50,000.

Mortality/Morbidity

The cause of death in more than 50% of patients with ataxia-telangiectasia is recurrent respiratory infections.

Increased susceptibility to cancer contributes to early mortality in one third to one half of cases. Ataxia-telangiectasia is an autosomal recessive syndrome in which cancers develop in affected homozygotes at a rate approximately 100 times higher than in unaffected age-matched subjects. Retrospective studies have shown that persons heterozygous for the ataxia-telangiectasia gene, who make up about 1% of the general population, also have an excess risk of cancer, particularly breast cancer in women. Patients with ataxia-telangiectasia and cells derived from homozygotes and heterozygotes are unusually sensitive to ionizing radiation.

Sex

Males and females are affected equally.

Age

The mean age of patients with ataxia-telangiectasia at the time of presentation is 2.5-7 years.

Clinical

History

The syndrome of ataxia-telangiectasia is characterized by pathological changes in various systems of the body. Clinically, the central nervous system, eye, skin, upper and lower respiratory tracts, immune system, and viscera are involved.

• Central nervous system
  • Cerebellar and extrapyramidal systems are the most affected.
  • Truncal ataxia is the first presenting symptom of ataxia-telangiectasia and usually appears after the child starts to walk. The first manifestations of truncal ataxia are swaying of the head and trunk on standing and even sitting. The ataxia is progressive and is accompanied by loss of deep tendon reflexes, dystonia, drooling, and dysarthria. Motor function continues to deteriorate, and, by age 10 years, it leads to serious disability, making the use of a wheelchair necessary.
  • Mental changes are not detectable in the earlier stages of ataxia-telangiectasia. As the child grows older, deterioration in mental processes occurs with slowing of reactions and lack of responsiveness. Evidence of mental retardation becomes apparent as ataxia-telangiectasia progresses.
• Eye
  • Telangiectasia of the conjunctiva has a later onset than ataxia and usually appears at age 3-7 years. The telangiectasia is first noted in the interpalpebral bulbar conjunctiva away from the limbus. Eventually, the ocular telangiectasia becomes generalized and simulates a conjunctivitis.
  • Oculomotor abnormalities appear early in ataxia-telangiectasia and consist of an inability to execute voluntary gaze movements rapidly or on command. Version movements are not restricted, but, on command gaze, they are performed in a halting dyssynergistic fashion. Nystagmus may reduce distance visual acuity and impair fixation. The vestibulo-ocular movements are preserved, but there is a poor ability to initiate saccades. Convergence ability frequently is impaired.
  • Visual acuity, pupillary reflex responses, and fundi are normal.
• Skin
  • Cutaneous telangiectasia becomes apparent at age 3-7 years. It is first seen on the ears and palate, across the butterfly area of the face, and the bridge of the nose. As the patient gets older, the telangiectasia extends to the neck, the dorsum of the hands and feet, and in the antecubital and popliteal areas. The telangiectatic vessels originate from the subpapillary venous plexuses.
  • Vitiligo and premature graying of the hair have been observed. Other skin manifestations of ataxia-telangiectasia are as follows: seborrheic dermatitis, atopic dermatitis, café au lait spots, scleroderma-like changes, and nummular eczema.
• Upper and lower respiratory tracts
  • Frequent sinopulmonary infections are common manifestations of ataxia-telangiectasia. The onset of these frequent respiratory infections tends to occur at age 4-6 years.
  • Recurrent bronchitis and sinusitis lead to bronchiectasis and pulmonary fibrosis. The recurrent respiratory infections are the cause of death during adolescence or young adulthood even with optimal antimicrobial and supportive treatment.
• Immune system
  • A common feature in ataxia-telangiectasia is the deficiency of immunoglobulin A (IgA) associated with normal or elevated levels of immunoglobulin G (IgG) and immunoglobulin M (IgM). Normally, IgA represents approximately 90% of the globulin in nasal secretions and 5% of the serum globulin. Since nasal secretions are associated with antiviral activity and are deficient in ataxia-telangiectasia, there appears to be a causal relationship to the susceptibility for respiratory infection observed in ataxia-telangiectasia.
  • Immunological abnormalities in ataxia-telangiectasia include the following: decreased peripheral lymphoid tissue, stunted growth, lymphopenia, absence of delayed hypersensitivity, impaired skin homograft rejection, impaired circulating antibody response to some (weak) antigens, and impaired T-cell function. An elevated alpha-fetoprotein level, present in almost all patients with ataxia-telangiectasia, often is associated with pathologic conditions of the liver and chronic hepatitis.
• Viscera: Hypoplasia or atrophy of the thymus gland is a characteristic finding in ataxia-telangiectasia. Ataxia-telangiectasia is associated with glucose intolerance and insulin resistance probably due to defects in the affinity of the receptors for insulin.

Physical

• The facies are usually dull, relaxed, and sad, but they are in sharp contrast to the cheerful alert appearance when the child is made to smile.
• Hair and skin tend to be coarse and dry. Some gray hair is visible.
• Ataxia of stance and gait, greatly diminished tendon reflexes, dysmetria of the arm movements, decreased tone in the arms and legs, and flexor plantar reflexes are present.
• Vascular markings of the bulbar conjunctiva, external ears, nasal septum, butterfly of the face, and hard and soft palates are seen.
• Tympanic membranes usually are scarred and thickened.
• Postnasal drainage and drooling usually are present.
• Inspiratory and expiratory rales are present in the lungs.
• Testicular or ovarian atrophy is often present.

Causes

• DNA processing or repair protein is the suspected common denominator in ataxia-telangiectasia.
• Ataxia-telangiectasia is inherited as autosomal recessive, and the gene for it has been localized to band 11q22-23.

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