Ataxia Telangiectasia

• Chloe Mander Nunneley, M.D.
• Joseph S. Kass, M.D., J.D.
• Nicole J. Ullrich, M.D., PH.D.

 Basic Information

Definition

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder of childhood that results from defective DNA repair mechanisms. AT is a multisystem disease characterized by progressive cerebellar ataxia, choreoathetosis, oculocutaneous telangiectasias (Fig. E1), frequent infections, increased sensitivity to ionizing radiation, and predisposition to malignancies.

ICD-10CM CODES
G11.3	Cerebellar ataxia with defective DNA repair

Epidemiology & Demographics

Incidence

1/40,000 live births; it is estimated that 1.4% to 2% of whites in the U.S. carry one defective AT gene. It is the second most common cause of autosomal recessive ataxia after Friedreich’s ataxia.

Peak Incidence

Childhood (onset at age 1-5 years)

Predominant Sex

Males and females are equally affected.

Genetics

Condition is autosomal recessive and progressive. The defective gene, designated ATM (for AT mutated), has been mapped to chromosome 11q22-23. More than 100 mutations have been discovered. The gene product, expressed in all tissues, encodes a large nuclear and cytoplasmic protein kinase that is a member of the phosphatidylinositol-3 kinases and another region similar to DNA repair genes. It becomes recruited and activated by double-stranded DNA breaks and phosphorylates several downstream proteins, which lead to cell cycle arrest, DNA repair, or apoptosis. Developing lymphocytes also require the ATM gene product for V(D)J recombination, an essential step in the diversification of lymphocyte antigen receptors.

Physical Findings & Clinical Presentation

1. •

   Children show normal early development until they start to walk, when gait and truncal ataxia become apparent. Thereafter, children develop polyneuropathy, progressive apraxia of eye movements, slurred speech, choreoathetosis, mild diabetes mellitus, delayed physical and sexual development, and signs of premature aging (graying of the hair, loss of skin elasticity and subcutaneous fat).

2. •

   Progression, at times, may be so indolent that the condition is misdiagnosed as cerebral palsy.

3. •

   Children with AT experience deterioration of motor skills. By the second decade of life, most patients rely on wheelchairs for at least part of the day. Progressive oromotor difficulties also develop over time, placing patients at risk for aspiration.

4. •

   Typically, individuals with AT initially have normal intelligence that deteriorates over time until it plateaus at approximately 10 years of age. As deterioration of motor skills occurs much more aggressively, scholastic skills can become impeded, leading to inaccurate results on traditional timed neuropsychological assessments. Deterioration of speech is typically noted after 5 to 8 years of age.

5. •

   Telangiectasias are virtually pathognomonic for AT and can aid in diagnosis, but they typically appear after 6 years of age. Sometimes either a complete absence of telangiectasias or a delay in the appearance of telangiectasias results in a delayed diagnosis. Telangiectasias occur primarily in the bulbar conjunctivae and have been misdiagnosed as conjunctivitis. The telangiectasias can progress over the surface of the ears and cheeks, in the corners of the eyes, on exposed parts of the neck, on the bridge of the nose, and in the flexor creases of the forearms. Children with AT may also have café-au-lait macules, hypopigmented macules, or melanocytic nevi.

6. •

   Immunodeficiencies occur in 60% to 80% of individuals with AT due to B-cell and T-helper cellular dysfunction and defective V(D)J recombination, leading to abnormal immunoglobulin subclasses. Serum and saliva IgA is absent in 70% to 80%. Serum IgE is low or absent in 80% to 90%, and serum IgM may be elevated. Thymic and other lymphoid tissue frequently have hypoplastic and embryonic appearance. Impaired humoral and cellular immunities lead to recurrent sinopulmonary infections. The severity of immunodeficiency is unrelated to the severity of neurologic phenotype and is also not progressive. Recurrent sinopulmonary infections and aspirations, however, can lead to bronchiectasis later in life.

7. •

   In the central nervous system, there is loss of Purkinje cells in the cerebellum, and surviving Purkinje cells may contain eosinophilic cytoplasmic inclusions. Older individuals experience demyelination of the posterior columns and dorsal spinocerebellar tracts. There are also reports of anterior horn cell loss. Peripheral nerves can develop lipid inclusions in Schwann cells, resulting in secondary axonal degeneration.

8. •

   Malignancy: Beyond 10 years of age, the incidence rate is 1% per year; the overall risk rate is approximately 30% to 40%, of which 85% of cases are leukemia and lymphoma. Predisposition to other cancers (e.g., breast cancer) may also exist, thought to be caused by the phosphorylation of the tumor-suppressor/breast cancer susceptibility gene BRCA1 by ATM.

9. •

   Up to 2% of the U.S. population may be carriers of AT. Heterozygote/carriers of the ATM gene are thought to have none of the classic manifestations of AT; however, they may have a greater incidence of malignancy at a younger age.

Etiology

1. •

   Cytogenetics show a 7;14 translocation in 5% to 15% of individuals with AT. Cloning and sequencing has identified the ATM (Ataxia Telangiectasia, Mutated, Mapped to chromosome 11q22.3) gene, a protein kinase that is either missing or defective. The ATM mutation delays accumulation of the tumor-suppressor p53 in response to DNA damage, thereby increasing cancer risk. Cells are susceptible to damage by both ionizing radiation and chemotherapeutic agents that cause double-stranded DNA breakages (also see “Genetics” section).

Diagnosis

Differential Diagnosis

Early-onset ataxia:

1. •

   Friedreich’s ataxia

2. •

   Abetalipoproteinemia (Bassen-Kornzweig syndrome)

3. •

   Acquired vitamin E deficiency

4. •

   Early-onset cerebellar ataxia with retained reflexes (EOCA)

5. •

   Ataxia-ocular apraxia type 1 (AOA1)

6. •

   Ataxia-ocular apraxia type 2 (AOA2)

7. •

   Ataxia telangiectasia-like disorder (ATLD)

8. •

   Spinocerebellar ataxia

9. •

   Juvenile GM2 gangliosidosis

10. •

    Juvenile sulfatide lipidosis

11. •

    Marinesco-Sjögren’s syndrome

12. •

    Hartnup disease and maple syrup urine disease

13. •

    Infantile adrenoleukodystrophy (X-linked)

Workup

Diagnosis relies on the constellation of clinical findings, including ataxia and speech changes, as well as family history and neuroimaging studies.

Laboratory Tests

1. •

   Acanthocytes are frequently seen on smear.

2. •

   Serum immunoglobulin levels (IgA, IgG, IgE, and IgG subclasses) should be measured to evaluate for immunoglobulin deficiency and oligoclonal gammopathy.

3. •

   Serum α-fetoprotein is increased in more than 95% of patients with AT older than the age of 8 mo.

4. •

   Prenatal testing is available. Fibroblasts can be screened for abnormal sensitivity to ionizing radiation.

5. •

   Immunoblotting is the most sensitive and specific way to detect the ATM protein. Approximately 90% of individuals have no detectable ATM protein.

Imaging Studies

CT or MRI scans will show cerebellar atrophy in nearly all children with ATM between 2 and 8 years of age. Telangiectasias may be observed as punctate hemosiderin deposits.

Treatment

1. •

   No proven disease-specific treatment is currently available. Treatment is focused on amelioration of disease manifestations.

2. •

   Surveillance for infections and neoplasms is necessary. Individuals with frequent and severe infections may benefit from intravenous immunoglobulin. Some have been placed on prophylactic antibiotics. Children should be immunized with pneumococcal and influenza vaccines.

3. •

   The cloning and sequencing of the gene for AT have opened several avenues for intervention, including gene therapy, targeted pharmacologic intervention to correct the function of the altered protein, and direct replacement of the functional protein.

4. •

   Recent studies suggest symptomatic improvement with glucocorticoids, which are postulated to induce alternative splicing of the ATM protein and result in retained protein kinase activity.

Nonpharmacologic Therapy

1. •

   Minimize radiation because it may induce further chromosomal damage and lead to neoplasms. Even diagnostic radiographs should be limited because of the theoretical risk that radiation may lead to chromosomal breakages.

2. •

   Monitor swallowing as needed to evaluate for aspiration.

3. •

   Physical and occupational therapy to maintain flexibility and minimize contractures.

Complementary & Alternative Medicine

1. •

   Antioxidant treatment with vitamin E is often given empirically, though it has not been formally tested. α-Lipoic acid crosses the blood-brain barrier and may therefore have some advantage.

Disposition

1. •

   AT has a poor prognosis given the multisystem involvement; however, the expected life span has increased considerably. Most individuals now live beyond 25 yr of age and some into the fourth and fifth decades of life. Morbidity is typically related to either infection or neoplasm.

Referral

1. •

   Immunology

2. •

   Neurology

3. •

   Gastroenterology and nutrition

4. •

   Physical and occupational therapy

5. •

   Genetic counselor

Pearls & Considerations

Comments

1. •

   Most common cause of hereditary ataxia

2. •

   Defect in DNA repair

3. •

   Predisposition to frequent infections, malignancies, and sensitivity to ionizing radiation

Patient/Family Education

1. Ataxia Telangiectasia Children’s Project: www.atcp.org

2. National Ataxia Foundation (NAF): www.ataxia.org

Related Content

1. Ataxia, progressive (Algorithm in Section III)

2. Ataxia (Related Key Topic)