Pediatrics

Ataxia-Telangiectasia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has ataxia-telangiectasia? What are the typical findings for this disease?

The most common symptoms are developmental delay in motor skills and speech in early childhood, with a gradually progressive mixed movement disorder composed of ataxia, chorea, and the onset of dystonia. The movement disorder should be apparent at age 1-4 years. The child will learn to walk but will have problems with balance. Other key findings include oculomotor apraxia and telangiectasias of conjunctivae (appear later).

Ataxia-telangiectasia (AT) is a multisystem disease; immunodeficiency is common and children may initially present with recurrent viral or bacterial sinopulmonary infections secondary to immunoglobulin deficiency. There is also a risk of malignancies, especially leukemia/lymphoma.

What other disease/condition shares some of these symptoms?

Early-onset degenerative movement disorders are rare, and the diagnostic process is difficult and expensive. Referral to a child neurologist with experience in movement disorders is recommended.

Similar ataxias include the ataxias with oculomotor apraxia (types 1 and 2), Mre11 antibody deficiency, childhood-onset gait ataxia with cerebellar atrophy, metabolic diseases presenting with ataxia, and childhood-onset spinocerebellar ataxias. Early-onset choreas can also be in the differential diagnosis.

The distinction from Friedreich's ataxia and ataxia with vitamin E deficiency should be clinically apparent, as these are sensory ataxias with distinct features and a later age of onset.

What caused this disease to develop at this time?

AT is a genetic autosomal recessive disease.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The most useful initial test when AT is suspected is an alpha fetoprotein (AFP) serum determination. Elevated AFP after infancy is supportive of the AT diagnosis in this clinical setting.

Would imaging studies be helpful? If so, which ones?

In general, magnetic resonance imaging of the brain is the most useful imaging study and should be obtained in children with progressive neurologic symptoms localizing to the central nervous system.

Confirming the diagnosis

Childhood ataxias and other progressive movement disorders are rare. The diagnostic process is complex, and the expense is often greater than the cost of consulting with a child neurologist. Therefore, in general the most effective strategy is referral to a child neurologist or movement disorder neurologist.

In the case of a child younger than 4 years of age presenting with progressive ataxia, dystonia, or chorea, a serum AFP determination is the most useful test to evaluate for possible AT. Additional testing will be needed to identify immune deficiency (low IgG levels). Subsequent confirmatory diagnostic testing can include an assay of the ataxia telangiectasia mutated (ATM) protein level and molecular genetic testing for ATM.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

If the child has frequent severe pulmonary or sinus infections, refer to an immunology or pulmonary medicine specialist for aggressive pulmonary hygiene and intravenous immunoglobulin replacement therapy.

Limit radiography because of sensitivity to ionizing radiation and risks of malignancy

Refer to physical, occupational, and speech therapists

Recommend genetic counseling (risk of future child being affected is 25%)

Refer to AT clinic; more information can be found at Ataxia Telangiectasia Children's Project (http://www.atcp.org)/

Some symptomatic treatment for dystonia may be helpful, for example, botulinum toxin injections for cervical dystonia as well as oral trihexyphenidyl therapy. There is no medical treatment for the ataxia.

What are the adverse effects associated with each treatment option?

Risks of intravenous immunoglobulin therapy consist of infusion-related complications, including headache and aseptic meningitis. Treatment should managed by experts.

What are the possible outcomes of ataxia-telangiectasia?

AT is a progressive, degenerative disorder that leads to loss of ambulation, global motor and cognitive impairments, dependence on others for activities of daily living, and a shortened life span. Most affected individuals now live beyond age 25 years with advances in respiratory and immunologic care. Treatment of neurologic manifestions is symptomatic.

What causes this disease and how frequent is it?

AT is inherited in an autosomal recessive manner. The prevalence is 1 in 40,000 to 1 in 100,000 live births. Mutations in the ATM gene are responsible for AT.

How do these pathogens/genes/exposures cause the disease?

ATM protein is a kinase involved in DNA repair. It regulates pathways that respond to DNA strand breaks either in meiosis or due to damaging agents.

Are additional laboratory studies available; even some that are not widely available?

Very specialized additional testing may include ATM protein immunoblotting, testing of ATM-dependent phosphorylation of ATM substrates, radiosensitivity assays, and ATM serine/threonine kinase activity.

How can this disease be prevented?

There are no treatments to prevent this genetic disease. Genetic counseling is recommended.

What is the evidence?

Cabana, MD, Crawford, TO, Winkelstein, JA. "Consequences of the delayed diagnosis of ataxia-telangiectasia". Pediatrics. vol. 102. 1998. pp. 98-100.

(This case series demonstrates that clinicians have often failed to make the diagnosis in children who were symptomatic for several years because the disease was not suspected until telangiectasias appeared. It emphasizes the importance of testing alpha fetoprotein levels early when a child shows neurologic or immunologic symptoms.)

Lavin, MF, Gueven, N, Bottle, S. "Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia". Br Med Bull. vol. 81-82. 2007. pp. 129-47.

Crawford, TO, Skolasky, RL, Fernandez, R. "Survival probability in ataxia telangiectasia". Arch Dis Child. vol. 91. 2006. pp. 610-1.

(A case series with information on survival and cause of death in AT.) (This is an excellent review of the clinical and molecular features of ataxia-telangiectasia and current multidisciplinary treatment strategies.)
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