Ataxia-Telangiectasia Workup

Updated: Jun 08, 2022
  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
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Laboratory Studies

Laboratory markers are important for both diagnosis and prognosis. The most constant markers are elevated levels of alpha-fetoprotein (AFP) and carcinoembryonic antigen and chromosomal abnormalities, especially inversions and translocations involving chromosomes 7 and 14, though neither of these abnormalities is always found and their demonstration requires specific techniques available in only a few centers.

The demonstration of humoral or cellular immunologic defects may also permit an early diagnosis, although such defects are nonspecific and present less frequently.

The dysgammaglobulinemia of ataxia-telangiectasia includes an absent or low level of immunoglobulin A (IgA), including secretory IgA; a normal or low level of immunoglobulin G (IgG); and an elevated or normal level of immunoglobulin M (IgM). Elevated IgM is evident in only 60% of patients. [8] IgA deficiency is found in about 70% of patients with ataxia-telangiectasia syndrome. A deficit in IgG2 and IgG4 subclasses has been demonstrated in several patients, and IgE may also be absent or low.

Defects of cellular immunity include a low lymphocyte count, a poor response to skin tests to common antigens, low T-lymphocyte proliferation in the presence of mitogens, and deficient antibody production to viral or bacterial antigens. Excessive T-cell suppressor activity and intrinsic B-cell defects have been described in some patients, suggesting disturbances of immunoregulatory mechanisms. The incidence of immunologic abnormalities increases with the age of the patients.

Genetic testing

Increased chromosomal breakage after exposure of cell cultures to ionizing radiation is rapidly increasing diagnostic importance, though not yet a routine procedure. Such tests have been considered for the prenatal diagnosis of ataxia-telangiectasia but are being supplanted by DNA diagnosis.

Protein-truncation testing of the entire ATM complementary DNA (cDNA) reveals as much as 66% of truncating mutations in the group with mutant alleles. These rapid assays detected mutations in 76% of Costa Rican patients, 50% of Norwegian patients, 25% of Polish patients, and 14% of Italian patients.

Identification of the disease gene for ataxia-telangiectasia has opened a number of avenues for research. While further mutation analysis will provide insight into the defect and genotype-phenotype correlations, it is also possible to contemplate correction of the abnormal phenotype by using full-length ATM (A-T, mutated) cDNA transfer. Full-length constructs that have been cloned and introduced into other vectors may allow for the correct radiosensitive phenotype. Insertion of the full-length cDNA into other vectors may allow for correction in vivo. Antibodies against the ATM protein are being used for screening tumor samples for loss of expression. Other approaches, such as the yeast 2-hybrid system, will be used to identify additional cellular proteins that associate with ATM.

Because ataxia-telangiectasia heterozygotes appear to be predisposed to a number of tumors, including breast cancer, it may become useful in the future to screen selected at-risk individuals for ATM mutations. Such persons might include members of families with a history of breast cancer or individuals who show an adverse reaction to radiation therapy. The observation that approximately 70% of mutations in the ATM gene known to date appear to encode truncated proteins with premature stop codons will allow for application of such assays as the protein truncation test, which is capable of detecting a single mutated allele. It may also be possible to carry out rapid screening with antibodies to detect ataxia-telangiectasia heterozygotes with ATM of both normal size and reduced size. At one center in Canada using newborn screening, one child was documented per year, as compared with five new cases of severe combined immunodeficiency per year. [52]


Imaging Studies

MRI and sporadically made CT scan often show evidence of nonspecific cerebellar atrophy with widened cerebellar sulci and enlargement of the fourth ventricle. According to Tavani et al, cerebellar atrophy found on MRIs progresses with age, starting from early childhood. [53] Cerebral white matter dysmyelination or demyelination, microhemorrhages and teleangiectases also are reported. [49] See image shown below.

Chest MRI showing a hyperintense lesion in the rig Chest MRI showing a hyperintense lesion in the right mediastinum corresponding to lymphoma.

Radiologic findings of decreased or absent adenoidal tissue in the nasopharynx on lateral skull radiographs are so typical in ataxia-telangiectasia that they are of value in confirming the diagnosis. Chest radiographs may show a small or absent thymic shadow, decreased mediastinal lymphoid tissue, and pulmonary changes similar to those seen in cystic fibrosis. Hypoplastic peripheral lymphoid tissue is such a consistent clinical finding in ataxia-telangiectasia that the appearance of lymphadenopathy or even easily palpable lymph nodes has been highly suggestive of lymphoma.


Other Tests

Electromyogram (EMG) and nerve conduction velocities are frequently normal in small children. In later stages of the disease, when the anterior horn cells are involved and peripheral neuropathy has occurred, the EMG shows signs of denervation and the nerve conduction velocity is reduced, especially in sensory fibers.

Electrooculography is valuable in corroborating the characteristic oculomotor abnormality of ataxia-telangiectasia and differentiating ataxia-telangiectasia from Friedreich ataxia.


Histologic Findings

The major pathological marker of ataxia-telangiectasia in the CNS is degeneration of Purkinje and granule cells in the cerebellum. No vascular abnormalities are usually found, except late degenerative gliovascular nodules in the white matter. Lesions of the basal ganglia are found only occasionally. Degeneration of spinal tracts and anterior horn cells is often present in late cases. Nucleocytomegaly is a feature of several cell types throughout the body.

Biopsy specimens have shown that the typical skin changes in ataxia-telangiectasia are similar to those seen in cumulative actinic damage and, thus, are suggestive of progeric changes. The predilection of both the progeric skin changes and the oculocutaneous telangiectases for sun-exposed areas further suggests increased propensity to actinic damage. Histologically, cutaneous granulomas with this primary immunodeficiency disorder may be sarcoidal, tuberculoid, palisaded, or undefined, with several different granulomatous patterns sometimes evident in the same biopsy specimen. [43]