The diagnosis of ataxia-telangiectasia (A-T) is based primarily on clinical examination and should include progressive cerebellar ataxia with onset between 1 and 3 years of age. Ocular apraxia is a reliable diagnostic criterion after 3 years of age. Telangiectasias often are manifested several years after the onset of ataxia; the degree of telangiectasia is quite variable from family to family. Serum α-fetoprotein (AFP) is elevated in 95 percent of patients. Magnetic resonance imaging shows a dystrophic cerebellum. Karyotyping, if successful, reveals characteristic translocations involving chromosomes 14q11-12, 14q32, 7q35, and 7p14. Immunodeficiency and cancer, usually lymphoid, are observed in many A-T patients. Most patients have no measurable ATM (A-T mutated) protein in lysates of their cells or cell lines, while a few have small amounts.

Because A-T patients are radiosensitive, conventional doses of radiation therapy are contraindicated. In all young patients with lymphoid malignancies, an underlying diagnosis of A-T should be considered before one calculates doses of radiation or radiomimetic drugs.

The incidence of A-T is estimated at 1 per 40,000 live births in the United States. The carrier frequency was estimated at 1 percent; recent molecular studies support this early estimate. In some assays, carriers are indistinguishable from normal individuals. Despite this, female carriers are reported to be at a fivefold increased risk of breast cancer. Carriers may account for 5 percent of all cancer patients in the United States. Carriers are intermediate in their in vitro responses to ionizing radiation-induced DNA damage. Whether they are clinically more radiosensitive than normals is not known. Conventional wisdom suggests that exposure of A-T carriers to ionizing radiation should be minimized. However, mammograms are recommended, and the same age-dependent schedule as for noncarriers should be followed. Thus far, attempts to demonstrate an increased frequency of ATM mutations in breast cancer patients have not corroborated earlier epidemiologic observations. Given the lack of convincing data on cancer risks for A-T carriers, it is prudent to advise carriers only that the possibility of an increased cancer risk is still under investigation.

The ATM gene and gene product(s) are very large: 3056 amino acids, 350 kDa, a 13-kb transcript (and smaller, alternatively spliced products), and 66 exons that cover 150 kb of genomic DNA. ATM is expressed in all organs tested. ATM belongs to a large-molecular-weight family of protein kinases. Delayed or reduced expression of p53 in radiation-damaged A-T cells suggests that ATM interacts with proteins upstream of p53 in sensing double-strand break DNA damage. The ATM gene product also plays a role in gametogenesis, as part of the synaptonemal complex.

Seventy percent of ATM mutations result in a shortened (truncated) protein. These mutations are found over the entire gene and are best detected by mRNA-based techniques that first translate the mRNA to cDNA by RT-PCR before screening for mutations. The favored RT-PCR-based methods are PTT, REF, SSCP, and direct sequencing. Rapid assays that are DNA-based are being developed for the more common mutations, and for mutations that are common to particular ethnic populations, such as the Amish, Moroccan Jews, Sardinians, Italians, British, Costa Ricans, Norwegians, Poles, Turks, Iranians, and Hispanics.

Several related syndromes overlap with A-T. Nijmegen Breakage syndrome (NBS) Berlin Breakage syndrome (BBS) share t(7;14) translocations, radiosensitivity, immunodeficiency, and cancer susceptibility with A-T, but these patients do not have ataxia, telangiectasia, or elevated AFP. NBS/BBS patients are microcephalic and mentally retarded and sometimes have syndactyly or anal stenosis. NBS and BBS result from mutations in the same gene, NBS1, on chromosome 8q21. ATFresno combines the A-T and NBS syndromes. ATFresno patients have ATM mutations. Ninety percent of European NBS/BBS patients carry a 657del5 Slavic mutation. Patients with hMre11 deficiency share the progressive ataxia, radiosensitivity, and t(7;14) chromosomal aberrations with A-T patients; however they have normal AFP, no telangiectasia, and a milder phenotype.

A-T is a very pleiotropic syndrome that stems from the defective functioning of a single gene—Purkinje cells degenerate and migrate abnormally in the cerebellum during prenatal development; the thymus remains embryonic; histology of most organs shows variability in nuclear size, i.e., nucleomegaly; and radiation hypersensitivity. The ATM gene product senses double-stranded DNA breaks, probably by phosphorylating pivotal molecules such as p53; when the ATM protein is defective, the signal to arrest the cell cycle is not given and DNA damage does not get properly repaired before the next replication cycle begins. A-T cells have G1, S, and G2/M checkpoint defects. In addition to phosphorylating p53, the ATM protein phosphorylates IkB-α, to release the transcription factor NFkB. It also interacts with RPA, Chk1, Chk2, Rb, c-abl, ATR, MLH1, and Rad51. Thus, by functioning as a hierarchical protein kinase, the ATM protein acts on both cell-cycle signaling and on the processing of double-strand DNA breaks, whether physiological, as in meiotic recombination and gene rearrangements, or nonphysiological double-strand breaks, as in the DNA damage caused by environmental agents.

Therapy for A-T patients remains restricted mainly to supportive care. Free-radical scavengers are recommended, such as vitamin E, α-lipoic acid, and coenzyme Q10. Daily folic acid may minimize chromosome breakage events. Physical therapy is expremely important to avoid debilitating contractures. Patients with frequent severe infections may require intravenous γ-globulin.