Elsevier

DNA Repair

Volume 3, Issues 8–9, August–September 2004, Pages 1187-1196
DNA Repair

Review
Ataxia–telangiectasia, an evolving phenotype

https://doi.org/10.1016/j.dnarep.2004.04.010Get rights and content

Abstract

Ataxia–telangiectasia (A-T) is a progressive neurodegenerative disorder, with onset in early childhood and a frequency of approximately 1 in 40,000 births in the United States. A-T is seen among all races and is most prominent among ethnic groups with a high frequency of consanguinity. The syndrome includes: progressive cerebellar ataxia, dysarthric speech, oculomotor apraxia, choreoathetosis and, later, oculocutaneous telangiectasia. Immunodeficiency with sinopulmonary infections, cancer susceptibility (usually lymphoid), and sensitivity to ionizing radiation are also characteristic. Laboratory findings include: (1) elevated alphafetoprotein (AFP), (2) cerebellar atrophy on magnetic resonance imaging, (3) reciprocal translocations between chromosomes 7 and 14 in lymphocytes, (4) absence or dysfunction of the ATM protein, (5) radiosensitivity, as demonstrated by colony survival assay (CSA), and (6) mutations in the ATM gene. The latter are usually truncating or splicing mutations; ∼10% are missense mutations. Mutations are found across the entire gene. Almost all recurring mutations are found on unique haplotypes that represent founder effects and ancestral relationships between patients. In addition to radiosensitivity and sensitivity to radiomimetic chemicals, the phenotype of A-T cells includes defective damage-induced activation of the cell cycle checkpoints at G1, S and G2/M. With the aid of molecular testing, A-T can now be distinguished from other autosomal recessive cerebellar ataxias (ARCAs) such as Friedreich ataxia, Mre11 deficiency (AT-like disease), and the oculomotor apraxias 1 (aprataxin deficiency) and 2 (senataxin deficiency). Other “A-T variants” include: (1) Nijmegen breakage syndrome (NBS) or nibrin/Nbs1 deficiency, with microcephaly and mental retardation but without ataxia, apraxia, or telangiectasia, and 2) A-TFresno, a phenotype that combines features of both NBS and A-T, with mutations in the ATM gene. The term “A-T variant” has a diminishing usefulness.

Section snippets

The classical A-T phenotype

A-T is primarily an early-onset, progressive, neurodegenerative disorder [1], [2], [3], [4] that is transmitted as an autosomal recessive disorder. It occurs in approximately 1 per 40,000 live births in the US. This frequency varies considerably from country to country depending upon the degree of inbreeding and the ability to distinguish it from other neurological disorders. At first, infants appear normal; they begin walking at a normal age of one year. However, by 2–3 years, staggering

Variability within the classical A-T phenotype

Within the classical phenotype of A-T, some variability can be appreciated. In general, however, older patients with fully expressed disease manifest a very homogenous syndrome. Thus, it is the onset and progression of signs and symptoms that provide most of the variability. Rare bona fide A-T patients do not develop noticeable ataxia until their teens.

Members of a British family who were homozygous for the 7271 T > G mutation were still walking unaided at 30 years (discussed further below). It

A-T variants

The term ‘A-T variant’ was used originally to describe patients from the Netherlands, with Nijmegen Breakage Syndrome, who had a cellular phenotype similar to A-T cells, (i.e., radiosensitivity and translocations involving chromosomes 7 and 14), in addition to immunodeficiency and cancer predisposition [42], [43]. However, these patients were microcephalic and mentally retarded and did not manifest ataxia or telangiectasia. So there is little danger of clinically confusing the two disorders

Mutations in A-T patients

The number of unique ATM mutations in A-T patients now exceeds 400 (see www.benaroyaresearch.org/bri_investigators/atm.htm). Most patients inherit different mutations from each parent; they are compound heterozygotes. Approximately 85% of these mutations are either nonsense or splicing types, creating mainly frameshifts and premature termination codons that result in null mutations. These occur over the entire gene and none accounts for more than 3% frequency. With very few exceptions, all

A-TFresno variant

The first A-T variant that was shown to link to chromosome 11q23 was A-TFresno [65]. These patients were 9-year-old twins of Mexican origin with progressive cerebellar ataxia and telangiectasia, but with microcephaly and mental retardation as well. The cells from these patients were radiosensitive. Later a homozygous mutation, IVS33 + 2T > C, was found in the ATM gene [21]. No mutations were found in the NBS gene. Since then we have studied three similar patients; ATM mutations have been found

Conclusion

The A-T syndrome or phenotype is now more easily understood in molecular terms than it was just ten years ago. The hierarchical function of ATM as a serine/threonine kinase on multiple substrates allows us to appreciate how a monogenic disorder like A-T can include such a pleiotropic phenotype. Molecular understanding also allows for a definitive diagnosis of A-T, carefully including all patients with deficient ATM protein or function, or ATM mutations, while excluding patients who do not

Acknowledgements

This work was supported by grants from the Department of Energy (87ER60548), US Public Health Service (CA57569, CA76513, NS35322), the A-T Medical Research Foundation (Los Angeles), A-T Medical Research Trust (England), APRAT (France), and the Joseph Drown Foundation. We thank Rashmi Shukla, Shareef Nahas, and Midori Mitui for their assistance and critical comments in the preparation of the manuscript.

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