ReviewAtaxia–telangiectasia, an evolving phenotype
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.
References (65)
- et al.
Ataxia–telangiectasia: diagnosis and treatment
Semin. Pediatr. Neurol.
(2003) - et al.
Early diagnosis of ataxia–telangiectasia using radiosensitivity testing
J. Pediatr.
(2002) - et al.
Genotype–phenotype relationships in ataxia–telangiectasia and variants
Am. J. Hum. Genet.
(1998) - et al.
Ataxia–telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity
Mol. Genet. Metab.
(2000) Ataxia telangiectasia: new neurons and ATM
Trends Mol. Med.
(2001)- et al.
ATM mutations and phenotypes in ataxia–telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer
Am. J. Hum. Genet.
(1998) - et al.
Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T → G mutations, showing a less severe phenotype
J. Biol. Chem.
(2001) - et al.
Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype
Am. J. Hum. Genet.
(1998) - et al.
Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome
Cell
(1998) - et al.
Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia–telangiectasia-like syndrome) is linked to chromosome 9q34
Am. J. Hum. Genet.
(2000)