Ataxia-Telangiectasia and variants

Ataxia-telangiectasia (A-T) is an autosomal recessive multisystem disorder with early-onset cerebellar ataxia as its defining neurologic feature. It is the most common, recessively inherited, cerebellar ataxia in children under 5 years of age, with a prevalence of 1/40,000 to 1/100,000 live births (Swift, 1985). The accompanying extra-neural features aid in its clinical diagnosis and include conjunctival and cutaneous telangiectases, elevated levels of serum alpha-fetoprotein, chromosome aberrations, immunodeficiency with recurrent sinopulmonary infection, cancer susceptibility, and radiation hypersensitivity. Since identification of the causative gene, ATM (for Ataxia-Telangiectasia mutated), on chromosome 11q22-q23 (Gatti et al., 1988; Savitsky et al., 1995), the molecular basis of certain aspects of the disease have become clearer, though others remain to be elucidated (Gatti et al., 1998; Meyn, 1997; Shiloh and Rotman, 1996).

Note: see also cards on genes ATM, and NBS1 , and on cancer prone diseases Ataxia telangectasia and Nijmegen breakage syndrome

CLINICAL FEATURES

Progressive cerebellar ataxia is almost always the presenting symptom and becomes apparent as early as the first year of life. Truncal and gait ataxia are slowly and steadily progressive, although between the ages of 2 and 5 years normal development of motor skills may temporarily mask this decline. This cerebellar degeneration typically leads to wheelchair dependence by the second decade. Migration abnormalities of prenatal Purkinje cell (PC) as well as post-natal PC degeneration have been seen (Vinters et al., 1985), with thinning of the molecular and granule cell layers and minor changes in dentate and olivary nuclei and medullary tracts. Oculomotor abnormalities may also be seen. The typical patient with A-T is of normal intelligence, although the motor abnormalities make formal psychometric testing and standard learning programs difficult.

Telangiectases appear an average of two to four years after onset of the neurologic syndrome and are progressive. They are composed of dilated capillaries in the conjunctiva, and, later, on the ears, over the bridge of the nose, in the antecubital fossae, behind the knees, or more diffusely. They do not occur on internal organs nor are they generally associated with bleeding problems.

Over the course of their lives, nearly 40% of A-T patients will develop a malignancy (Morrell et al., 1986). Roughly 85% of these malignancies will be either leukemia or lymphoma, which in younger patients may occasionally precede the onset of ataxia. Children will most often develop acute lymphocytic leukemia (ALL) of T-cell origin, rather than the pre-B cell form seen in common childhood ALL. Leukemia in older A-T patients is usually an aggressive T-cell process with morphology similar to a chronic lymphoblastic leukemia (T-CLL, or T-cell prolymphocytic leukemia, T-PLL) (Taylor et al., 1996). Lymphomas are more often non-Hodgkin's, extra-nodal, infiltrative, B-cell types, and harder to diagnose in their early stages (Murphy et al., 1999). Solid tumors of other tissues occur more commonly as the A-T patient matures, and are being seen in greater numbers as these patients are living longer (Morrell, 1968).

Treatment of A-T patients with cancer with conventional doses of ionizing radiation results in life-threatening sequelae characteristic of much higher doses. In vitro, fibroblasts and lymphoblasts from A-T homozygotes show sensitivity to a number of radiomimetic and free-radical-producing agents (Taylor et al., 1985; Shiloh et al., 1985). This finding led to the development of the highly sensitive and reasonably specific diagnostic test, the colony survival assay (CSA) (Huo et al., 1994).

Moderate cellular and humoral immunodeficiency, with low levels of certain immunoglobulin classes, in conjunction with difficulties in swallowing, lead to frequent pulmonary infections in A-T patients. The incidence and severity of infections varies widely between patients, with some being severely affected, while others have no particular difficulty.

A-T, as in other syndromes manifesting chromosomal instability (e.g., Fanconi anemia, xeroderma pigmentosum xeroderma pigmentosum, Bloom syndrome), shows progeroid features (Gatti and Walford, 1981). Young A-T patients may have strands of gray hair or keratoses and basal cell carcinomas. These signs may be related to the accelerated telomeric shortening mentioned above, to increased tissue turnover, and/or to the exaggerated effects of oxidative damage.

Endocrine defects typically result in gonadal abnormalities. Most female patients ultimately begin regular menstrual cycles, but may enter menopause prematurely. Most male patients develop normal secondary sexual characteristics. Retardation in somatic growth is seen in about 75%. Pituitary function studies show no consistent abnormalities. Some patients develop insulin-resistant diabetes in their late teens, with hyperglycemia without glycosuria or ketosis, possibly due to a particular IgM antibody directed against insulin receptors (Gatti and Walford, 1981).

CYTOGENETIC FEATURES

Karyotyping of peripheral lymphocytes from A-T homozygotes shows nonrandom chromosomal rearrangements which preferentially involve chromosomal breakpoints at 14q11, 14q32, 7q35, 7p14, 2pll, and 22q11, and correlate with the regions of the T-cell and B-cell receptor gene complexes (Aurias, 1986). Telomere shortening and fusions, with normal telomerase activity (Pandita et al., 1995), have been observed in peripheral blood lymphocytes of A-T patients, especially in pre-leukemic T-cell clones (Metcalfe et al., 1996).

BIOLOGICAL FEATURES

AFP levels are usually elevated, and are a reliable clinical marker after the age of 2. The high levels of AFP are felt to be of hepatic origin and may be accompanied by elevations of other liver enzymes, with no evidence of liver disease at postmortem (Ishiguro et al., 1986; Gatti and Walford, 1981; McFarlin et al., 1972).

Virtually all A-T homozygotes that have come to postmortem examination have a small, embryonic thymus, but the resulting immunodeficiencies can be quite variable, even within the same family, suggesting a problem with maturation of B and T cell precursors. IgA, IgE, and IgG2 deficiencies are most common, with the accompanying risk of recurrent sinopulmonary infection (Roifman and Gelfand, 1985). Elevated serum IgM levels may occasionally progress to a high blood viscosity syndrome, with splenomegaly, lymphoadenopathy, neutropenia, thrombocytopenia, and congestive heart failure. T-cell deficiencies occur in half the patients, with abnormal skin test antigen and PHA responses (Paganelli et al., 1992). In a British study of 70 patients (Woods and Taylor, 1992), 10% had severe immunodeficiencies, while nearly 40% had normal immunologic function.

CLINICOPATHOLOGY OF THE A-T HETEROZYGOTE

The carrier frequency for ATM is estimated at 1%. Carriers are normal neurologically, although they have in vitro radiosensitivity values that are intermediate between homozygotes and normals (Taylor et al., 1985; Paterson et al., 1985; Weeks et al., 1991). It remains unclear whether this translates to any greater risk during exposure to ionizing radiation clinically (diagnostic X-rays, radiation therapy), although results from Broeks suggest that A-T heterozygotes are more frequent among breast cancer patients who develop a second breast tumor after radiotherapy (Broeks et al., 2000). Studies of mice heterozygous for Atm show an increased frequency of dysplastic breast cells in irradiated animals, supporting an increased cancer risk for heterozygotes that is related to their mutagen exposure (Weil et al., 2001). These data suggest that perhaps Swift's recommendation that female relatives of A-T patients avoid mammography is good advice, although the benefit drawn from early detection is largely thought to outweigh the very small chance that the screening could actually provoke a breast tumor, especially when up-to-date mammography equipment with the lowest possible dose is used. Excessive numbers of ATM heterozygotes have not been identified among patients over-reacting to radiotherapy, nor have ATM heterozygotes diagnosed with cancer been noted to have unusual reactions to irradiation, suggesting that their radiosensitivity in vivo is not great (Clarke et al., 1998; Hall et al., 1998).

CANCER RISK OF AT CARRIERS

Several authors have reported that the incidence of cancer in A-T heterozygotes was higher than that in the general population, most notably breast cancer in female heterozygotes less than 60 years of age (Swift et al., 1991; Pippard et al., 1988; Borreson et al., 1990). Other cancers were also mentioned, such as stomach and liver cancer (Swift et al., 1991; Chessa et al., 1994). Several authors now agree that the relative risk of breast cancer in heterozygotes is between 3.3 and 3.9 (Easton, 1994; Inskip et al., 1999; Athma et al., 1996; Janin et al., 1999), with a greater RR at younger ages and no significantly increased risk above age 60, while the relative risk for other types of cancer is not elevated. This modest risk, however, may correspond to a significant percentage of breast cancer in the population at large being attributable to heterozygosity at ATM: if 1% of the population is heterozygous at ATM, and the RR of breast cancer is about 3, then 2 to 4% of new breast cancer cases may be due to defects in ATM.

A few groups have searched for constitutional ATM mutations in circulating lymphocytes from sporadic breast cancer cases, and have not found an increased carrier frequency (Fitzgerald et al., 1996; Bebb et al., 1999). Thus, it seems that heterozygosity for ATM is not associated with a tendency toward breast cancer, even though family studies indicate increased risk. There may be several reasons for this discrepancy, first, PTT only identifies 60 to 70% of mutations in A-T homozygotes, and these are not necessarily representative of those associated with breast cancer (Telatar et al., 1996). Secondly, the frequency of A-T heterozygotes in the population is not well defined, although 1% is often cited (Swift et al., 1986; Easton, 1994). Therefore, the low numbers of constitutional mutations found in the above studies do not exclude a role for ATM in breast cancer. Larger study populations and more sensitive techniques to detect ATM mutations are needed before any significant difference between the study and control groups can be reliably defined.

Other groups have looked for ATM mutations in familial breast cancer familial breast cancer, again without finding excessive numbers of constitutional heterozygotes (Vorechovsky et al., 1996a; Bay et al., 1998; Chen et al., 1998). It is in fact unlikely that heterozygosity for ATM would lead to identifiable cancer families, due to the low relative risk involved.

Although the truncating mutations found in A-T patients have not been found frequently in breast cancer patients, it is curious that small changes in the ATM sequence are found much more frequently in breast cancer cases than in the healthy population (Gatti et al., 1999). These changes include missense and silent mutations as well as nucleotide changes in the introns. Although some of these will certainly turn out to be innocuous polymorphisms, others may indeed be associated with reduced or altered function of the ATM protein.

Loss of heterozygosity (LOH) at the ATM locus has been found in 30 to 60% of cancers, (Hampton et al., 1994; Rio et al., 1998; Uhrhammer et al., 1999), suggesting that ATM may have a role in tumorigenesis, although it is difficult to interpret this type of study due to the large region of chromosome 11q that may be involved in the LOH, and the fact that genes near to ATM may also be involved. In addition, in breast and colon cancer the incidence of LOH at the ATM locus is not very much higher than background.

The demonstration of the inactivation of the ATM protein in tumors would more precisely define its importance. A few cases have been described, where the wild-type allele of ATM is inactivated in the tumor tissue of a heterozygote, but the loss of ATM has not been described generally in breast oncogenesis (Chen et al., 1998; Vorechovsky et al., 1996b; Bay et al., 1999). More definitive studies using antibodies against ATM on tumor tissue sections are underway in several laboratories.

Somatic mutations of both alleles of ATM have been found in T-prolymphocytic leukemia, in mantle cell lymphoma and in chronic B-lymphoid leukemias, suggesting that in these types of malignancy ATM does play a tumor-suppressor role (Vorechovsky et al., 1998; Stankovic et al., 1999; Bullrich et al., 1999; Shaffner et al., 2000). This is an interesting finding, because although A-T homozygotes are prone to these types of cancer, they have not been described in A-T heterozygotes.

STRUCTURE AND FUNCTION OF THE ATM PROTEIN

The ATM gene occupies ~150 kb of 11q22.3-q23.1 (Platzer et al., 1997) (Fig1). ATM is transcribed from a bi-directional promoter that also drives expression of the NPAT/Cand3/E14 gene (Platzer et al., 1997; Imai et al., 1997), although the significance of this co-expression is unknown. There are also two alternative exons 1, although differential expression of the mRNA isoforms in different tissues or in response to different stimuli has not been described, nor is there any change in the amino acid sequence of the resulting protein, since translation is initiated in exon 3. The 13 kb ATM mRNA, with its 9168 bp of coding sequence, appears to be expressed in most tissues and stages of development (Savitsky et al., 1995). Notably, expression does not vary with the cell cycle or increase in response to irradiation (Brown et al., 1997).

Homologs of ATM have been identified in other mammals and in fish and amphibians, though no true yeast homolog has been identified. Several proteins with homology to ATM have been found, including the catalytic subunit of DNA-PK and ATR. The greatest similarity between these proteins is in the kinase domain, and together they form a sub-family of PI3-kinase-related proteins.

The protein:

The 350 kDa ATM protein contains a leucine zipper, a domain with homology to the S. pombe Rad3 protein, and a protein kinase domain homologous to the PI3K family (Chen and Lee, 1996). ATM is localized mostly to the nucleus, but is also found in cytoplasmic vesicles (Chen and Lee, 1996; Gately et al., 1998; Watters et al., 1997). ATM has been shown to associate with DNA, with particular affinity for DNA ends (Smith et al., 1999). This DNA end-binding activity suggests that ATM might be the/a primary sensor of DNA double-strand breaks (DSBs). In the presence of DNA DSB damage, ATM phosphorylates a variety of protein targets and activates several different signaling cascades (Figure 2). In contrast to the mRNA, ATM protein does become more abundant in response to IR, although only in cells such as lymphocytes, that express low basal levels: no change is seen in cells expressing high levels of ATM (Fang et al., 2001). In addition, ATM becomes more tightly attached to the nuclear matrix and/or chromatin in the presence of DNA damage (Andegeko et al., 2001).

G1 cell cycle arrest: ATM induces G₁ phase arrest through the action of several intermediates. One of the most important targets is the phosphorylation of p53 on ser15 (Canman et al., 1998; Khanna et al., 1998; Watterman et al., 1998). Among the genes whose transcription is induced by p53 is the cdk-inhibitor p21Waf1/Cip1 p21^Waf1/Cip1, which plays a key role in inhibiting the transition from G₁ to S phase.

ATM also induces G₁ arrest through the phosphorylation of cAbl (Shafman et al., 1997; Baskaran et al., 1997), which in turn activates both the p53 homolog p73 and the SAPK pathway to block progression to S phase.

S phase arrest: the phosphorylation of cAbl also serves to halt progression within S phase by inhibiting Rad51Rad51, a single-stranded DNA binding protein essential for replication. Replication Protein A (RPA), another protein essential for the progression of DNA replication, is inhibited by ATM through phosphorylation of its 34 kDa subunit. ATM has been shown to phosphorylate Ser222 of the FANCD2 protien, which is essential for S phase arrest in response to treatment with DNA cross-linking agents (Grompe and D'Andrea, 2001). Two authors have shown that ATM is not, however, required for the decatenation checkpoints in S phase or late G2 phase, underlining the existence of multiple checkpoints throughout the cell cycle (Montecucco et al., 2001; Deming et al., 2001). Abnormalities in S phase lead to the quantifiable phenotype known as ‘radiation resistant DNA synthesis’, or RDS in cells from A-T homozygotes.

G2 cell cycle arrest: ATM inhibits cells from entering mitosis after irradiation through the phosphorylation of at least two targets, Chk1 and Chk2. The literature is occasionally indistinct on the subject of G₂ arrest in A-T cells, most likely because there are two arrest points, and only one is defective in A-T. Immediately after DNA damage, the defective cell cycle checkpoint can be measured as a failure to diminish the numbers of cells that enter mitosis in the hours that follow irradiation. In contrast, at later times there is clearly an increase in G₂ cells which is readily detectable by FACS analysis. This late G₂ accumulation is due to cells that were in G₁ or S at the time of irradiation, which replicated their DNA in spite of the presence of DSBs, and which have now triggered a distinct G₂ checkpoint.

Figure 2. In response to DNA double-strand breaks, ATM interacts with many different proteins to induce cell cycle arrest, increase DNA repair, and inhibits apoptosis.

Radiosensitivity is a constant feature of A-T and is thought to be due to excessive apoptosis. How ATM inhibits apoptosis is not completely understood, and may be different according to the type of tissue studied. One route is through the phosphorylation of IkB. IkB is an inhibitor of NFkB, and its phosphorylation leads to the release of NFkB sequestered in the cytoplasm. NFkB now translocates to the nucleus, where it acts as a transcriptional regulator of anti-apoptotic genes. A second level of apoptosis control acts through p53, though the mechanism is likely to be indirect. Cultured A-T fibroblasts undergo apoptosis in response to irradiation, and this process may be inhibited by the inactivation of p53. As we have seen, ATM activates the cell cycle arrest functions of p53, but it is as yet unknown how the inhibition of p53’s pro-apoptotic functions works. It is possible that ATM-/- cells allow replication of damaged DNA templates, which in turn trigger p53 through independent mechanisms.

A third pathway through which ATM inhibits apoptosis might be through the ceramide synthesis cascade. This signaling cascade is initiated at the cell membrane in response to irradiation, and is dysregulated in A-T cells. It is not yet known how ATM is involved, and whether the detection of DNA damage is necessary or if ATM might detect some other damage signal.

Most of the functions described above take place in the nucleus, where ATM surveys the DNA for DSBs, and phosphorylates its substrates when necessary. The phosphorylation of IkB (and possibly of cAbl) occurs in the cytoplasm, however, and the proteins of the ceramide signaling pathway are located on membranes accessible from the cytoplasm. Some authors have proposed that the pool of ATM associated with cytoplasmic vesicles performs functions distinct from genomic surveillance. ATM has been shown to associate with beta-adaptin in the cytoplasm and may be involved in vesicle trafficking and intercellular communication, and it is this aspect which may eventually explain the specific degeneration of cerebellar Purkinje cells.

A-T cells exhibit subtle defects in DSB repair: they take longer to repair DSBs and the repair of plasmid substrates is often inexact. While ATM itself does not seem to play a direct role in the rejoining of DSBs, it is involved in the control of this process. As we have seen, ATM activates GADD45 indirectly though p53. In addition, BRCA1 has been shown to be phosphorylated by ATM in response to DSBs and this phosphorylation is essential to relieve the radiation sensitivity of BRCA1-mutant cells (Cortez et al., 1999). BRCA1 has been described as being necessary for the aggregation of Rad51 complexes or Rad50/Mre11/nibrin at DSB sites, in addition to being a transcriptional activator. Rad50 and Rad51 are both required for the repair of DSBs, and BRCA1 may provide a link in the signaling cascade that activates repair. Finally, ATM probably activates DSB repair through Rad50/Mre11/nibrin independently from BRCA1. Two groups have now shown that ATM phosphorylates H2AX within seconds of DSB damage (Burma et al., 2001; Andegeko et al., 2001). H2AX-P promotes chromatin decondensation and is a major signal for DNA repair. The speed of this phosphorylation also provides more circumstantial evidence for ATM as an actual sensor of DSBs, although there is as yet no direct evidence for this.

Cells experiencing DSB damage in G₁ or G₀ repair this damage through non-homologous end joining, a process controlled by DNA-PK. The relationship between ATM and DNA-PK is as yet unclear, since the abundant Ku subunits of DNA-PK can bind to DNA ends on their own and recruit DNA-PKcs to the sites for repair. This temporal difference in the choice of DSB repair mechanism may be the main reason why two apparently redundant mechanisms are both essential, another being that some are unrepairable by NHEJ due to the poor quality of the DNA ends. In any case, Atm-/-/SCID double-knockout mice are inviable after 12 days gestation (Gurley 2001), demonstrating the additive effect of these two DSB signaling/repair proteins. Ku70 has been shown now to be essential for the binding of the Rad50 / Mre11 / nibrin complex at DSB sites, however, and the similarities of the cellular phenotypes of A-T and NBS (nibrin-deficient) cells suggests that this may provide the link between ATM and DNA-PK. Cells experiencing DSB damage in G₂ favor homologous recombination between sister chromatids for repair.

Since the cloning of ATM, the vast majority of A-T patients have been found to carry mutations in the ATM gene. There are a few cases, however, where no mutation was detectable in the gene, and the ATM protein was present in cellular extracts. Stewart has now described mutations in the hMre11a gene in four such patients from two families (1999). Interestingly, cell fusion experiments in the 1980’s indicated that there were four complementation groups for A-T (Jaspers et al., 1988). After the cloning of ATM, it was shown that mutations in this one gene were present in all four ‘complementation groups’, sometimes identical mutations, and the multigenic theory of A-T was essentially discarded as an experimental artifact (Savitsky et al., 1995). The hMre11a gene is located about 30 cM proximal to ATM on the long arm of chromosome 11, at band q22.1.

The phenotypes of human patients with ATM and hypomorphic hMre11 mutations are very nearly identical. ATLD patients (for ataxia-telangiectasia-like disorder) may have a slightly milder phenotype than A-T patients, but still within the range of phenotypes found for classic A-T patients. The phenotypic differences are apparent at the cellular level: the induction of p53 is nearly normal, and clonogenic survival and radioresistant DNA synthesis curves are intermediate between that of A-T patients and normal subjects. Intriguingly, these cellular phenotypes of ATLD are identical to those of NBS patients, even though the neural phenotypes are different (there being no microcephaly or mental retardation in ATLD, nor cerebellar ataxia in NBS). Recall that NBS patients have mutations in the gene encoding nibrin, a subunit of Rad50/Mre11/nibrin.

The four patients described with hMre11 mutations are two homozygotes for a nonsense mutation at codon 633, and two compound heterozygotes for a null mutation and a substitution of serine for asparagine at amino acid 117. Both the nonsense and missense mutated proteins produce stable products that are able to associate with Rad50 and nibrin, although the aggregation of this complex at DSB sites is abnormal. Data from mMre11 knockout mice indicate that these human mutations are most likely to be partially functional, because a null allele of mMre11 is lethal during embryogenesis, as are null alleles for mRad50 (mice with Nbs1 mutations have are similar to Atm-/- mice, with growth retardation, lymphoid developmental defects, lymphoid thymomas, radiosensitivity and female - though not male - sterility) (Xiao and Weaver, 1997; Kang et al., 2002).

The interaction between ATM and Mre11 is becoming more clear. The Rad50/Mre11/nibrin complex has described as containing (an) additional protein(s) of high molecular weight, and probably associates loosely or transiently with several other proteins, including BRCA1 and ATM. Clearly, ATM, Mre11, nibrin, and BRCA1 are all required for the aggregation of Rad50 at DSB sites. ATM phosphorylates both nibrin and Mre11, and in the absence of nibrin, ATM fails to phosphorylate Mre11 (Wu et al., 2000; Kim et al., 1999). Rad50, Mre11, and the yeast analog of nibrin, xrs5, all perform essential repair functions and their loss is lethal. The loss of regulatory proteins such as ATM or BRCA1, or the reduced function of nibrin or Mre11 is tolerated but decreases the efficiency of repair.

1. Radiosensitivity: without ATM, DNA damage triggers apoptosis in sensitive cell types. Radiosensitivity is not due to acquired mutations and karyotypic inviability, but to programmed cell elimination.

2. Cancer risk: A-T cells either create or tolerate chromosomal rearrangements more than other cells. These rearrangements may hit genes critical for normal cell growth and thus initiate cancer. The lack of ATM is not directly tumorigenic, but rather allows other mutation events. The stereotypical chromosomal rearrangements seen in A-T lymphocytes are evidence of this problem with genomic stability. A new study in Atm-/- mice, however, showed that spontaneous mutation rates were not increased in samples of ear and spleen tissue, suggesting that not all tissues are equally sensitive to the effects of ATM loss (Turker et al., 1999).

3. Immunodeficiency: without ATM, the process of V(D)J recombination is not properly supervised, and aberrant chromosomes are created. Most cells recognize the anomaly and commit suicide (leading to the hypoplastic thymus), but others escape this control and are detected as circulating lymphocytes carrying the 7;7, 7;14, and 14;14 rearrangements characteristic of A-T. That the immunodeficiency in A-T is not as severe as other syndromes reflects the ability of A-T cells to create functional V(D)J recombination events at reduced frequency.

4. Cerebellar degeneration: this aspect of A-T is as yet unexplained by the known molecular functions of the protein, though several theories have been advanced. 1) aberrant migration of Purkinje cells 2) oxidative damage leads to cell death, 3) an autoimmune process destroys the Purkinje cells. An excess of oxidative stress in the cerebellum (and elsewhere) is currently the favored hypothesis for this degeneration (Stern et al., 2002).

GENOTYPE/PHENOTYPE CORRELATIONS

Over 300 disease-causing ATM mutations have been identified, extending over each of the 66 exons, and patients from non-consanguineous families are typically compound heterozygotes. Although founder effect mutations account for significant proportions of A-T patients in various ethnic populations, they do not account for significant numbers of A-T patients in heterogeneous populations such as the United States.

A-T variants, who do not meet all the clinical criteria for A-T (i.e., relatively late-onset of ataxia or chorea, unusually long survival, absence of telangiectases, normal AFP levels, normal immune status, intermediate levels of radiosensitivity) have been shown for the most part to have ATM mutations. These have been homo- or at least heterozygous for milder missense, splice-site, or small, non-critical insertion/deletion abnormalities that could allow production of up to 17% of normal ATM protein. Nonsense, frame-shift, or in-frame changes, causing two truncating mutations, with production of little or no ATM protein in over 85% of patients, result in the more typical A-T phenotype with lower mean survivals.

Many other patients with phenotypes typical of A-T (DiRocco, 1999; Hernandez et al., 1993) have not been shown to have mutations in the ATM gene, and may represent mutations in other genes that interact with the ATM protein. One of these proteins has been identified as Mre11, as discussed above.

TREATMENT OF A-T

At present there is no definitive gene-based therapy, neuroprotective therapy, or neural-restorative therapy to halt or reverse progression of the neurologic symptoms of A-T. The extraneural symptoms have many conventional treatment options, especially in the important areas of pulmonary infection and malignancy. Infection is usually with common microbes, not opportunistic organisms (despite the combined immunodeficiency), so prompt treatment with appropriate antibiotics and attention to aggressive pulmonary hygiene can prevent future complications (resistant infections, bronchiectasis, chronic respiratory failure, and aspiration).

Regular physical examinations with blood counts and blood chemistries can serve as an early screen for leukemia/lymphoma and other cancers. Routine pelvic exams and breast exams in young women, prostate screening in young men, and skin exams in both should be instituted. Non-radiologic imaging studies should be used when any area of concern is raised (MRI, ultrasound). Should a malignancy occur, treatment protocols utilizing lower doses of radiation therapy and alternatives to radiomimetic and neurotoxic agents should be sought, and chemotherapy protocols with a high risk of developing a second malignancy (topoisomerase inhibitors) should be modified. Young children presenting with leukemia or lymphoma, or any other malignancy, should be screened for the presence of A-T before a treatment regimen is begun. Because of the extreme cancer susceptibility of these patients, they should be encouraged to avoid excess sun exposure by keeping skin covered and wearing a hat and sunscreen when outdoors.

Neurorehabilitation strategies and symptomatic medication can improve neurologic performance and reduce the risk of long-term complications from increasing immobility (deconditioning, contractures, decubiti, pneumonia, bladder infections, constipation). Physical therapy can help the patient maintain independence, continue in school, and enjoy leisure pursuits with family and friends. Pool exercise, speech therapy, remedial learning programs, and appropriate adaptive equipment also reduce the ultimate handicaps of these patients.

Most A-T patients in the United States and western Europe live well beyond 20 years, thanks to improved health maintenance and rehabilitation options. This is a major change from just a few years ago, when it was unusual for patients to live past their teens, but much work still needs to be done.

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