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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. 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, 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.

Ataxia-Telangiectasia Syndrome - Usmle case based discussion

Carriers are normal neurologically, although they have in vitro radiosensitivity values that are intermediate between homozygotes and normals Taylor et al. 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. 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.

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.


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. Other cancers were also mentioned, such as stomach and liver cancer Swift et al. Several authors now agree that the relative risk of breast cancer in heterozygotes is between 3. 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.

Thus, it seems that heterozygosity for ATM is not associated with a tendency toward breast cancer, even though family studies indicate increased risk. Therefore, the low numbers of constitutional mutations found in the above studies do not exclude a role for ATM in breast cancer.

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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. 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.

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. 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. 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.

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. 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 bp of coding sequence, appears to be expressed in most tissues and stages of development Savitsky et al. Notably, expression does not vary with the cell cycle or increase in response to irradiation Brown et al. Homologs of ATM have been identified in other mammals and in fish and amphibians, though no true yeast homolog has been identified.

The greatest similarity between these proteins is in the kinase domain, and together they form a sub-family of PI3-kinase-related proteins. ATM is localized mostly to the nucleus, but is also found in cytoplasmic vesicles Chen and Lee, ; Gately et al.

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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. G1 cell cycle arrest: ATM induces G 1 phase arrest through the action of several intermediates. One of the most important targets is the phosphorylation of p53 on ser15 Canman et al.

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. 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. 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 G 2 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.

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In contrast, at later times there is clearly an increase in G 2 cells which is readily detectable by FACS analysis. This late G 2 accumulation is due to cells that were in G 1 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 G 2 checkpoint. Figure 2.

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. 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.

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Cultured A-T fibroblasts undergo apoptosis in response to irradiation, and this process may be inhibited by the inactivation of p 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. 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. 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.

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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. 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. Cells experiencing DSB damage in G 2 favor homologous recombination between sister chromatids for repair.

There are a few cases, however, where no mutation was detectable in the gene, and the ATM protein was present in cellular extracts.

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Stewart has now described mutations in the hMre11a gene in four such patients from two families The hMre11a gene is located about 30 cM proximal to ATM on the long arm of chromosome 11, at band q 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. The four patients described with hMre11 mutations are two homozygotes for a nonsense mutation at codon , and two compound heterozygotes for a null mutation and a substitution of serine for asparagine at amino acid 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.

Ataxia-telangiectasia - Genetics Home Reference - NIH

The interaction between ATM and Mre11 is becoming more clear. Rad50, Mre11, and the yeast analog of nibrin, xrs5, all perform essential repair functions and their loss is lethal. Radiosensitivity is not due to acquired mutations and karyotypic inviability, but to programmed cell elimination.

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.

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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. 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. 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. An excess of oxidative stress in the cerebellum and elsewhere is currently the favored hypothesis for this degeneration Stern et al. Over 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. One of these proteins has been identified as Mre11, as discussed above.

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.

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. Telangiectasias appear as tiny, red, spider-like veins.