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Results for “Ataxia Telangiectasia”

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At least 19 recordsLinked to original sources
PubMed1986

[Studies on Epstein-Barr virus (EBV) infection and reactivity of peripheral B lymphocytes to EBV in patients with ataxia telangiectasia].

Ataxia telangiectasia (AT) is a primary immunodeficiency syndrome characterized by oculocutaneous telangiectasia, ataxia, recurrent infection and development of malignancies. Epstein-Barr virus (EBV) is a B-cell lymphocytotropic virus which causes infectious mononucleosis and is also highly associated with Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disorders in immunodeficient patients. 10 Japanese patients with AT were studied concerning the status of EBV infection by specific EBV serology, and reactivity of peripheral lymphocytes to EBV. All the AT patients had high EBV antibody titers of IgG to viral capsid antigen (VCA) and early antigen (EA), while low titers of IgG to EBV-associated nuclear antigen (EBNA), compared with age and sex matched healthy controls. However, significant differences were not apparent with antibodies to several other viruses between the AT patients and controls. These antibody characteristics were thought to be that an activated EBV infection occurred in AT patients. Then the lymphocytes were exposed to B95-8 strain EBV. There was no significant differences in EBNA induction frequency at 24 hours prior to cellular DNA synthesis, between the AT and controls. EBV-specific T cell killer function was very low as judged with the days of establishment of lymphoblastoid cells expressing EBNA on all cells after EBV exposure, when compared with the lymphocytes from controls. These AT lymphoblastoid cells easily expressed EA and VCA by cultivation at lower temperature of 33 degrees C, 12-0-tetradecanoyl-phorbol-13-acetate treatment, 60Co irradiation and by P3HR-1 strain EBV infection. Malignant transformation with high colony forming efficiency in soft agarose and tumor formation in nude mice easily occurred with some of AT lymphoblastoid cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2003

Oxidative stress in ataxia telangiectasia.

Ataxia telangiectasia is one of a group of recessive hereditary genomic instability disorders and is characterized by progressive neurodegeneration, immunodeficiency and cancer susceptibility. Heterozygotes for the mutated gene are more susceptible to cancer and to ischaemic heart disease. The affected gene, ATM (ataxia telangiectasia mutated), has been cloned and codes for a protein kinase (ATM), which orchestrates the cellular response to DNA double-strand breaks after ionising radiation. An underlying feature of ataxia telangiectasia is oxidative stress and there is chronic activation of stress response pathways in tissues showing pathology such as the cerebellum, but not in the cerebrum or liver. ATM has also been shown to be activated by insulin and to have a wider role in signal transduction and cell growth. Many, but not all, aspects of the phenotype can be attributed to a defective DNA damage response. The oxidative stress may result directly from accumulated DNA damage in affected tissues or ATM may have an additional role in sensing/modulating redox homeostasis. The basis for the observed tissue specificity of the oxidative damage in ataxia telangiectasia is not clear.

Animals↗
PubMed1998

A double missense mutation in the ATM gene of a Dutch family with ataxia telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein levels, chromosomal instability, predisposition to cancer, and radiation sensitivity. We report the identification of a new, double missense mutation in the ataxia telangiectasia gene (ATM) of a Dutch family. This homozygous mutation consists of two consecutive base substitutions in exon 55: a T-->G transversion at position 7875 of the ATM cDNA and a G-->C transversion at position 7876. These transversions were confirmed by polymerase chain reaction/primer-induced restriction analysis with CelII. The double base substitution results in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 and of an alanine to a proline at codon 2626 of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. Furthermore, the Chou-Fasman and Robson predictions both demonstrate a change in the secondary structure of the ATM protein carrying the D2625E/A2626P mutation. These findings suggest that the double base substitution in the ATM gene is a disease-causing mutation.

Adolescent↗
PubMed2003

[From gene to disease; ataxia telangiectasia].

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterised by cerebellar ataxia, telangiectasia, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to cell kill by ionising radiation and abnormally resistant to inhibition of DNA synthesis by ionising radiation. The responsible gene, 'ataxia telangiectasia mutated' (ATM) plays a crucial role in a signal transduction pathway, regulating the cell cycle, and in preventing damaged DNA from being reproduced. This rare genetic disorder manifests itself during childhood. The illness is progressive and most individuals die in their second or third decade of life due to infections or cancer. AT is difficult to diagnose due to its rarity and clinical heterogeneity. Both a physical examination and several laboratory tests are necessary for establishing its proper diagnosis.

Antibody Formation↗
PubMed1994

Cerebral white-matter changes suggesting leukodystrophy in ataxia telangiectasia.

Ataxia telangiectasia is an autosomal recessive disorder characterized by progressive cerebellar ataxia, recurrent sinopulmonary infections, oculocutaneous telangiectasia, selective immunoglobulin deficiency, and defective cellular immunity. We report a 4-year-old girl with ataxia telangiectasia whose initial magnetic resonance imaging (MRI) scan at 17 months of age showed leukoencephalopathy compatible with a leukodystrophy, a neuroimaging feature of ataxia telangiectasia that has not been described. Ataxia telangiectasia was not suspected until the child developed more typical clinical features. Diffuse white-matter high signal intensity on T2-weighted MRI scans may occur in the early stages of ataxia telangiectasia. This disease should be considered in the differential diagnosis of any child with a history and MRI findings suggestive of one of the leukodystrophies. The nonneurologic manifestations of ataxia telangiectasia may be of help diagnostically in this clinical setting.

Ataxia Telangiectasia↗
PubMed2005

Mutation analysis of the ATM gene in two Chinese patients with ataxia telangiectasia.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein level, chromosomal instability, predisposition to cancer, and radiation sensitivity. Although a lot of mutations in the ATM gene have been described, there is still no report about ATM mutations in Chinese population. Using a molecular approach, we screened for ATM mutations in two patients from two unrelated Chinese families. 100 normal controls were analyzed to exclude possibility of polymorphism. Two novel mutations in the ATM gene were identified. The first one is a novel, homozygous, 1346G>C (Gly449Ala) missense mutation. The second one is a compound heterozygous mutation, which consists of a novel, 610G>T (Gly204Stop) nonsense mutation, combined with a previously reported, 6679C>T (Arg2227Cys) missense mutation. The transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are not localized either in the conserved PI-3 kinase domain or in the other domains of the ATM protein. The phenotypic features were characterized by progressive cerebellar ataxia, ocular telangiectasia, elevated alpha-fetoprotein level, immunodeficiency (agammaglo-bulinemia and T-cell defect), and rearrangements of chromosomes 7 and 14; brain MRI showed cerebellar atrophy, brain SPECT showed cerebellar regional cerebral blood flow (rCBF) hypoperfusion. To our knowledge, this is the first report of ATM mutations in Mainland China, in which the transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are two novel, disease-causing mutations.

Adolescent↗
PubMedDate not supplied

Monoclonal gammopathy of the immunoglobulin A class in a two-year-old girl with ataxia telangiectasia.

Ataxia telangiectasia is an autosomal recessive neurologic disorder which is frequently associated with a deficiency of IgA immunoglobulin. We report an unusual case of monoclonal gammopathy of the IgA kappa type in a 2-year-old female patient newly diagnosed with ataxia telangiectasia. Quantitative analysis of the patient's immunoglobulins revealed a marked elevation in the IgA fraction with a value of 672 mg/dL (normal 14-123 mg/dL). The IgG and IgM fractions were normal. Serum protein electrophoresis showed a band of restricted mobility present in the gamma region, which was identified as a monoclonal IgA kappa immunoglobulin on immunofixation electrophoresis. This is the first case report of a patient with ataxia telangiectasia associated with an IgA monoclonal gammopathy.

Ataxia Telangiectasia↗
PubMed2004

ATM and ataxia telangiectasia.

Ataxia telangiectasia (AT) has long intrigued the biomedical research community owing to the spectrum of defects that are characteristic of the disease, including neurodegeneration, immune dysfunction, radiosensitivity and cancer predisposition. Following the identification of mutations in ATM (ataxia telangiectasia, mutated) as the underlying cause of the disease, biochemical analysis of this protein kinase has shown that it is a crucial nexus for the cellular response to DNA double-stranded breaks. Many ATM kinase substrates are important players in the cellular responses that prevent cancer. Accordingly, AT is a disease that results from defects in the response to specific types of DNA damage. Thus, although it is a rare neurodegenerative disease, understanding the biology of AT will lead to a greater understanding of the fundamental processes that underpin cancer and neurodegeneration.

Ataxia Telangiectasia↗
PubMed1993

Variants of Nijmegen breakage syndrome and ataxia telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by telangiectasia, progressive ataxia, sinopulmonary infections and a combined immunodeficiency (usually consisting of IgA deficiency, IgE deficiency, IgG2 and IgG4 deficiency and a disturbed T cell immunity). The alpha-fetoprotein level is elevated. Cytogenetic studies reveal a very specific chromosome instability with multiple chromosome 7 and/or 14 rearrangements (preferential breakpoints 14q32, 14q12, 7q35 and 7p12). X-ray hypersensitivity is one of the hallmarks of the disease. Nijmegen Breakage Syndrome (NBS), an autosomal recessive disorder with some features of AT, was first reported in 1981. At this moment at least 19 patients have been recognized. Clinical symptoms are microcephaly from birth, a peculiar face, growth retardation, repeated respiratory tract infections and renal abnormalities. Immunological, cytogenetic and cell-biological findings in NBS are identical to AT. However, alpha-fetoprotein levels are not increased. A tendency toward malignancy has been demonstrated in both syndromes. Recently, we encountered three patients with variants of these syndromes.

Adolescent↗
PubMed1991

Ataxia telangiectasia presenting as an extrapyramidal movement disorder and ocular motor apraxia without overt telangiectasia.

Ataxia telangiectasia may present with few, if any, of its typical extraneurological manifestations, but the combination of an extrapyramidal movement disorder, ocular motor apraxia with head thrusting and cerebellar incoordination is characteristic. In this sporadic case there was no overt immune dysfunction, oculocutaneous telangiectasia were inconspicuous and the neurological presentation was atypical with dystonia predominating over cerebellar incoordination. The uncontrollable and disabling involuntary movements, which have not to our knowledge been described in ataxia telangiectasia before, showed a partial response to moderately large doses of benzhexol, but were refractory to all other medications. Treatment in the future is to be with increasing doses of benzhexol until the dystonia is controlled or larger doses cannot be tolerated.

Adult↗
PubMed2003

A structural characterization of in situ chromatin on cell lines isolated from patients affected by ataxia telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by numerous clinical and cellular features. The pleiotropic nature of the AT syndrome attests to the multiple roles of ATM, the protein codified by the gene altered in AT patients. We investigated if different mutations of ATM could reflect on different alterations of nuclear architecture and chromatin organization. We selected three lymphoblastoid cell lines isolated from AT patients affected by different mutations of ATM gene and one healthy control. We characterized the in situ chromatin structure of each cell line by a biophysical approach: (1) we evaluated the rearrangements of the chromatin domains at the level of single cell by quantitative fluorescence microscopy; (2) we analysed the changes of the average chromatin condensation by differential scanning calorimetry. The results show that the three different ATM mutations produce significant modifications of both nuclear architecture and chromatin condensation.

Ataxia Telangiectasia↗
PubMed2002

Elevated oxidative stress in patients with ataxia telangiectasia.

Ataxia telangiectasia (AT) is a pleiotropic genetic disorder characterized by progressive neurodegeneration, especially of cerebellar Purkinje cells, immunodeficiency, increased incidence of cancer, and premature aging. The disease is caused by functional inactivation of the ATM (AT-mutated) gene product, which is thought to act as a sensor of reactive oxygen species and oxidative damage of cellular macromolecules and DNA. The compound phenotype of AT might thus be linked to a continuous state of oxidative stress leading to an increase of programmed cell death (apoptosis). To assess this hypothesis, we analyzed lipid peroxidation products and the oxidative stress associated DNA base damage 8-hydroxy-2-deoxyguanosine in patients with AT. Oxidative damage to lipids and DNA was found to be markedly increased in AT patients. These results indicate that ATM might play an important role in the maintenance of cell homeostasis in response to oxidative damage. In this context, a better control of levels of reactive oxygen species could be a rational foundation of therapeutic intervention to help alleviate some of the symptoms associated with AT.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Mutations revealed by sequencing the 5' half of the gene for ataxia telangiectasia.

Ataxia telangiectasia is a recessive disorder in which patients show a progressive cerebellar degeneration leading to ataxia, abnormal eye movements and deterioration of speech. Other features include ocular telangiectasia, high serum AFP levels, immunodeficiency, growth retardation and an increased predisposition to some tumours, particularly T cell leukaemia and lymphoma. We report the 1348 amino acid sequence of the N-terminal half of the A-T gene product which, together with the previously published C-terminal half, completes the sequence of the A-T protein. No homologies with other genes have been found within the N-terminal half of the A-T protein. We have also identified six mutations affecting the N-terminal half of the protein. One of these mutations was found to be associated with a haplotype that is common to four apparently unrelated families of Irish descent. All the patients so far examined for both A-T alleles were shown to be compound heterozygotes. None of these mutations affected a putative promoter region which may direct divergent transcription of both the A-T gene and a novel gene E14. The ability to recognise mutations across the entire coding sequence of the A-T gene provides a practical advantage to A-T families since a DNA based prenatal diagnosis will be possible in families where the mutations are identified irrespective of the level of radiosensitivity in these families.

Amino Acid Sequence↗
PubMed2005

Molecular pathology of ataxia telangiectasia.

Ataxia telangiectasia (A-T) is one of a group of autosomal recessive cerebellar ataxias. Presentation is usually by the age of 2 years and ataxia of both upper and lower limbs develops, such that by early teenage most patients require a wheelchair for mobility. Speech and eye movement are also affected. Other important features are t(7;14) translocations, immunodeficiency, a high serum alpha fetoprotein concentration, growth retardation, telangiectasia-most noticeably on the bulbar conjunctiva-and a very high risk of developing a lymphoid tumour. Patients also show an increased sensitivity to ionising radiation. The classic form of A-T results from the presence of two truncating ATM mutations, leading to total loss of the ATM protein, a protein kinase. Importantly, A-T shows clinical heterogeneity, including milder forms where neurological progression may be slower or of later onset. In these cases there is a correlation between the preservation of neurological function, decreased radiosensitivity, and the degree of retained ATM protein kinase activity. Considerable scope remains for understanding the progress of the disorder in relation to the types of ATM mutation present.

Ataxia Telangiectasia↗
PubMed1993

Atypical clinical presentation of ataxia telangiectasia.

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency with recurrent infections, IgA and IgE deficiency, and increased incidence of malignancies. The pathognomonic biological abnormalities consist of spontaneous chromosomal instability resulting in a high in vivo occurrence of cells with translocations, especially involving chromosomes 7 and 14, and a relative insensitivity of DNA replication in vitro to radiation exposure. We report on a patient with the biological hallmarks of AT but with atypical clinical manifestations. Although progressive cerebellar ataxia was present, the neurological picture was broader than that usually seen in AT and included peripheral polyneuropathy and spinal atrophy. On the other hand, telangiectasias, recurrent infections, malignancies, IgA deficiency, or other immunological abnormalities were not present. This illustrates that the clinical picture of AT is broad and nonspecific, and highlights the diagnostic value of cytogenetic analysis and studies of radioresistance of DNA synthesis.

Adult↗
PubMed1994

[Histological and radiobiological study on adult cases with ataxia telangiectasia].

Ataxia telangiectasia (AT) is a hereditary disease that involves both the immune and nervous system; its pathogenesis is believed to be due to disturbances in DNA repair system. Because children are usually affected, reports concerning adult patients are rare. In the present study, we performed comprehensive clinical, histological, and radiobiological examinations on two adult female siblings, currently 23 and 19 years old. The initial symptom was an ataxic gait, which began in the elder sister at the age of 20 and the younger sister at the age of 18. Both had mild telangiectasia in the bulbar conjunctiva and auricula. The neurological manifestations of both were gaze nystagmus, cerebellar ataxia, hyporeflexia, and vibratory sensation disturbance. Only the elder sister showed stocking type sensory disturbance. The MRI of both patients revealed cerebellar atrophy, especially in vermis. After either X-ray irradiation or bleomycin treatment, fibroblast survival curve showed a marked, dose-dependent declined in both patients compared with normal controls. Similar patterns were observed in both patients. After bleomycin treatment, no differences in the survival ratio of cultured fibroblasts could be found between these adult patients and those observed in younger children with classic AT. Biopsied sural nerves showed a decrease in the number of large myelinated fibers, with a few myelinated axons having relatively thin myelin. There were severe atrophic changes, with regenerative myelinated fibers in the elder sister. In conclusion, both adult patients with delayed onset AT displayed similar bleomycin hypersensitivity in fibroblasts as would be expected in children with AT. Radiobiological examinations and sural nerve biopsy suggest that both disturbed cellular regeneration and atrophic process may play a role in the neural involvement in this disease.

Adult↗
PubMed2006

Survival probability in ataxia telangiectasia.

Ataxia telangiectasia is a rare, multiorgan neurodegenerative disorder with enhanced vulnerability to cancer and infection. Median survival in two large cohorts of patients with this disease, one prospective and one retrospective, is 25 and 19 years, with a wide range. Life expectancy does not correlate well with severity of neurological impairment.

Adolescent↗
PubMed1976

Abnormal collagen in ataxia telangiectasia.

Ataxia telangiectasia has been associated with varying clinical and laboratory abnormalities of the cutaneous, immune, neurological, and endocrine systems. Recently, a primary defect in tissue differentiation has been proposed as a probable cause of the disease. The presence of biochemically abnormal collagen in the skin of two siblings with the disease may further support this hypothesis.

Amino Acids↗