Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seventy individuals with ataxia telangiectasia were studied: 29 females and 41 males with an age range of 2 to 42 years. The majority (43/68) presented by 3 years of age with truncal ataxia. All had progressive, handicapping neurological symptoms exhibiting ataxia (70/70), ocular motor apraxia (70/70), an impassive face (70/70), dysarthria (70/70), chorea (68/70), dystonia (55/70) and peripheral neuropathy (50/70). Clinical immune deficiency was present in 43 of 70 patients. Ocular telangiectasia were seen in all but one case and excessive thinness in 54 of 70. The mean age of loss of walking was 10 years and of writing 8 years. All 60 tested showed increased sensitivity to ionizing irradiation, 43 of 48 had an elevated alpha-fetoprotein level and 14 of 21 had an immunoglobulin deficiency. Although there was a marked variation in disease findings sibs were always similar. The heterogeneity seen seems at odds with the unilocus linkage of ataxia telangiectasia to 11q23.
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PMID:Ataxia telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals. 137 28

Molecular epidemiology may help fill the gap between epidemiological and biological models for cancerogenesis, allowing useful comparisons between series of cases carrying different biological characteristics. The defective regulation of immune responses is probably the common basis of cancer origin in genetically determined immune deficiency (GDID). Lymphomas are the most common neoplasms, showing an extremely high incidence in early age, frequent unusual location (extra-nodal) and histology, and rapid progression and spread with little response to therapy. A high incidence of lymphoma is also found in acquired (AIDS) or iatrogenic (transplant recipients) immune defective patients. The emergence of a malignant clone may be linked to unregulated polyclonal B- or T-cell proliferation and to disturbances in chromosomal rearrangements and in clonal selection, which are unique features of the immune cells regulation. It is useful to compare patterns of malignancies observed in GDIDs and in chromosomal breakage syndromes (CBS). In ataxia-teleangectasia (AT), selective errors at sites of special recombination involved in immune cell rearrangements may account for both immune deficiency and frequent types of malignant transformation. Different cytogenetic alterations and different types of malignancies are more common in Bloom syndrome, and in other GDIDs unrelated to chromosomal fragility, possibly due to different regulatory impairments. Viral infection (EBV, HPV, CMV) is likely to be a factor in any of the above steps. Therefore, individual exposure to viral (or other environmental) agents may be related to frequent location (skin, ano-genital areas, digestive tracts) of nonlymphatic cancers both in some GDIDs and in acquired or iatrogenic immune deficiencies. Cells that are homozygous for GDID are not malignant themselves, but are more likely to undergo new mutations to malignancy, due both to disregulation of the immune system and to environmental agents.
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PMID:Molecular epidemiology of cancer in immune deficiency. 203 52

Mice infected with the LP-BM5 murine leukemia virus (MuLV) develop an immune deficiency syndrome together with an encephalopathy characterized by impairments in spatial learning and memory. These cognitive deficits are evident before the appearance of neuron loss and lymphoid cell invasion of the brain. Nonetheless, a prominent gliosis and a variety of neurochemical changes precede the development of cognitive deficits. The neurochemical abnormalities include significant decreases in striatal Met-enkephalin and substance P (but not somatostatin), increases in concentrations of quinolinic acid and platelet-activating factor, and alterations in brain fyn kinase. At this stage of the infection, some of these neurochemical changes can be reversed by glutamate receptor antagonists, cytokine inhibitors, and anti-retroviral agents. In later stages of the infection, however, the infected mice develop irreversible neuronal loss, invasion of hematopoietic cells, and increased viral burden in the CNS. In addition, motor-neuron dysfunction (hindlimb paralysis, weakness, and ataxia) and seizures are sometimes observed during the late stages of infection. Thus, the LP-BM5 MuLV-infected mouse is a useful model for studying the chronology of neurodegenerative changes, ranging from reversible neuron dysfunction to irreversible neuron loss, that are associated with retrovirus-induced immunodeficiency.
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PMID:The encephalopathy associated with murine acquired immunodeficiency syndrome. 962 8

To examine the role of tumor necrosis factor (TNF)-alpha in the pathogenesis of degenerative disorders of the central nervous system (CNS), transgenic mice were developed in which expression of murine TNF-alpha was targeted to astrocytes using a glial fibrillary acidic protein (GFAP)-TNF-alpha fusion gene. In two independent GFAP-TNFalpha transgenic lines (termed GT-8 or GT-2) adult (>4 months of age) animals developed a progressive ataxia (GT-8) or total paralysis affecting the lower body (GT-2). Symptomatic mice had prominent meningoencephalitis (GT-8) or encephalomyelitis (GT-2) in which large numbers of B cells and CD4+ and CD8+ T cells accumulated at predominantly perivascular sites. The majority of these lymphocytes displayed a memory cell phenotype (CD44high, CD62Llow, CD25-) and expressed an early activation marker (CD69). Parenchymal lesions contained mostly CD45+ high, MHC class II+, and Mac-1+ cells of the macrophage microglial lineage with lower numbers of neutrophils and few CD4+ and CD8+ T cells. Cerebral expression of the cellular adhesion molecules ICAM-1, VCAM-1, and MAdCAM as well as a number of alpha- and beta-chemokines was induced or upregulated and preceded the development of inflammation, suggesting an important signaling role for these molecules in the CNS leukocyte migration. Degenerative changes in the CNS of the GFAP-TNFalpha mice paralleled the development of the inflammatory lesions and included primary and secondary demyelination and neurodegeneration. Disease exacerbation with more extensive inflammatory lesions that contained activated cells of the macrophage/microglial lineage occurred in GFAP-TNFalpha mice with severe combined immune deficiency. Thus, persistent astrocyte expression of murine TNF-alpha in the CNS induces a late-onset chronic inflammatory encephalopathy in which macrophage/microglial cells but not lymphocytes play a central role in mediating injury.
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PMID:Late-onset chronic inflammatory encephalopathy in immune-competent and severe combined immune-deficient (SCID) mice with astrocyte-targeted expression of tumor necrosis factor. 973 27

Ataxia-telangiectasia (AT) is an autosomal recessive multisystem disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3-77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or alpha-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT.
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PMID:Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia. 1046 Apr 51

The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.
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PMID:The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. 1158

Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.
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PMID:Alpha-mannosidosis. 1865 71

ATM is a PI 3-kinase involved in DNA double-strand break repair. ATM deficiency leads to ataxia-telangiectasia (A-T), a syndrome of cancer susceptibility, hypersensitivity to ionizing radiation, immune deficiency, and sterility [1, 2]-phenotypes that can straightforwardly be attributed to a defective response to DNA damage. Yet patients with A-T also suffer from ataxia, speech defects, and abnormal body movements [3-5]-neurological phenotypes whose origins remain largely unexplained. Compounding the discordance, Atm mutations in mouse interfere with DNA repair but have only mild neurological symptoms [6-9], suggesting that the link between DNA damage and the death of neurons can be broken [10-12]. We find that in neurons, ATM protein has a substantial cytoplasmic distribution. We show that in Atm(tm1Awb) mice, hippocampal long-term potentiation is significantly reduced, as is the rate of spontaneous vesicular dye release, suggesting a functional importance of cytoplasmic ATM. In the cytoplasm, ATM forms a complex with two synaptic vesicle proteins, VAMP2 and synapsin-I, both of which must be phosphorylated to bind ATM. Also, cytoplasmic ATM physically associates with the homologous PI 3-kinase, ATR. The neurological symptoms of ataxia-telangiectasia may thus result from defective nonnuclear functions of ATM not associated with DNA repair.
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PMID:Cytoplasmic ATM in neurons modulates synaptic function. 1996 14

Ataxia telangiectasia (AT) is an autosomal recessive multisystem genetic disorder caused by a mutation in the ATM gene encoding for the ATM protein. AT systemic manifestations include cutaneous telangiectasias, radiosensitivity, immune deficiency with recurrent sinopulmonary infections, and a tendency to develop lymphoid malignancies. These complications are explained by the major role played by ATM in DNA repair. AT is also the second most common childhood onset neurodegenerative disorder of the cerebellum, presenting with progressive ataxia and oculomotor apraxia and often accompanied by extrapyramidal movement disorders. Ataxia typically begins around the time children start to walk at about 1 year of age and leads to wheelchair dependence by the second decade of life. Cerebellar atrophy is evident on imaging after 2 years of life and is progressive. Abnormal DNA repair mechanisms do not entirely explain the pathophysiology in nondividing neurons. The nervous system involvement is better explained by the role ATM plays in antioxidative defense, mitochondrial homeostasis, and DNA chromatin packing. A better understanding of the underlying pathophysiologic mechanisms of this devastating disease may enable disease-modifying treatments in the future. Meanwhile, treatment is mainly supportive and does not change the poor prognosis of the disease although it improves the patient's quality of life.
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PMID:Ataxia telangiectasia. 2656 81

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
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PMID:Functional classification of ATM variants in ataxia-telangiectasia patients. 3105 87


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