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)

Mutations in senataxin have been described recently in 24 cases of French-Canadian descent with ataxia-oculomotor apraxia 2. This recessive ataxia is associated with an elevation in alpha-fetoprotein as in ataxia-telangiectasia. Because ataxia-telangiectasia cells are highly radiosensitive, we used a colony survival assay to measure the radiosensitivity of lymphoblastoid cell lines derived from five French-Canadian patients with ataxia-oculomotor apraxia 2. Two were homozygous for the common French-Canadian L1976R SETX missense mutation; the three others were compound heterozygotes for the common mutation and three different missense mutations. Overall, lymphoblastoid cell lines derived from these cases did not show significant variation from a normal response to 1 Gray of ionizing radiation but the two patients who were homozygous for the common L1976R mutation fell in the intermediate or non-diagnostic range.
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PMID:Ataxia-oculomotor apraxia 2 patients show no increased sensitivity to ionizing radiation. 1772 Apr 98

Ataxia telangiectasia (A-T) is a progressive neurodegenerative disease with onset in early childhood, caused by mutations in the ATM (ataxia-telangiectasia mutated) gene. Diagnosis relies on laboratory tests showing high levels of serum alphafetoprotein, cell sensitivity to ionizing radiation (IR) and absence or reduced levels of ATM protein. Many tests, however, are not sufficiently sensitive or specific for A-T, have long turnaround times, or require large blood samples. This prompted us to develop a new flow cytometry method for the diagnosis of A-T based on the measurement of histone H2AX phosphorylation. We established normal ranges of histone H2AX phosphorylation after 2 Gy IR by testing T-cell lines, lymphoblastoid cell lines (LCLs) and/or peripheral blood mononuclear cells (PBMCs) or both from 20 genetically proven A-T and 46 control donors. To further evaluate the specificity and sensitivity of the test, we analyzed cells from 19 patients suspected of having A-T, and from one Friedreich Ataxia, one Ataxia with Oculomotor Apraxia type 2, and one Nijmegen Breakage Syndrome patients. Phosphorylated histone H2AX mean fluorescence intensity of irradiated A-T cells was significantly lower than that of healthy donors. The intrastaining, intraassay, and interassay imprecisions were <or=13.22%. Sensitivity and specificity were virtually 100% when the test was performed on PBMCs. Screening of 19 consecutive new patients with suspected A-T classified 15 patients as non-A-T and four as A-T; diagnosis of the latter four was subsequently confirmed by DNA sequencing to identify ATM mutations. The Friedreich Ataxia patient, the Ataxia with Oculomotor Apraxia type 2 patient and the Nijmegen Breakage Syndrome patient were classified as non-A-T. This flow cytometry test is very sensitive, specific and rapid, and requires only 2 ml of blood. It may thus be proposed for the early differential diagnosis of A-T as an alternative to methods requiring the production of LCLs.
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PMID:A rapid flow cytometry test based on histone H2AX phosphorylation for the sensitive and specific diagnosis of ataxia telangiectasia. 1843 95

Ataxia-telangiectasia (AT) belongs to a group of recessively inherited disorders characterized by progressive ataxia and oculomotor apraxia. Included in this group are AT, ataxia-telangiectasia-like disorder (ATLD), ataxia with oculomotor apraxia type 1 (AOA 1), ataxia with oculomotor apraxia type 2 (AOA 2), and the recently described AOA3. Common to this group is the underlying cellular defect in the recognition and repair of double-strand or single-strand DNA breaks. Clinical and laboratory features allow one to distinguish between these various disorders. In this report, we describe a child with early onset progressive ataxia, oculomotor apraxia, ocular telangiectasia, and white-matter changes by magnetic resonance imaging, which appears to be yet another novel form of AOA. We designate this condition as AOA-WM to call attention to the central demyelination seen in this variety of ataxia with oculomotor apraxia.
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PMID:Ataxia with oculomotor apraxia. 1907 31

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.
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PMID:Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. 1969 32

We report on 2 brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. They both had ataxia with cerebellar atrophy and mental retardation. They had the same mutation of the MRE11 gene, which has not been reported previously (c.727T>C and g.24994G>A).
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PMID:Two brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. 1973 84

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

The diagnosis of rare inherited diseases is becoming more and more complex as an increasing number of clinical conditions appear to be genetically heterogeneous. Multigenic inheritance also applies to the autosomal recessive progressive cerebellar ataxias (ARCAs), for which 14 genes have been identified and more are expected to be discovered. We used homozygosity mapping as a guide for identification of the defective locus in patients with ARCA born from consanguineous parents. Patients from 97 families were analyzed with GeneChip Mapping 10K or 50K SNP Affymetrix microarrays. We identified six families homozygous for regions containing the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) gene, two families homozygous for the ataxia-telangiectasia gene (ATM), two families homozygous for the ataxia with oculomotor apraxia type 1 (AOA1) gene, and one family homozygous for the AOA type 2 (AOA2) gene. Upon direct gene testing, we were able to identify a disease-related mutation in all families but one of the two kindred homozygous at the ATM locus. Although linkage analyses pointed to a single locus on chromosome 11q22.1-q23.1 for this family, clinical features, normal levels of serum alpha-foetoprotein as well as absence of mutations in the ATM gene rather suggest the existence of an additional ARCA-related gene in that interval. While the use of homozygosity mapping was very effective at pointing to the correct gene, it also suggests that the majority of patients harbor mutations either in the genes of the rare forms of ARCA or in genes yet to be identified.
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PMID:Molecular diagnosis of known recessive ataxias by homozygosity mapping with SNP arrays. 2079 53

Maintaining genomic integrity is critical to avoid life-threatening disorders, such as premature aging, neurodegeneration and cancer. A multiprotein cascade operates at sites of DNA double-strand breaks (DSBs) to recognize, signal and repair damage. RNF168 (ring-finger nuclear factor) contributes to this emerging pathway of several E3 ubiquitin ligases that perform sequential ubiquitylations on damaged chromosomes, chromatin modifications essential for aggregation of repair complexes at the DSB sites. Here, we report the clinical and cellular phenotypes associated with a newly identified homozygous nonsense mutation in the RNF168 gene of a patient with a syndrome mimicking ataxia-telangiectasia. The mutation eliminated both of RNF168's ubiquitin-binding motifs, thus blocking progression of the ubiquitylation cascade and retention of repair proteins including tumor suppressors 53BP1 and BRCA1 at DSB sites, consistent with the observed defective DNA damage checkpoints/repair and pronounced radiosensitivity. Rapid screening for RNF168 pathway deficiency was achieved by scoring patients' lymphoblastoid cells for irradiation-induced nuclear foci containing 53BP1, a robust assay we propose for future diagnostic applications. The formation of radiation-induced DSB repair foci was rescued by ectopic expression of wild-type RNF168 in patient's cells, further causally linking the RNF168 mutation with the pathology. Clinically, this novel syndrome featured ataxia, telangiectasia, elevated alphafetoprotein, immunodeficiency, microcephaly and pulmonary failure and has implications for the differential diagnosis of autosomal recessive ataxias.
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PMID:Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. 2139 1

Ataxia-telangiectasia-like disorder (ATLD) due to mutations in the MRE11 gene is a very rare autosomal recessive disease, described so far in only 20 patients. Little is known about the onset of the first symptoms or the clinical course of the disease. The present report contributes to the diagnosis of ATLD and its prognosis at onset. We report 30 years of clinical and ophthalmic observations and the results of quantitative magnetic resonance (MR), MR spectroscopy (proton magnetic resonance spectroscopic imaging) and neuropsychological assessment in the first Italian siblings identified with ATLD. Although the disease had early onset and the clinical picture was initially severe, suggesting ataxia-telangiectasia, neurological impairment, ocular motor apraxia and neuropsychological tests showed very slow deterioration in adult age. The patients developed eye and head motor strategies to compensate ocular motor apraxia. MR measurements and MR spectroscopy disclosed widespread neuronal and axonal involvement. ATLD should be considered in patients with ocular apraxia and ataxia in infancy. The long follow-up provided insights into clinical outcome, with functional neuroimaging studies shedding light on the pathogenetic mechanisms of this rare disease.
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PMID:Clinical course of two Italian siblings with ataxia-telangiectasia-like disorder. 2343 2

The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging.
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PMID:A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging. 2352 41


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