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)

Pigs were treated with N2O which is known to impair vitamin B12 function in vivo. Such pigs demonstrated an inability to gain weight, progressive ataxia, and spinal neuropathy. The ataxia was totally and the neuropathy partially preventable by dietary methionine supplementation. Methionine synthase activity was inhibited in both the liver and brain. There was a marked elevation of S-adenosylhomocysteine in the neural tissues and a concomitant failure of S-adenosylmethionine to rise and thus maintain the methylation ratio, except when supplementary dietary methionine was added. In contrast, the methylation ratio in the rat was affected to a lesser extent. The neuropathy, it is suggested, is caused by raised S-adenosylhomocysteine levels in neural tissue; as a result, the methylation ratio is inverted and S-adenosylmethionine-dependent methylation reactions are inhibited.
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PMID:Methylation deficiency causes vitamin B12-associated neuropathy in the pig. 318 71

It is suggested that mammalian cells have evolved to respond to methionine deficiency since in such circumstances vital methylation reactions are put at risk, due to decreased levels of S-adenosyl-methionine. Enzymatic changes occurring as a result of decreased methionine, S-adenosylmethionine and S-adenosylhomocysteine, optimize the remethylation of homocysteine to methionine by decreasing homocysteine catabolism and channelling cellular folates into 5-methyltetrahydropteroylglutamate (5-CH3-H4 PteGlu). The latter, in addition to optimising the remethylation cycle, directs the folate cofactors away from purine and pyrimidine biosynthesis and decreases the rate of proliferation of rapidly dividing cells thus reducing competition for methionine incorporation into proteins. Decreased cellular homocysteine, as a result of decreased methionine, would also restrict cell division by decreased conversion of plasma 5-CH3-H4PteGlu into intracellular polyglutamates. Cobalamin deficiency, either nutritional or due to exposure to the Co (I) cobalamin inactivating agent nitrous oxide, prevents the demethylation of 5-CH3-H4PteGlu, which even in the presence of adequate amounts of homocysteine and methionine prevents rapidly proliferating cells from converting enough of the plasma 5-CH3-H4 PteGlu into folylpolyglutamate forms to permit normal DNA biosynthesis and cell replication. This, together with the trapping of the cellular folate cofactors in the 5-CH3-H4PteGlu form, results in megaloblastic changes occurring in tissues such as the marrow. The vital role of the methylation reactions was demonstrated by exposing monkeys to nitrous oxide which inactivated their methionine synthetase. The resultant ataxia and severe demyelination was prevented and diminished by methionine supplementation. When methionine synthetase was similarly inactivated in mice it was shown that while 5-CH3-H4PteGlu enters mammalian cells, it is not converted into a polyglutamyl form and subsequently leaves the cell unmetabolised. In similar experiments in rats methionine was found to have only a small effect in restoring folylpolyglutamate biosynthesis, contrary to previous reports using nutritionally cobalamin deficient animals. It was found that a decrease in the deoxythymidine salvage pathway by methionine, under the experimental conditions used, has led others to the mistaken conclusion that methionine has an 'anti-folate' effect in bone marrow, i.e. that it decreases folate availability for thymidylate synthetase.
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PMID:The role of methionine in the intracellular accumulation and function of folates. 661 25

1. Pigs treated with nitrous oxide for periods of 1, 2 and 4 months demonstrated markedly reduced levels of methionine synthase and concomitant reduction in the ratio of S-adenosylmethionine to S-adenosylhomocysteine, the methylation ratio, at all time intervals. 2. Both 'O' and 'N' methylations were significantly reduced in pigs after 4 months in nitrous oxide but not after shorter periods. 3. Hypomethylation correlated with the development of clinical ataxia, but was absent when the pigs were clinically normal. It also only occurred when the S-adenosylmethionine level fell. 4. Rats maintained in nitrous oxide for 4 months showed a marked reduction of methionine synthase but no reduction in the methylation ratio or in brain hypomethylation. None of the rats became clinically ataxic. 5. Using an exogenous protein as a methyl group acceptor, it was demonstrated in an in vitro assay that the methyltransferase enzymes responsible for brain 'O' and 'N' methylation were not affected per se by nitrous oxide treatment. 6. It is concluded that reduction of the methylation ratio in the brain of pigs as a consequence of methionine synthase inhibition leads to brain hypomethylation. This hypomethylation could affect critical components of nerve tissue, inducing the vacuolar myelopathic changes seen in the spinal cord of these animals, which mimic those of subacute combined degeneration in man.
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PMID:Demonstration of hypomethylation of proteins in the brain of pigs (but not in rats) associated with chronic vitamin B12 inactivation. 778 50

We report a case of distal posterior inferior cerebellar artery (PICA) aneurysm associated with acute subdural hematoma (SDH). The patient was a 68-year-old female who was found unconscious at home and transferred to the emergency medical center in a state of deep coma. Her consciousness on admission to the center was 200P (Japan coma scale), E1V1M2 (Glasgow Coma Scale), and the Hunt & Kosnik grade was grade IV. She was in a state of decerebrate condition. Computed tomography (CT) scans revealed diffuse subarachnoid hemorrhage that was located mainly in the posterior fossa, as well as intraventricular hemorrhage in the third and fourth ventricles. It also disclosed an intracerebellar hematoma (ICH) of the vermis and an acute SDH of the left posterior fossa. The first cerebral angiographic examinations on admission demonstrated no aneurysm. However, emergency surgery was performed immediately in order to improve her poor condition. Ventricular drainage and removal of the acute SDH were carried out. Postoperatively, her consciousness improved gradually to 20P. Ventricular peritoneal shunt was performed three weeks later. Her consciousness improved up to 3P and she showed only slight truncal ataxia. She was admitted to our hospital for rehabilitation at two months after the first surgery. Repeated angiography was performed and demonstrated an aneurysm in the telovelotonsillar segment of the left PICA. The aneurysm was successfully clipped via a midline suboccipital approach. Her postoperative course was uneventful, and she continues to undergo rehabilitation. Aneurysms of the posterior fossa associated with acute SDH are extremely rare. Only two cases have been reported for distal PICA aneurysm cases. The CT scans in our patient revealed not only SAH but also SDH in the posterior fossa and ICH in the vermis. Over 100 cases of distal PICA aneurysms have been described in the literature. We analyzed the relationship between the portions with the ruptured aneurysms and CT findings. Aneurysms which were located at the proximal portion of the distal PICA mainly showed SAH and IVH. On the other hand, ICHs of the vermis and cerebellum were characteristic CT findings of ruptured aneurysms which were located more distal to the telovelotonsillar segment, and were evident in 14% of cases of such aneurysms. ICH and SDH were not found in aneurysms which were located in portions more proximal to the telovelotonsillar segment. These characteristic findings were related to the complex anatomical courses of the PICA. The distal portions of the PICA run between the vermis and cerebellar hemisphere, so that if an aneurysm ruptures at these portions, ICHs in the vermis and cerebellum tend to occur. In cases such as ours, because of the characteristic CT findings, effort to detect a distal PICA aneurysm should be made at first surgery, along with ventricular drainage and removal of the SDH. The surgical procedures and outcome of cases with distal PICA aneurysms are also discussed.
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PMID:[A ruptured aneurysm of the distal posterior inferior cerebellar artery associated with acute subdural hematoma of the posterior fossa: a case report]. 918 91