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)

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

The pig has been proposed as a potential animal model for methanol-induced neuro-ocular toxicosis in humans because of its low liver tetrahydrofolate levels and slower rate of formate metabolism compared to those of humans. To examine the validity of this animal model, 12 4-month-old female minipigs (minipig YU) were given a single oral dose of water or methanol at 1.0, 2.5, or 5.0 g/kg body wt by gavage (n = 3 pigs/dose). Dose-dependent signs of acute methanol intoxication, which included mild CNS depression, tremors, ataxia, and recumbency, developed within 0.5 to 2.0 hr, and resolved by 52 hr. Average maximum methanol concentrations in plasma, of 3100 +/- 700 (SD), 6200 +/- 2300, and 15,200 +/- 900 micrograms/ml were reached within 0.5 to 4 hr following methanol administration in animals given 1.0, 2.5, or 5.0 g methanol/kg, respectively. The mean initial elimination half-lives of methanol were 9.0 +/- 1.6, 22.4 +/- 6.1, and 18.9 +/- 4.3 hr, for 1, 2.5, and 5.0 g/kg doses, respectively. In 3 minipigs, a transient increase in plasma formate concentration (1.74-3.40 mEq/liter vs control = 0.5 +/- 0.3 mEq/liter) occurred 4 to 30 hr following methanol administration. Methanol- and formate-dosed pigs did not develop optic nerve lesions, toxicologically significant formate accumulation, or metabolic acidosis. Based on results following a single dose, female minipigs do not appear to be overtly sensitive to methanol and thus may not be a suitable animal model for acute methanol-induced neuro-ocular toxicosis.
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PMID:Acute methanol toxicity in minipigs. 850 8

A 4-year-old female patient presents to the pediatric emergency department with acute onset of ataxia and occipital headache. Initial investigation, including computed tomography imaging, failed to demonstrate any focal neurologic lesion. Subsequent studies, however, reveal an acute thrombosis of the superior cerebellar artery. Further work up identified the likely causative factor to be a heterozygous mutation at the methylene tetrahydrofolate reductase gene. In this case report, we will discuss the work-up of pediatric ataxia, the evaluation and management of cerebrovascular accidents in children, and the association between stroke and mutation of the methylene tetrahydrofolate reductase gene.
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PMID:Ataxia and Headache in a Child: A Case of Acute Cerebellar Infarction. 2877 66