Maple syrup urine disease, thiamine

Polled hereford calves in Australia develop maple syrup urine disease relatively often/ 6 One cause was established as a mutation that introduces a stop codon that causes premature termination within the leader peptide during synthesis of the thiamin diphosphate-dependent El subunit. A similar biochemical defect in a mutant of Bacillus subtilis causes difficulties for this bacterium, which requires branched-chain fatty acids in its membranes. Branched acyl-CoA derivatives are needed as starter pieces for their synthesis (Chapter 29). With the oxidative decarboxylation of the necessary oxoacids blocked, the mutant is unable to grow unless supplemented with branched-chain fatty acids. 

Some patients with maple syrup urine disease respond to high doses (10 to 1,000 mg per day) of thiamin in some patients, the defect is clearly in the Ela subunit, which has a for thiamin diphosphate 16-fold higher than normal. 

In vitro, thiamin diphosphate inhibits the kinase that phosphorylates and inactivates branched-chain oxo-acid dehydrogenase, and might be expected to increase the activity of the enzyme in tissues, thus offering an alternative mechanism for thiamin-responsive maple syrup urine disease. However, this seems not to be relevant in vivo, possibly because tissue concentrations of thiamin diphosphate do not rise high enough to affect the activity of the kinase. In thiamin-deficient animals, there is an increase in the total liver content... 

Apeirt from children with thiamin-responsive maple syrup urine disease (Section 6.3.1.4) and thiamin-responsive megaloblastic anemia (Section 6.2), there are no established pharmacological uses of thieimin other than the treatment of deficiency. Because of the neurological involvement in thiamin deficiency, the vitamin has been used in nerve tonics, edthough there is no evidence that it has any effect except in cases of deficiency. 

Branched-chain ketoaciduria (commonly known as Maple Syrup Urine Disease MSUD) is another ailment that may be caused by thiamine deficiency. In MSUD, the oxidative decarboxylation of alpha-keto acids derived from, i.e. valine, isoleucine, and leucine, is blocked due to an inadequate supply of the coenzyme thiamine pyrophosphate (TPP). Clinical symptoms of MSUD include mental and physical retardation. Describe briefly the structure of Riboflavin (Vitamin B-2) and its biochemical role. 

Absorption and Metabolism of Thiamin Biochemistry of Huamin Thiamin Deficiency Assessment of Thi in Status Determination of tite Thiamin Requiremoit Use of Thiamin in Maple Syrup Urine Disease Riboflavin... 

Four inherited disorders responsive to treatment with pharmacological doses of thiamine are summarized in Table 38-1. However, at least for megaloblastic anemia and maple syrup urine disease, more nonresponsive than responsive cases are known. Since thiamine is promptly excreted in the urine, excessive intake is not associated with toxicity. 

Wadman, 1971). The possibility of double heterozygosity in these patients has been suggested (Scriver and Rosenberg, 1973 Zaleski etal, 1973). Other variant forms are much more rare, with a mild variant and patients with thiamin-responsive forms of the disease being described (Scriver and Rosenberg, 1973 Dancis and Levitz, 1978 Duran era/., 1978b Pueschal era/., 1979). A patient with valine toxic intermittent maple syrup urine disease has also been described (Zipf era/., 1979). 

In a rare autosomal recessive condition (discovered in 1954) the urine and perspiration has a maple syrup odor/ High concentrations of the branched-chain 2-oxoacids formed by transamination of valine, leucine, and isoleucine are present, and the odor arises from decomposition products of these acids. The branched-chain amino acids as well as the related alcohols also accumulate in the blood and are found in the urine. The biochemical defect lies in the enzyme catalyzing oxidative decarboxylation of the oxoacids, as is indicated in Fig. 24-18. Insertions, deletions, and substitutions may be present in any of the subunits (Figs. 15-14,15-15). The disease which may affect one person in 200,000, is usually fatal in early childhood if untreated. Children suffer seizures, mental retardation, and coma. They may survive on a low-protein (gelatin) diet supplemented with essential amino acids, but treatment is difficult and a sudden relapse is apt to prove fatal. Some patients respond to administration of thiamin at 20 times the normal daily requirement. The branched-chain oxoacid dehydrogenase from some of these children shows a reduced affinity for the essential coenzyme thiamin diphosphate.d... 

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