A derangement in B12 metabolism associated with homocystinemia, cystathioninemia, hypomethioninemia and methylmalonic aciduria
TL;DR: According to autopsy, this infant could not adequately metabolize B, and as a result failed to accumulate coenzymatically-active derivatives of vitamin B, in normal amounts, and it is suggested that therapeutic benefit may derive from the administration of forms of 6, that could circumvent the metabolic block, by giving substances that could stimulate the non-B, -dependent methionine-synthesizing system or by the Administration of methamphetamineionine in large doses.
About: This article is published in The American Journal of Medicine.The article was published on 1970-03-01. It has received 128 citations till now. The article focuses on the topics: Methylmalonic aciduria & Cyanocobalamin.
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01 Jan 1982
TL;DR: The final unique stage in the metabolism of L-isoleucine involves the cleavage of 2-methylacetoacetyl-CoA to acetyl- coA and propionyl- CoA and methylmalonyl-Co a (Section 10.4).
Abstract: The final unique stage in the metabolism of L-isoleucine involves the cleavage of 2-methylacetoacetyl-CoA to acetyl-CoA and propionyl-CoA (Section 104) The propionyl-CoA is further metabolized to methylmalonyl-CoA by a biotin-dependent carboxylase and subsequently via succinyl-CoA into the tricarboxylic acid cycle L-Valine is also metabolized ultimately to methylmalonyl-CoA (Section 104), and thus these two branched-chain amino acids form the major precursors of propionyl-CoA and methylmalonyl-CoA Other precursors of propionyl-CoA include methionine, threonine, oddcarbon-number fatty acids and cholesterol The methylmalonyl-CoA produced by propionyl-CoA carboxylase occurs as the D(S)-enantiomer and is racemized to the L(R)-enantiomer by methylmalonyl-CoA racemase L(R)Methylmalonyl-CoA is then metabolized to succinyl-CoA by a vitamin B12-dependent mutase prior to introduction of the modified molecule into the tricarboxylic acid cycle
635 citations
TL;DR: The novelty of the hypothesis is the assertion that impairment of one homocysteine metabolic pathway must lead to the impairment of the otherhomocysteines metabolic pathway to cause homocysteinemia, which extends the simplistic view that a block of only one of the pathways is sufficient to cause Homocysteemia.
558 citations
TL;DR: A reduced ability to metabolise homocysteine in some patients with premature coronary artery disease when this pathway is stressed is suggested.
Abstract: Homocystinuria, an abnormality of methionine metabolism is associated with severe vascular disease in infancy and childhood. Homocysteine is formed during the metabolism of methionine and accumulations of this and of cysteine-homocysteine mixed disulfide in the plasma indicate a partial block in the methionine degradation pathway. Methionine metabolism was investigated in 25 patients aged under 50 with angiographically proved coronary artery disease and in 22 control patients, of whom 17 had normal coronary arteries at angiography and 5 were healthy volunteers. After an overnight fast, venous blood was drawn before and 4 h after oral L-methionine, 100 mg/kg. Plasma methionine levels at 4 h were not different in the two groups, but there were significant differences in the levels of cysteine-homocysteine mixed disulfide. This was detected in 5 of 22 in the noncoronary group and in higher concentration in 17 of 25 coronary patients (P less than 0-01). Age, weight, height, body-mass index, glucose tolerance, fasting serum urate, and triglycerides were not different, but serum cholesterol was higher in the coronary patients (P lessthan 0.01). These results suggest a reduced ability to metabolise homocysteine in some patients with premature coronary artery disease when this pathway is stressed.
532 citations
TL;DR: Some patients with pernicious anemia who were intermittently treated with cyanocobalamin were found to have elevated serum levels of total homocysteine while they were free of hematologic and neurologic abnormalities.
Abstract: To determine if levels of serum total homocysteine are elevated in patients with either cobalamin or folate deficiency, we utilized a new capillary gas chromatographic-mass spectrometric technique to measure total homocysteine in the serum of 78 patients with clinically confirmed cobalamin deficiency and 19 patients with clinically confirmed folate deficiency. Values ranged from 11 to 476 mumol/liter in the cobalamin-deficient patients and 77 of the 78 patients had values above the normal range of 7-22 mumol/liter as determined for 50 normal blood donors. In the cobalamin-deficient patients, serum total homocysteine was positively correlated with serum folate, mean corpuscular volume, serum lactate dehydrogenase, serum methylmalonic acid, and the degree of neurologic involvement, and inversely correlated with platelets and hematocrit. In the folate-deficient patients, values for serum total homocysteine ranged from 17 to 185 mumol/liter and 18 of the 19 patients had values above the normal range. Some patients with pernicious anemia who were intermittently treated with cyanocobalamin were found to have elevated serum levels of total homocysteine while they were free of hematologic and neurologic abnormalities. The measurement of serum total homocysteine will help define the incidence of cobalamin deficiency and folate deficiency in various patient populations.
473 citations
TL;DR: HOMOCYSTEINE is a non–protein-forming, sulfur amino acid whose metabolism is at the intersection of two metabolic pathways1: remethylation and transsulfuration.
400 citations
References
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Book•
01 Jan 1969
TL;DR: The reviewer was left with the impression that more attention is paid to these tests in the author's departments than is usually done in Great Britain.
Abstract: Chapter I contains an adequate account of the chemistry of the plasma proteins. This section could, of course, have been expanded, but to have done so would have upset the balance of the book. Study of this chapter would be a good introduction to the more detailed original literature. The chemical methods of determining proteins are described in Chapter II. Chapter III-' Methods of Examination '-describes the procedures such as salting-in, salting-out, precipitation by various combinations of organic solvents at low concentration and electrolytes (cf. the studies of E. J. Cohn and his colleagues), electrophoresis (in free solution and on supporting media), immunoelectrophoresis and ultracentrifugation, which have provided so much of the present body of knowledge concerning the plasma proteins. Chapter IV, 'Clinical Chemical Methods ', and Chapter V, ' Clinical Significance of the Plasma Proteins ', deal with the practical details and the interpretation of the results of the various ' empirical' tests which depend upon changes in the composition and stability of the plasma proteins. The reviewer was left with the impression that more attention is paid to these tests in the author's departments than is usually done in Great Britain. Chapter VI, 'Clinical Significance of the Dysproteinaemias and Paraproteinaemias', reduplicates some of the material given in the earlier chapters but is, in the present writer's opinion, the best in the book.
1,408 citations
TL;DR: The Pharmacopeia was called into being by physicians in 1820, and in 1850 pharmacists were admitted to the convention; since then physicians have gradually relinquished control to pharmacists, and to-day the authors are confronted with an anomalous condition.
Abstract: It is not my present purpose to add to the many reviews or criticisms of the Pharmacopeia, but to call attention to two conditions, hoping that steps may be taken by this Section looking to their improvement. The first is the general loss of interest on the part of physicians in the revision of the Pharmacopeia. The Pharmacopeia was called into being by physicians in 1820, and in 1850 pharmacists were admitted to the convention; since then physicians have gradually relinquished control to pharmacists, and to-day we are confronted with an anomalous condition, in that the committee of revision of 1900, consisting of twenty-five men, numbered nineteen pharmacists or men identified with pharmaceutic institutions, and but six whose interests were entirely with medicine. For example, Dr. Squibb was almost universally known as a manufacturing pharmacist. Only ten members of the committee of revision had the title of M.D. This condition
1,350 citations
TL;DR: A deficiency, or absence, of cystathionine synthetase activity has been demonstrated in liver obtained from a mentally retarded child with homocystinuria.
Abstract: A deficiency, or absence, of cystathionine synthetase activity has been demonstrated in liver obtained from a mentally retarded child with homocystinuria.
470 citations
TL;DR: The one-step procedure for disaccharidase activity assay is conveniently veniently used on the ultramicro scale, and the method then utilizes only about 1 25 of the amount of tissue needed for a previously described two-step method, which is therefore especially suitable for the analysis of pieces of mucosa obtained by peroral capsular biopsy.
388 citations
TL;DR: Two unrelated cases of a new syndrome are now described with a congenital metabolic acidosis resulting from a block in the conversion of methylmalonic acid to succinic acid, and preliminary investigations to elucidate the metabolic defect are presented.
Abstract: Although metabolic acidosis from a variety of causes is very frequent in infancy, congenital acidosis appears to be extremely rare. Two unrelated cases of a new syndrome are now described with a congenital metabolic acidosis resulting from a block in the conversion of methylmalonic acid to succinic acid. The first had persistent mild acidosis with acute episodes of severe metabolic acidosis during the first year of life. He was thought to have renal tubular acidosis, albeit atypical, and died during an acute episode at 2 years of age in 1959. His disorder was always considered to have been similar to that of the later case, and this was confirmed 7 years after death by an examination of his stored plasma. The second child, born in 1960, had persistent acidosis with acute exacerbations from the first week of life. She was found to have renal tubular acidosis, confirmed by the hydrogen ion clearance index, and treatment with alkalis was instituted, but her course was atypical. In one severe episode of acidosis it was noted that she was excreting a very acid urine during treatment, in spite of a normal blood pH and plasma bicarbonate. An analysis of the urine for organic acids revealed that she was excreting large amounts of methylmalonic acid, an intermediate in the metabolism of some amino acids and of fatty acids with an odd number of carbon atoms. The effect of the metabolic block on protein and carbohydrate metabolism has also been studied, and preliminary investigations to elucidate the metabolic defect are presented.
311 citations