Detection of heterozygotes for homocystinuria: Study of sulphur-containing amino acids in plasma and urine after L-methionine loading

Sardharwalla, I. B.; Fowler, Brian; Robins, Alexander; Komrower, G. M.

doi:10.1136/adc.49.7.553

Cited by 78 publications

(24 citation statements)

References 10 publications

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“…In addition to deficiencies of folate and cobalamin, a deficiency of pyridoxal also increases tHcy; this is particularly evident after a methionine load (30). This is due to an impairment in the conversion of Hcy to cysteine via the transsulfuration pathway, since the two enzymes of this pathway employ pyridoxal 5=-phosphate as cofactors.…”

Section: E63 Formate and One-carbon Metabolismmentioning

confidence: 99%

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Lamarre

Molloy

Reinke

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Lamarre SG, Molloy AM, Reinke SN, Sykes BD, Brosnan ME, Brosnan JT. Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. 1 H-NMR metabolomic analysis of sera from vitamin B12-deficient rats. In addition to the expected increases in methylmalonate and homocysteine (Hcy), we observed an approximately sevenfold increase in formate levels, from 64 M in control rats to 402 M in vitamin B 12-deficient rats. Urinary formate was also elevated. This elevation of formate could be attributed to impaired one-carbon metabolism since formate is assimilated into the one-carbon pool by incorporation into 10-formyl-THF via the enzyme 10-formyl-THF synthase. Both plasma and urinary formate were also increased in folate-deficient rats. Hcy was elevated in both the vitamin B12-and folate-deficient rats. Although plasma Hcy was also elevated, plasma formate was unaffected in vitamin B6-deficient rats (impaired transsulfuration pathway). These results were in accord with a mathematical model of folate metabolism, which predicted that reduction in methionine synthase activity would cause increased formate levels, whereas reduced cystathionine ␤-synthase activity would not. Our data indicate that formate provides a novel window into cellular folate metabolism, that elevated formate can be a useful indicator of deranged one-carbon metabolism and can be used to discriminate between the hyperhomocysteinemia caused by defects in the remethylation and transsulfuration pathways. VITAMIN B 12 DEFICIENCY RESULTS IN A WIDE SPECTRUM of hematologic and neuropsychiatric disorders. The detection of vitamin B 12 deficiency has traditionally been based on low serum vitamin B 12 levels, with supportive clinical evidence of disease. It is now recognized that serum vitamin B 12 may be insufficient to detect a deficiency, especially in the case of elderly subjects without hematologic abnormalities. The measurement of metabolites such as homocysteine (Hcy) and methylmalonic acid (MMA) has been shown to be more sensitive in diagnosing vitamin B 12 deficiency (33, 34). In a search for novel biomarkers of vitamin B 12 deficiency, we fed rats a vitamin B 12 -deficient diet and subjected their sera to 1 H-NMR metabolomic analysis. Together with the expected increased concentrations of Hcy and MMA, we found an approximately sevenfold increase in both serum and urinary formate concentrations in the vitamin B 12 -deficient animals.We confirmed that elevated formate would also be found in folate-deficient rats, since impaired folate metabolism (via the methylfolate trap) is a well-recognized consequence of vitamin B 12 deficiency (12, 31, 32) and because formate is incorporated into 10-formyl-tetrahydrofolate (THF) via 10-formyl-THF synthase (37). Both folate and vitamin B 12 deficiencies are characterized by elevated plasma Hcy. A deficiency of pyridoxal (vitamin B 6 ) also causes elevated plasma Hcy, which becomes more pronounced after methionine loading (18). This is due to impaired removal of Hcy ...

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Section: E63 Formate and One-carbon Metabolismmentioning

confidence: 99%

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Lamarre

Molloy

Reinke

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…4 Methionine taken orally is converted to homocysteine by demethylation, and the effect of an oral load can be used as a diagnostic test to identify individuals with enzyme defects who show an exaggerated rise in homocysteine levels. 5 Endothelial injury appears to be an early event in the promotion of atherogenesis 6 and may be one mechanism whereby homocysteine leads to an increased risk of both arterial and venous disease. Studies in vitro have demonstrated that homocysteine may injure endothelium, 7,8 but the mechanism for such an effect is not yet known.…”

mentioning

confidence: 99%

Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults

et al. 1998

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Background-Elevated plasma homocysteine is a risk factor for arteriosclerosis, but a cause-and-effect relationship remains to be fully established. Endothelial dysfunction, an early event in the atherogenic process, has been shown to be associated with hyperhomocysteinemia in experimental and human studies. To further establish a direct relationship between changes in plasma homocysteine and endothelial dysfunction, we investigated whether moderate hyperhomocysteinemia induced by an oral methionine load would acutely impair flow-mediated endothelium-dependent vasodilatation in healthy adults. Methods and Results-Twenty-four healthy volunteers completed a randomized crossover study in which an oral methionine load (0.1 g/kg) was administered on 1 of 2 study days, 7 days apart. At each visit, plasma homocysteine and brachial artery endothelium-dependent and -independent dilatation were measured at baseline and at 4 hours. To further elucidate the temporal relationship between methionine, homocysteine, and endothelial function, an oral methionine load was administered in 10 subjects on a separate visit, and the time courses of plasma methionine, homocysteine, and flow-mediated brachial artery dilatation were measured at baseline and after 1, 2, 3, 4, and 8 hours.

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“…In the fasting state, obli gate heterozygotes have normal or slightly increased plasma homocysteine concentra tions [21,[45][46][47], but after methionine load ing their mean concentration increases more than it does in normal controls [21,46,48], though considerable overlapping may occur [21,46], Measuring the postmethionine load (0.1 g/kg body weight), plasma peak of free homocysteine disulfides with reference to sex and menopausal status, Boers et al [46] could identify 18 of 20 obligate heterozy gotes (90%) whose values did not overlap normal control ranges. When methionine loading was combined with the more labo rious method of determining cystathionine [3-synthase activity in cultured skin fibro blasts, all of the 20 obligate heterozygotes were correctly identified [46], Of 20 obligate heterozygotes investigated at our laboratory, 12 (60%) were identified by measuring total plasma homocysteine (free plus protein bound) 4 h after a methionine load (3.8 g/m2 body surface area =0.1 g/kg body weight; fig.…”

Section: Identifying Heterozygotes For Cystathionine ß-Synthase Deficmentioning

confidence: 99%

Plasma Homocysteine and Methionine Tolerance in Early-Onset Vascular Disease

Brattström

Israelsson

Hultberg

1989

Pathophysiol Haemos Thromb

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In three different studies we tested the hypothesis that early-onset vascular disease is associated with impaired homocysteine metabolism which could contribute to the development of arteriosclerosis and thrombosis. In patients with occlusive vascular disease before the age of 60, a post-methionine load increase of plasma homocysteine exceeding the highest value for comparable healthy control subjects was found in 1 of 21 with myocardial infarction (5%), 14 of 37 with aorto-iliac disease (38%), and 17 of 53 with cerebrovascular disease (32%). This might indicate heterozygosity for homocystinuria due to cystathionine β-synthase deficiency. Concentrations of serum vitamin B₁₂ and red cell folate had an important modulating effect on plasma homocysteine concentrations in the fasting state.

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Detection of heterozygotes for homocystinuria: Study of sulphur-containing amino acids in plasma and urine after L-methionine loading

Cited by 78 publications

References 10 publications

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults

Plasma Homocysteine and Methionine Tolerance in Early-Onset Vascular Disease

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