Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women
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Betaine
Plasma homocysteine
Homocystinuria
Cystathionine beta-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 micromol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 micromol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control.
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Betaine supplementation in humans has been shown to lower plasma homocysteine concentrations in modestly hyperhomocysteinemic patients. Betaine treatment is associated with increased plasma low-densitylipoprotein (LDL) cholesterol, suggesting that although betaine supplementation lowers homocysteine, a risk factor for cardiovascular disease, changes in blood lipids may have a counterbalancing effect. However, whether the betaine effect on LDL concentration is a clinically significant problem that should change treatment options or is simply an artifact needs further study.
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Abstract—A modest homocysteine elevation is associated with an increased cardiovascular risk. Marked circulating homocysteine elevations occur in homocystinuria due to cystathionine β-synthase (CβS) deficiency, a disorder associated with a greatly enhanced cardiovascular risk. Lowering homocysteine levels reduces this risk significantly. Because homocysteine-induced oxidative damage may contribute to vascular changes and extracellular superoxide dismutase (EC-SOD) is an important antioxidant in vascular tissue, we assessed EC-SOD and homocysteine in patients with homocystinuria. We measured circulating EC-SOD, total homocysteine (free plus bound), and methionine levels during the treatment of 21 patients with homocystinuria, 18 due to CβS deficiency, aged 8 to 59 years, and 3 with remethylating defects. We measured total homocysteine by immunoassay, EC-SOD by ELISA, and methionine by amino acid analysis and assessed interindividual and intraindividual relationships. There was a significant, positive relat...
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Homocystinuria is a medical condition that can have widespread and harmful effects on multiple organ systems within the body. This disease is caused by a deficiency in one of the enzymes involved in the methionine metabolism pathway. One example would be a deficiency in cystathionine-β-synthase (CBS), which is seen in classical homocystinuria. A deficiency in CBS can lead to elevated levels of homocysteine (HCY) and possible depletion of methionine and/or cysteine. There are several different treatment options for patients with this condition, one of which is the administration of the drug betaine. Here we review the use of betaine to decrease these elevated levels of homocysteine back to within normal ranges. Published literature indicates that the use of this choline derivative is most beneficial to patients who are either not compliant with the recommended low methionine and low protein diet or wish to consume a less restricted diet.
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Classical homocystinuria is a rare genetic disease caused by cystathionine β-synthase deficiency, resulting in homocysteine accumulation. Growing evidence suggests that reduced fat mass in patients with classical homocystinuria may be associated with alterations in choline and homocysteine pathways. This study aimed to evaluate the body composition of patients with classical homocystinuria, identifying changes in body fat percentage and correlating findings with biochemical markers of homocysteine and choline pathways, lipoprotein levels and bone mineral density (BMD) T-scores.Nine patients with classical homocystinuria were included in the study. Levels of homocysteine, methionine, cysteine, choline, betaine, dimethylglycine and ethanolamine were determined. Body composition was assessed by bioelectrical impedance analysis (BIA) in patients and in 18 controls. Data on the last BMD measurement and lipoprotein profile were obtained from medical records.Of 9 patients, 4 (44%) had a low body fat percentage, but no statistically significant differences were found between patients and controls. Homocysteine and methionine levels were negatively correlated with body mass index (BMI), while cysteine showed a positive correlation with BMI (p<0.05). There was a trend between total choline levels and body fat percentage (r=0.439, p=0.07). HDL cholesterol correlated with choline and ethanolamine levels (r=0.757, p=0.049; r=0.847, p=0.016, respectively), and total cholesterol also correlated with choline levels (r=0.775, p=0.041). There was no association between BMD T-scores and body composition.These results suggest that reduced fat mass is common in patients with classical homocystinuria, and that alterations in homocysteine and choline pathways affect body mass and lipid metabolism.
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Betaine and methionine have been shown to be effective in preventing perosis and promoting growth in chicks when added to a simplified diet. They were ineffective when added to a purified diet of higher methionine content. In contrast, choline prevented perosis and promoted growth on both diets.
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Methionine is an essential amino acid that is in high demand in neonates for protein synthesis as well as for transmethylation (TM) reactions, such as creatine synthesis and DNA methylation. TM reactions produce homocysteine, which can be either converted to cysteine or re‐methylated to methionine via folate or betaine (synthesized from choline). It is unclear whether both remethylation pathways are equally important in neonates for remethylation. The objective of this study was to determine whether supplementation with folate, betaine or a combination of both (n=6) can re‐synthesize methionine for protein synthesis when dietary methionine is limiting. In piglets adapted to low‐methionine diets devoid of folate, choline and betaine, we measured 13 C‐phenylalanine oxidation pre‐ and post‐supplementation as an indicator of protein synthesis. Prior to supplementation, plasma folate (‐60%), betaine (‐95%), dimethylglycine (‐95%), choline (‐60%) and cysteine (‐45%) were all lower (p<0.05) compared to baseline with no change in homocysteine. Post‐supplementation, phenylalanine oxidation levels were ~30% lower (p<0.05) with any methyl donor supplementation with no difference among groups. This demonstrates an equal capacity for betaine and folate to remethylate methionine for protein synthesis and warrants future research on betaine in the infant diet. Grant Funding Source : Supported by Canadian Institutes of Health Research
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