Cystathionine β-synthase deficiency: Effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria

Singh, Rani H.; Kruger, Warren D.; Wang, Liqun; Pasquali, Marzia; Elsas, Louis J.

doi:10.1097/01.gim.0000117334.84388.f4

Cited by 28 publications

(21 citation statements)

References 29 publications

(29 reference statements)

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“…As the accumulation of Hcy caused by CBS deficiency should alter the amount of downstream thiol metabolites, a comprehensive analysis of biological thiols should offer useful information to understand the pathology of disease. However, only Hcy, Cys, and GSH have been measured in humans and animal models of homocystinuria [5][6][7][8][9][10][11]. Considering that γGluCys and CysGly are precursors and degradation products of GSH, respectively, simultaneous analysis of all the thiols mentioned above should offer helpful information to reveal how Hcy accumulation leads to diverse symptoms and to investigate suitable indicators of disease progression.…”

Section: Introductionmentioning

confidence: 99%

Quantification of Biological Thiols in the Plasma of a Homocystinuria Model with Cystathionine β-Synthase Deficiency Utilizing Hydrophilic Interaction Liquid Chromatography and Fluorescence Detection

et al. 2016

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Biological thiols -homocysteine (Hcy), cysteine (Cys), γ-glutamylcysteine (γGluCys), glutathione (GSH), and cysteinylglycine (CysGly) -in plasma samples of cystathionine β-synthase (CBS, EC 4.2.1.22)-deficient mice were quantified using hydrophilic interaction liquid chromatography (HILIC) and fluorescence detection. Mice deficient in CBS provide a model mouse of homocystinuria, an inherited metabolic disease characterized by the abnormal accumulation of Hcy in urine and blood. For quantification, the thiols were derivatized with ammonium 7-fluoro-2,1,3-benzoxadiazole-4-sulfonate (SBD-F), followed by separation with an amide column containing a mobile phase of acetonitrile-40 mM ammonium formate buffer (pH 3.0) (75/25, v/v). The total concentrations of Hcy in the plasma samples of CBS-wild type (-WT), -heterozygous (-Hetero), and -knockout (-KO) mice were 24.7, 29.3, and 237.7 μmol/L, respectively; 236.4, 178.7, and 78.5 μmol/L for Cys; 5.80, 4.87, and 0.75 μmol/L for γGluCys; 64.6, 74.0, and 51.2 μmol/L for GSH; and 2.48, 3.98, and 0.90 μmol/L for CysGly. The concentration of Hcy was significantly increased, while Cys, γGluCys, and CysGly concentrations were significantly decreased in CBS-KO mice compared to those in CBS-WT mice. The results indicated that biological thiols other than Hcy could also be utilized for the evaluation and investigation of homocystinuria pathologies.

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Section: Introductionmentioning

confidence: 99%

Quantification of Biological Thiols in the Plasma of a Homocystinuria Model with Cystathionine β-Synthase Deficiency Utilizing Hydrophilic Interaction Liquid Chromatography and Fluorescence Detection

et al. 2016

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“…In humans, there is little safety data regarding the use of betaine in healthy individuals. In hyperhomocysteinemic patients, betaine is used to lower plasma homocysteine concentrations (Wilcken et al, 1983;Singh et al, 2004), which is suggested to be an independent risk factor for coronary heart disease (El-Khairy et al, 1999;Chambers et al, 2000;Humphrey et al, 2008). Hyperhomocysteinemia is also associated with hyperinsulinemia and insulin resistance, which in turn increases the risk of cardiovascular diseases (Meigs et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Long-term effect of betaine on risk factors associated with the metabolic syndrome in healthy subjects

et al. 2010

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Background/Objectives: To examine the effects of betaine on serum lipid profile, plasma homocysteine concentration and hemostatic factors in healthy subjects. Subjects/Methods: Altogether, 63 volunteers (27 ± 8 years, body mass index 22.6 ± 2.4 kg/m 2 ) participated in a placebocontrolled, randomized, parallel double-blinded study. The intervention lasted for 6 months during which the subjects consumed mineral water 500 ml/day with (betaine group, n ¼ 32) or without (control group, n ¼ 31) a 4-g betaine supplementation.Results: There was a significant interaction of time and group (general linear model) in serum total and low-density lipoprotein (LDL)-cholesterol concentrations and total-to-high-density lipoprotein (HDL)-cholesterol ratio without a significant difference between or within the groups. Concentrations of serum HDL-cholesterol, triglycerides or oxidized LDL did not change during the study. Plasma homocysteine concentration did not change in either of the groups. Plasma plasminogen activator inhibitor 1 concentration increased in the betaine group (P ¼ 0.028) and decreased in the control group (P ¼ 0.006). There was a significant interaction of time and group (general linear model) in plasma fibrinogen and blood hemoglobin concentration without a significant difference between or within the groups. There were no changes in parameters regarding the function of the liver or kidney. Conclusions: Betaine had no effect on serum lipid profile in long term in young healthy subjects. The lowering effect on plasma homocysteine concentration was weak.

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“…Without riboflavin administration, there is no doubt that taking high doses of betaine would have become difficult for this patient. Variable betaine compliance has been reported as an issue for the treatment of pyridoxine non-responsive homocystinuria (Singh et al 2004). Side effects such as odour may have contributed to this lack of compliance and led to suboptimal control of patients' metabolic state.…”

Section: Discussionmentioning

confidence: 99%

Riboflavin-Responsive Trimethylaminuria in a Patient with Homocystinuria on Betaine Therapy

et al. 2011

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A 17-year-old female patient with pyridoxine non-responsive homocystinuria, treated with 20 g of betaine per day, developed a strong body odour, which was described as fish-like. Urinary trimethylamine (TMA) was measured and found to be markedly increased. DNA mutation analysis revealed homozygosity for a common allelic variant in the gene coding for the TMA oxidising enzyme FMO3. Without changing diet or betaine therapy, riboflavin was given at a dose of 200 mg per day. An immediate improvement in her odour was noticed by her friends and family and urinary TMA was noted to be greatly reduced, although still above the normal range.Gradual further reductions in TMA (and odour) have followed whilst receiving riboflavin. Throughout this period, betaine compliance has been demonstrated by the measurement of dimethylglycine (DMG) excretion, which has been consistently increased. Marked excretions of DMG when the odour had subsided also demonstrate that DMG was not the source of the odour.This patient study raises the possibility that betaine may be converted to TMA by intestinal flora to some degree, resulting in a significant fish odour when oxidation of TMA is compromised by FMO3 variants. The possibility exists that the body odour occasionally associated with betaine therapy for homocystinuria may not be related to increased circulating betaine or DMG, but due to a common FMO3 mutation resulting in TMAU. Benefits of riboflavin therapy for TMAU for such patients would allow the maintenance of betaine therapy without problematic body odour.

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Cystathionine β-synthase deficiency: Effects of betaine supplementation after methionine restriction in B6-nonresponsive homocystinuria

Cited by 28 publications

References 29 publications

Quantification of Biological Thiols in the Plasma of a Homocystinuria Model with Cystathionine β-Synthase Deficiency Utilizing Hydrophilic Interaction Liquid Chromatography and Fluorescence Detection

Quantification of Biological Thiols in the Plasma of a Homocystinuria Model with Cystathionine β-Synthase Deficiency Utilizing Hydrophilic Interaction Liquid Chromatography and Fluorescence Detection

Long-term effect of betaine on risk factors associated with the metabolic syndrome in healthy subjects

Riboflavin-Responsive Trimethylaminuria in a Patient with Homocystinuria on Betaine Therapy

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