To explore the pathogenesis of cystathionine beta-synthase (CBS) deficiency and to test the efficacy of pharmacological therapy we examined a panel of metabolites in nine homocystinuric patients under treated and/or untreated conditions. Off pharmacological treatment, the biochemical phenotype was characterized by accumulation of plasma total homocysteine (median 135 micromol/L) and blood S -adenosylhomocysteine (median 246 nmol/L), and by normal levels of guanidinoacetate and creatine. In addition, enhanced remethylation was demonstrated by low serine level (median 81 micromol/L), and by increased concentration of methionine (median 76 micromol/L) and N -methylglycine (median 6.8 micromol/L). Despite the substantially blocked transsulphuration, which was evidenced by undetectable cystathionine and severely decreased total cysteine levels (median 102 micromol/L), blood glutathione was surprisingly not depleted (median 1155 micromol/L). In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 micromol/L after withdrawal versus 33 micromol/L under treatment conditions), total cysteine levels (139 versus 211 micromol/L) and plasma serine levels (53 versus 103 micromol/L) on and off treatment demonstrated the efficacy of long-term pyridoxine/betaine administration ( p <0.05). The treatment also decreased blood S -adenosylhomocysteine level (133 versus 59 nmol/L) with a borderline significance. In summary,our study shows that conventional treatment of CBS deficiency by diet and pyridoxine/betaine normalizes many but not all metabolic abnormalities associated with CBS deficiency. We propose that the finding of low plasma serine concentration in untreated CBS-deficient patients merits further exploration since supplementation with serine might be a novel and safe component of treatment of homocystinuria.

Institute of Inherited Metabolic Diseases Department of Pediatrics Charles University 1st Faculty of Medicine Ke Karlovu 2 128 08 Prague 2 Czech Republic

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Blood. 1993 Jun 15;81(12):3404-13 PubMed

Cancer Res. 1983 Sep;43(9):4142-7 PubMed

Metabolism. 1993 Nov;42(11):1448-60 PubMed

Biochem Biophys Res Commun. 2000 Nov 2;277(3):668-74 PubMed

Clin Chem. 2001 Oct;47(10 ):1821-8 PubMed

Clin Chim Acta. 2001 Jun;308(1-2):173-8 PubMed

J Inherit Metab Dis. 2002 May;25(2):119-25 PubMed

Metabolism. 1987 Feb;36(2):198-201 PubMed

Am J Hum Genet. 2001 Jun;68(6):1506-13 PubMed

Metabolism. 2002 Aug;51(8):981-8 PubMed

Metabolism. 1975 Jun;24(6):721-35 PubMed

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