Homocystinuria due to cystathionine beta-synthase deficiency: novel biochemical findings and treatment efficacy.

Abstract

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 In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 micromol/L after withdrawal versus 33 micromol/L under treatment conditions), total cysteine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.

• Authors: M Orendác, J Zeman, S P Stabler, R H Allen, J P Kraus, O Bodamer, S Stöckler-Ipsiroglu, J Kvasnicka, V Kozich
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 26 Issue 8 Pg. 761-73 ( 2003) ISSN: 0141-8955 [Print] United States
• PMID: 14739681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• S-Adenosylmethionine
• S-Adenosylhomocysteine

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• Female
• Homocystinuria (metabolism, therapy)
• Humans
• Male
• S-Adenosylhomocysteine (blood)
• S-Adenosylmethionine (blood)