TY - JOUR
T1 - Homocystinuria due to cystathionine β-synthase deficiency
T2 - Novel biochemical findings and treatment efficacy
AU - Orendáč, M.
AU - Zeman, J.
AU - Stabler, S. P.
AU - Allen, R. H.
AU - Kraus, J. P.
AU - Bodamer, O.
AU - Stöckler-Ipsiroglu, S.
AU - Kvasnička, J.
AU - Kožich, V.
N1 - Funding Information:
The authors thank the patients, their parents and the phy sicians and nurses of the Department of Pediatrics for participation in the study . We thank Ing. Adolf Mˇhl for determination of guanidinoacetate and creatine levels, and Dr Jakub Krijt for measurement of blood glutathione and total cysteine levels. The expert technical assistance of Tereza Paterova¤ , Martina Vackova¤ and Bev Raab is highly acknowledged. This study was supported by a research project of Charles University , First Faculty of Medicine, Prague No. VZ 11110003, and by grant No. VZ 64165 from the Ministry of Health of the Czech Republic.
PY - 2003
Y1 - 2003
N2 - To explore the pathogenesis of cystathionine β-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 μmol/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 μmol/L), and by increased concentration of methionine (median 76 μmol/L) and N-methylglycine (median 6.8 μmol/L). Despite the substantially blocked transsulphuration, which was evidenced by undetectable cystathionine and severely decreased total cysteine levels (median 102 μmol/L), blood glutathione was surprisingly not depleted (median 1155 μmol/L). In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 μmol/L after withdrawal versus 33 μmol/L under treatment conditions), total cysteine levels (139 versus 211 μmol/L) and plasma serine levels (53 versus 103 μmol/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.
AB - To explore the pathogenesis of cystathionine β-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 μmol/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 μmol/L), and by increased concentration of methionine (median 76 μmol/L) and N-methylglycine (median 6.8 μmol/L). Despite the substantially blocked transsulphuration, which was evidenced by undetectable cystathionine and severely decreased total cysteine levels (median 102 μmol/L), blood glutathione was surprisingly not depleted (median 1155 μmol/L). In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 μmol/L after withdrawal versus 33 μmol/L under treatment conditions), total cysteine levels (139 versus 211 μmol/L) and plasma serine levels (53 versus 103 μmol/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.
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U2 - 10.1023/B:BOLI.0000009963.88420.c2
DO - 10.1023/B:BOLI.0000009963.88420.c2
M3 - Article
C2 - 14739681
AN - SCOPUS:0942266395
VL - 26
SP - 761
EP - 773
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
SN - 0141-8955
IS - 8
ER -