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Homocystinuria due to cystathionine β‐synthase deficiency: Novel biochemical findings and treatment efficacy
Author(s) -
Orendáč M.,
Zeman J.,
Stabler S. P.,
Allen R. H.,
Kraus J. P.,
Bodamer O.,
StöcklerIpsiroglu S.,
Kvasnička J.,
Kožich V.
Publication year - 2003
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/b:boli.0000009963.88420.c2
Subject(s) - cystathionine beta synthase , homocystinuria , homocysteine , medicine , endocrinology , serine , betaine , methionine , pyridoxine , chemistry , transsulfuration , creatine , biochemistry , amino acid , enzyme
Summary: 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 In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 µmol/L after withdrawal versus 33 µmol/L under treatment conditions), total cysteine levels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.