title: 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 In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 micromol/L after withdrawal versus 33 micromol/L under treatment conditions), total cysteine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.affiliation: Institute of Inherited Metabolic Diseases, Department of Pediatrics, Charles University-First Faculty of Medicine, Ke Karlovu 2, 128-08 Prague 2, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Orendác
authors.forename: J
authors.initials: J
authors.lastname: Zeman
authors.forename: S P
authors.initials: SP
authors.lastname: Stabler
authors.forename: R H
authors.initials: RH
authors.lastname: Allen
authors.forename: J P
authors.initials: JP
authors.lastname: Kraus
authors.forename: O
authors.initials: O
authors.lastname: Bodamer
authors.forename: S
authors.initials: S
authors.lastname: Stöckler-Ipsiroglu
authors.forename: J
authors.initials: J
authors.lastname: Kvasnicka
authors.forename: V
authors.initials: V
authors.lastname: Kozich
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006712:Homocystinuria / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D008297:Male; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood
chemical_list: D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine