Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial.
Betaine
Cystathionine-beta-synthase deficiency
Homocysteine
Hyperhomocysteinemia
Methionine
Pharmacokinetics
S-adenosylmethionine
cblC deficiency
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
14 11 2022
14 11 2022
Historique:
received:
01
07
2022
accepted:
30
10
2022
entrez:
15
11
2022
pubmed:
16
11
2022
medline:
18
11
2022
Statut:
epublish
Résumé
Betaine is an "alternate" methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients. We compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients. We conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day. Eleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006). Our analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia. Clinical Trials, NCT02404337. Registered 23 May 2015-prospectively registered, https://clinicaltrials.gov .
Sections du résumé
BACKGROUND
Betaine is an "alternate" methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients.
AIMS
We compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients.
METHODS
We conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day.
RESULTS
Eleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006).
CONCLUSIONS
Our analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia.
TRIAL REGISTRATION
Clinical Trials, NCT02404337. Registered 23 May 2015-prospectively registered, https://clinicaltrials.gov .
Identifiants
pubmed: 36376887
doi: 10.1186/s13023-022-02567-4
pii: 10.1186/s13023-022-02567-4
pmc: PMC9664596
doi:
Substances chimiques
Betaine
3SCV180C9W
Cystathionine beta-Synthase
EC 4.2.1.22
Methionine
AE28F7PNPL
S-Adenosylmethionine
7LP2MPO46S
Homocysteine
0LVT1QZ0BA
Banques de données
ClinicalTrials.gov
['NCT02404337']
Types de publication
Randomized Controlled Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
417Informations de copyright
© 2022. The Author(s).
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