甜菜碱在 CBS 和 cblC 缺乏症中的疗效和药代动力学：一项交叉随机对照试验。

Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial.

机构信息

Laboratoire de Biochimie-Hormonologie, Hôpital Robert Debré, APHP, Filière G2M, Paris, France.

Laboratoire de Biochimie Métabolique, Hôpital Necker-Enfants-Malades, APHP, 149 Rue de Sèvres, Filière G2M, Paris, France.

出版信息

Orphanet J Rare Dis. 2022 Nov 14;17(1):417. doi: 10.1186/s13023-022-02567-4.

DOI:10.1186/s13023-022-02567-4

PMID:36376887

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9664596/

Abstract

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 .

摘要

背景

甜菜碱是一种“替代”供甲基体，可用于甜菜碱同型半胱氨酸甲基转移酶（BHMT）催化的同型半胱氨酸再甲基化，该酶主要在肝脏和肾脏中表达。甜菜碱已在吡哆醇无反应性胱硫醚 β-合酶（pnrCBS）和钴胺素 C（cblC）缺乏症中使用了 30 多年，以降低高同型半胱氨酸血症，尽管人们对这些患者的最佳治疗剂量及其药代动力学知之甚少。

目的

我们比较了影响 pnrCBS 或 cblC 缺乏症儿童的 2 种甜菜碱剂量（100mg/kg/天与 250mg/kg/天）。我们还测量了这些患者单次给予甜菜碱（100 或 250mg/kg）后的药代动力学参数。

方法

我们进行了一项前瞻性、随机、交叉临床试验，评估结果为盲法。主要结局是在接受 1 个月的口服甜菜碱治疗后，100 与 250mg/kg/天的总血浆同型半胱氨酸（tHcy）浓度是否等效。

结果

11 例患者完成了研究（5 例 pnrCBS，6 例 cblC）。在 1 个月的治疗期间，两种甜菜碱剂量的 tHcy 浓度等效。多变量分析显示，甜菜碱剂量对蛋氨酸（Met）（p=0.01）和 S-腺苷甲硫氨酸（SAM）浓度（p=0.006）有显著影响。

结论

我们的分析表明，在 pnrCBS 和 cblC 缺乏症中，增加甜菜碱剂量至 100mg/kg/天以上以降低 tHcy 浓度并没有明显益处。然而，增加甜菜碱至 250mg/kg/d 可以通过增加 Met 和 SAM 浓度使 cblC 患者受益，因为低 Met 和 SAM 浓度与该疾病的病理生理学有关。相比之下，在 pnrCBS 缺乏症中，甜菜碱剂量高于 100mg/kg/天可能对已有高蛋氨酸血症的患者有害。