Department of Pediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
JAMA Neurol. 2014 Feb;71(2):188-94. doi: 10.1001/jamaneurol.2013.4915.
The impact of betaine treatment on outcome in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency is presently unclear.
To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency.
MEDLINE, EMBASE, and Cochrane databases between January 1960 and December 2012.
Studies that described patients with severe MTHFR deficiency who received betaine treatment.
We identified 15 case reports and case series, totaling 36 patients. Data included the following: (1) families with 2 or more patients with severe MTHFR deficiency, of whom at least 1 received betaine, or (2) single patients with severe MTHFR deficiency treated with betaine. To define severe MTHFR deficiency, methionine, homocysteine, MTHFR enzyme activity in fibroblasts, or mutations (in the MTHFR gene) had to be described as well as the effect of treatment (survival and/or psychomotor development). We compared the outcome in treated vs untreated patients and early- vs late-treated patients. Sensitivity analysis was performed to address definition of early treatment. To further assess the impact of treatment on mortality, we performed a subanalysis in families with at least 1 untreated deceased patient.
Survival and psychomotor development.
Eleven of 36 patients (31%) died. All deaths occurred in patients who did not receive treatment or in patients in whom treatment was delayed. In contrast, all 5 early-treated patients survived. Subgroup analysis of patients with deceased siblings-their genotypically identical controls-revealed that betaine treatment prevented mortality (P = .002). In addition, psychomotor development in surviving patients treated with betaine was normal in all 5 early-treated patients but in none of the 19 surviving patients with delayed treatment (P < .001).
Early betaine treatment prevents mortality and allows normal psychomotor development in patients with severe MTHFR deficiency, highlighting the importance of timely recognition through newborn screening.
目前尚不清楚甜菜碱治疗对严重亚甲基四氢叶酸还原酶（MTHFR）缺乏症患者结局的影响。
研究甜菜碱治疗对严重 MTHFR 缺乏症患者发育和生存的影响。
1960 年 1 月至 2012 年 12 月期间的 MEDLINE、EMBASE 和 Cochrane 数据库。
描述接受甜菜碱治疗的严重 MTHFR 缺乏症患者的研究。
我们确定了 15 例病例报告和病例系列研究，共计 36 例患者。数据包括：（1）有 2 个或更多严重 MTHFR 缺乏症患者的家庭，其中至少 1 例接受了甜菜碱治疗，或（2）接受甜菜碱治疗的单个严重 MTHFR 缺乏症患者。为了定义严重的 MTHFR 缺乏症，必须描述蛋氨酸、同型半胱氨酸、成纤维细胞中的 MTHFR 酶活性或突变（在 MTHFR 基因中），以及治疗效果（生存和/或精神运动发育）。我们比较了治疗组与未治疗组患者以及早期治疗组与晚期治疗组患者的结局。进行敏感性分析以解决早期治疗的定义问题。为了进一步评估治疗对死亡率的影响，我们对至少有 1 例未治疗死亡患者的家族进行了亚组分析。
生存和精神运动发育。
36 例患者中有 11 例（31%）死亡。所有死亡均发生在未接受治疗的患者或治疗延迟的患者中。相比之下，所有 5 例早期治疗患者均存活。对有死亡兄弟姐妹的患者（其基因型相同的对照）进行亚组分析表明，甜菜碱治疗可预防死亡（P=0.002）。此外，在接受甜菜碱治疗的存活患者中，精神运动发育在所有 5 例早期治疗患者中均正常，但在 19 例接受延迟治疗的存活患者中均未正常（P<0.001）。
早期甜菜碱治疗可预防严重 MTHFR 缺乏症患者的死亡并使其精神运动发育正常，这突出表明通过新生儿筛查及时发现疾病的重要性。
