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Original Investigation |

Survival and Psychomotor Development With Early Betaine Treatment in Patients With Severe Methylenetetrahydrofolate Reductase Deficiency

Eugene F. Diekman, MD1; Tom J. de Koning, PhD, MD2; Nanda M. Verhoeven-Duif, PhD3; Maroeska M. Rovers, PhD4,5; Peter M. van Hasselt, PhD, MD1
[+] Author Affiliations
1Department of Pediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands
2Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
3Department of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands
4Julius Centre, University Medical Centre Utrecht, Utrecht, the Netherlands
5Department of Epidemiology, Biostatistics, and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
JAMA Neurol. 2014;71(2):188-194. doi:10.1001/jamaneurol.2013.4915.
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Importance  The impact of betaine treatment on outcome in patients with severe methylenetetrahydrofolate reductase (MTHFR) deficiency is presently unclear.

Objective  To investigate the effect of betaine treatment on development and survival in patients with severe MTHFR deficiency.

Data Sources  MEDLINE, EMBASE, and Cochrane databases between January 1960 and December 2012.

Study Selection  Studies that described patients with severe MTHFR deficiency who received betaine treatment.

Data Extraction and Synthesis  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.

Main Outcomes and Measures  Survival and psychomotor development.

Results  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).

Conclusions and Relevance  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.

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Figure 1.
Study Selection

Identification process for eligible studies. MTHFR indicates methylenetetrahydrofolate reductase.

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Figure 2.
Kaplan-Meier Survival Curves of Treatment vs No Treatment and Early vs Delayed Treatment

A, Kaplan-Meier survival curve of treatment vs no treatment in all 36 patients (P < .001). B, Kaplan-Meier survival curve of early vs no early treatment in all 36 patients (P = .17).

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Figure 3.
Psychomotor Development

Comparison of patients with early vs delayed treated and psychomotor development (PMD). The sample size was 34 instead of 36 because PMD after treatment was not described in 2 patients.aFor early vs delayed treatment (excluding untreated patients), P < .001.

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