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. 2012;7(12):e51330.
doi: 10.1371/journal.pone.0051330. Epub 2012 Dec 5.

Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients

Catherine J Spellicy  1 , Hope Northrup, Jack M Fletcher, Paul T Cirino, Maureen Dennis, Alanna C Morrison, Carla A Martinez, Kit Sing Au
Affiliations

Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is associated with ADHD in myelomeningocele patients

Catherine J Spellicy et al. PLoS One. 2012.

Abstract

The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD) in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR), are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs) in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Simplified schematic of the folic acid metabolic cycle.
Folate receptors transport dietary folate into cells and the folate is converted into dihydrogolate (DHF) then tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). In the folate metabolic cycle, THF is converted to 5,10-methyleneTHF, a substrate of 5,10-methyleneTHF reductase (MTHFR), then to 5-methylTHF. 5-methylTHF can be recycled by methionine synthase/methionine synthase reductase (MTR/MTRR) to THF and methionine. Alternatively, 5-methylTHF can be use to synthesize purine. The Methionine can be used in the methionine cycle to produce S-Adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH) and homocysteine. Conversion of SAM to SAH requires betaine, a product of choline metabolism. SAM is a major cellular methylation agent for DNA, RNA, protein, and phospholipids.
Figure 2
Figure 2. Genomic structure of the MTHFR gene and the location of the seven SNPs examined in this study.
Shaded boxes represent the exons (1 to 12) of MTHFR gene and the line in between represent intron regions. Distances and locations are approximate.
See this image and copyright information in PMC

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