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5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination.

Molecular genetics and metabolism (2018-07-23)
Lance H Rodan, Wanshu Qi, Gregory S Ducker, Didem Demirbas, Regina Laine, Edward Yang, Melissa A Walker, Florian Eichler, Joshua D Rabinowitz, Irina Anselm, Gerard T Berry
ABSTRACT

Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MES hydrate, ≥99.5% (titration), pH 2.5-4.0 (0.5 M in H2O), BioXtra
Sigma-Aldrich
Magnesium acetate solution, BioUltra, for molecular biology, ~1 M in H2O
Sigma-Aldrich
Folinic acid calcium salt hydrate, BioXtra, ≥99.0% (HPLC)