Title5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination.
Publication TypeJournal Article
Year of Publication2018
AuthorsRodan, LH, Qi, W, Ducker, GS, Demirbas, D, Laine, R, Yang, E, Walker, MA, Eichler, F, Rabinowitz, JD, Anselm, I, Berry, GT
Corporate AuthorsUndiagnosed Diseases Network (UDN)
JournalMol Genet Metab
Date Published2018 09
KeywordsAmino Acid Transport Systems, Acidic, Antiporters, Brain, Carbon-Nitrogen Ligases, Epilepsy, Female, Folate Receptor 1, Hereditary Central Nervous System Demyelinating Diseases, Humans, Male, Metabolic Diseases, Microcephaly, Mitochondrial Diseases, Nervous System Malformations, Neuroaxonal Dystrophies, Psychomotor Disorders, Tetrahydrofolates

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.

Alternate JournalMol. Genet. Metab.
PubMed ID30031689
PubMed Central IDPMC6557438
Grant ListU01 HG007690 / HG / NHGRI NIH HHS / United States
U01 HG007943 / HG / NHGRI NIH HHS / United States
DP1 DK113643 / DK / NIDDK NIH HHS / United States
P30 CA072720 / CA / NCI NIH HHS / United States