5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Author Lance Rodan, Wanshu Qi, Gregory Ducker, Didem Demirbas, Regina Laine, Edward Yang, Melissa Walker, Florian Eichler, Joshua Rabinowitz, Irina Anselm, Gerard Berry, Undiagnosed Diseases Network (UDN) Publication Year 2018 Type Journal Article 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. Keywords Humans, Female, Male, Brain, Antiporters, Carbon-Nitrogen Ligases, Metabolic Diseases, Mitochondrial Diseases, Microcephaly, Tetrahydrofolates, Amino Acid Transport Systems, Acidic, Epilepsy, Folate Receptor 1, Hereditary Central Nervous System Demyelinating Diseases, Nervous System Malformations, Neuroaxonal Dystrophies, Psychomotor Disorders Journal Mol Genet Metab Volume 125 Issue 1-2 Pages 118-126 Date Published 2018 Sep ISSN Number 1096-7206 DOI 10.1016/j.ymgme.2018.06.006 Alternate Journal Mol Genet Metab PMCID PMC6557438 PMID 30031689 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML