@article{3371,
  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},
  author = {Lance Rodan and Wanshu Qi and Gregory Ducker and Didem Demirbas and Regina Laine and Edward Yang and Melissa Walker and Florian Eichler and Joshua Rabinowitz and Irina Anselm and Gerard Berry and Undiagnosed Diseases Network (UDN)},
  title = {5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination.},
  abstract = { <p>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.</p> },
  year = {2018},
  journal = {Mol Genet Metab},
  volume = {125},
  pages = {118-126},
  month = {2018 Sep},
  issn = {1096-7206},
  doi = {10.1016/j.ymgme.2018.06.006},
  language = {eng},
}