5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination
- Mol Genet Metab. 2018 Sep;125(1-2):118-126. doi: 10.1016/j.ymgme.2018.06.006.
- 1. Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
- 2. Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 3. Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, NJ, USA.
- 4. Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 5. Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- 6. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- 7. Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
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.