TY - JOUR
T1 - 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination
AU - Undiagnosed Diseases Network (UDN)
AU - Rodan, Lance H.
AU - Qi, Wanshu
AU - Ducker, Gregory S.
AU - Demirbas, Didem
AU - Laine, Regina
AU - Yang, Edward
AU - Walker, Melissa A.
AU - Eichler, Florian
AU - Rabinowitz, Joshua D.
AU - Rabinowitz, Joshua D.
AU - Berry, Gerard T.
N1 - Funding Information:
We thank the Gene Discovery Core of The Manton Center for Orphan Disease Research for providing resources and support in patient consenting, sample collection, sequencing and sharing of information and samples. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007690 to J.L. Research was also funded in part from NIH grants 1DP1DK113643 and P30CA072720 to J.D.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank the Gene Discovery Core of The Manton Center for Orphan Disease Research for providing resources and support in patient consenting, sample collection, sequencing and sharing of information and samples. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007690 to J.L. Research was also funded in part from NIH grants 1DP1DK113643 and P30CA072720 to J.D.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - 5,10-methenyltetrahydrofolate synthetase
KW - Folate
KW - Folinic acid
KW - Neurodegeneration
KW - Neurometabolism
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U2 - 10.1016/j.ymgme.2018.06.006
DO - 10.1016/j.ymgme.2018.06.006
M3 - Article
C2 - 30031689
AN - SCOPUS:85049954497
SN - 1096-7192
VL - 125
SP - 118
EP - 126
JO - Biochemical Medicine and Metabolic Biology
JF - Biochemical Medicine and Metabolic Biology
IS - 1-2
ER -