5,10-methenyltetrahydrofolate synthetase deficiency: An extreme rare defect of folate metabolism in two Dutch siblings

Lelde Liepina, Desiree E. C. Smith, Hidde Huidekoper, Shimriet Zeidler, Mirjam Wamelink, Marie-Claire de Wit, Martina Wilke, George Ruijter, J. rgen Bierau, Henk J. Blom

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Two siblings, presenting with a neurometabolic phenotype, were identified with 5, 10-methenyltetrahydrofolate synthetase (MTHFS) deficiency. Whole genome sequencing in both patients demonstrated an homozygous MTHFS variant NM_006441.3(MTHFS):c.434G > A, p.Arg145Gin, which has been described before. At baseline, both patients showed moderate hyperhomocysteinemia, decreased 5-methyltetrahydrofolate (5MTHF), and increased 5-formyltetrahydrofolate (5-FTHF) in whole blood. In CSF, 5MTHF levels were in the low-normal range and 5-FTHF was strongly increased. In our novel enzyme assay, MTHFS activity was deficient in cultured fibroblasts in both sisters. Oral treatment was initiated with escalating dose of 5-methyltetrahydrofolate (5MTHF) up to 12 mg and hydroxycobalamin 5 mg daily. Plasma homocysteine normalized and 5MTHF became elevated in the blood of both patients. The elevated 5FTHF levels increased further on treatment in blood and CSF. This regimen resulted in some clinical improvement of patient 1. In patient 2, the clinical benefits of 5MTHF supplementation were less obvious. It seems plausible that the alleviation of the deficient 5MTHF levels and normalization of homocysteine in blood are of some clinical benefit. On the other hand, the very high levels of 5FTHF may well be detrimental and may prompt us to decrease the dose of 5MTHF. In addition, we hypothesize that the crippled MTHFS enzyme may destabilize the purinosome, which is presumably not ameliorated by 5MTHF.
Original languageEnglish
Pages (from-to)49-55
Number of pages7
JournalJIMD reports
Issue number2
Publication statusPublished - 1 Mar 2024


  • 5,10-methenyltetrahydrofolate synthetase
  • cerebral hypomyelination
  • folate
  • neurometabolic

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