Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

Martina Huemer, Regina Mulder-Bleile, Patricie Burda, D. Sean Froese, Terttu Suormala, Bruria Ben Zeev, Patrick F. Chinnery, Carlo Dionisi-Vici, Dries Dobbelaere, Gulden Gokcay, Muebeccel Demirkol, Johannes Haeberle, Alexander Lossos, Eugen Mengel, Andrew A. Morris, Klary E. Niezen-Koning, Barbara Plecko, Rossella Parini, Dariusz Rokicki, Manuel SchiffMareike Schimmel, Adrian C. Sewell, Wolfgang Sperl, Ute Spiekerkoetter, Beat Steinmann, Grazia Taddeucci, Jose M. Trejo-Gabriel-Galan, Friedrich Trefz, Megumi Tsuji, Maria Antonia Vilaseca, Juergen-Christoph von Kleist-Retzow, Valerie Walker, Jiri Zeman, Matthias R. Baumgartner, Brian Fowler

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)


Background Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (

Methods Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts.

Results Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (1.7-34.8 %) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious.

Discussion MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

Original languageEnglish
Pages (from-to)115-124
Number of pages10
JournalJournal of Inherited Metabolic Disease
Issue number1
Publication statusPublished - Jan-2016



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