Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.

Department of Child and Adolescent Health Psychology Institute of Psychology University of Zürich Zürich Switzerland

Department of Paediatrics Landeskrankenhaus Bregenz Austria

Department of Psychosomatics and Psychiatry University Children's Hospital Zürich Zürich Switzerland

Division of Metabolism and Children's Research Center University Children's Hospital Zürich CH 8032 Switzerland

Institut National de la Santé et de la Recherche Médicale Unité 954 Nutrition Genetics and Environmental Exposure Medical Faculty and National Center of Inborn Errors of Metabolism University Hospital Center Nancy University Vandoeuvre lès Nancy France

Institute of Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

Radiz Rare Disease Initiative Zürich Clinical Research Priority Program for Rare Diseases University of Zürich Switzerland

Zurich Center for Integrative Human Physiology University of Zürich Zürich Switzerland

Hum Mutat. 2017 Jan;38(1):120-121. doi: 10.1002/humu.23132. PubMed

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