title: Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.
abstract: 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.
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.|Radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zürich, Switzerland.
authors.forename: D Sean
authors.initials: DS
authors.lastname: Froese
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.|Radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases, University of Zürich, Switzerland.|Department of Paediatrics, Landeskrankenhaus Bregenz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Huemer
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.
authors.forename: Patricie
authors.initials: P
authors.lastname: Burda
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Coelho
authors.affiliation: 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.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.affiliation: Department of Psychosomatics and Psychiatry, University Children's Hospital Zürich, Zürich, Switzerland.|Department of Child and Adolescent Health Psychology, Institute of Psychology, University of Zürich, Zürich, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Landolt
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine - Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Kožich
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.affiliation: Division of Metabolism and Children's Research Center, University Children's Hospital, Zürich, CH-8032, Switzerland.|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.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
mesh_terms: D017668:Age of Onset; D000818:Animals; D020134:Catalytic Domain; D030541:Databases, Genetic; D004195:Disease Models, Animal; D006712:Homocystinuria / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009128:Muscle Spasticity / Q000235:genetics*; D009154:Mutation; D015997:Neonatal Screening; D011618:Psychotic Disorders / Q000235:genetics
chemical_list: C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: MTHFR; genotype-phenotype correlation; homocystinuria; remethylation defects