title: Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency.
abstract: BACKGROUND
  Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients.
  
  
  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 (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland.|radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland.|Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Huemer
authors.affiliation: University Childrens' Hospital Basel (UKBB), Basel, Switzerland.
authors.forename: Regina
authors.initials: R
authors.lastname: Mulder-Bleile
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland.
authors.forename: Patricie
authors.initials: P
authors.lastname: Burda
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland.
authors.forename: D Sean
authors.initials: DS
authors.lastname: Froese
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland.
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.affiliation: Edmond and Lilly Safra Pediatric Hospital, Sheba Med Center and Sackler School of Medicine Tel Aviv, Tel Aviv, Israel.
authors.forename: Bruria Ben
authors.initials: BB
authors.lastname: Zeev
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: Centre de Référence Maladies Héréditaires du Métabolisme de l'enfant et de l'adulte, Hôpital Jeanne de Flandre, Lille, France.
authors.forename: Dries
authors.initials: D
authors.lastname: Dobbelaere
authors.affiliation: Istanbul Medical Faculty, Children's Hospital, Pediatric Nutrition and Metabolism, Istanbul University, Istanbul, Turkey.
authors.forename: Gülden
authors.initials: G
authors.lastname: Gökcay
authors.affiliation: Istanbul Medical Faculty, Children's Hospital, Pediatric Nutrition and Metabolism, Istanbul University, Istanbul, Turkey.
authors.forename: Mübeccel
authors.initials: M
authors.lastname: Demirkol
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
authors.affiliation: Villa metabolica, Center for Pediatric and Adolescent Medicine, MC Johannes-Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
authors.affiliation: Villa metabolica, Center for Pediatric and Adolescent Medicine, MC Johannes-Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Mengel
authors.affiliation: Willink Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, Manchester, UK.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Morris
authors.affiliation: Laboratory Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Klary E
authors.initials: KE
authors.lastname: Niezen-Koning
authors.affiliation: radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland.|Division of Child Neurology and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.affiliation: Unit for rare metabolic diseases, Department of Pediatrics, Fondazione MBBM/San Gerardo Hospital, Monza, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.affiliation: Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Rokicki
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Hôpital Robert Debré, APHP, INSERM U1141 and Université Paris-Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.affiliation: Children's Hospital Augsburg, Augsburg, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Schimmel
authors.affiliation: Department of Paediatrics, University Children's Hospital, Frankfurt am Main, Germany.|Bioscientia Institute for Laboratory Diagnostics, Ingelheim, Germany.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Sewell
authors.affiliation: Department of Pediatrics, Paracelsus Medical University (PMU), Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Department of General Pediatrics and Adolescent Medicine, University Children's Hospital, Freiburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Spiekerkoetter
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.affiliation: Department of Pediatrics, Section of Paediatric Neurology, University of Pisa, Pisa, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Taddeucci
authors.affiliation: Neurology Department, Hospital Universitario de Burgos, Burgos, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Trejo-Gabriel-Galán
authors.affiliation: Department of Pediatrics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Trefz
authors.affiliation: Department of Neuroscience, Jikei University School of Medicine, Minato, Tokyo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Tsuji
authors.affiliation: Laboratori de Malalties Metabòliques Hereditàrias, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: María Antònia
authors.initials: MA
authors.lastname: Vilaseca
authors.affiliation: Department of Paediatrics, University of Cologne, Cologne, Germany.
authors.forename: Jürgen-Christoph
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.affiliation: University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Walker
authors.affiliation: Department of Paediatrics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland. Matthias.baumgartner@kispi.uzh.ch.|radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland. Matthias.baumgartner@kispi.uzh.ch.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland. Brian.fowler@kispi.uzh.ch.|University Childrens' Hospital Basel (UKBB), Basel, Switzerland. Brian.fowler@kispi.uzh.ch.
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
mesh_terms: D001259:Ataxia / Q000235:genetics; D001622:Betaine / Q000627:therapeutic use; D002648:Child; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use; D056726:Genetic Association Studies / Q000379:methods; D006712:Homocystinuria / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008715:Methionine / Q000627:therapeutic use; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000235:genetics*; D009128:Muscle Spasticity / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011618:Psychotic Disorders / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D012189:Retrospective Studies; D013118:Spinal Cord Diseases / Q000235:genetics; D014805:Vitamin B 12 / Q000627:therapeutic use
chemical_list: D001622:Betaine; D005492:Folic Acid; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12