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. 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.

Bioscientia Institute for Laboratory Diagnostics Ingelheim Germany

Centre de Référence Maladies Héréditaires du Métabolisme de l'enfant et de l'adulte Hôpital Jeanne de Flandre Lille France

Children's Hospital Augsburg Augsburg Germany

Department of General Pediatrics and Adolescent Medicine University Children's Hospital Freiburg Germany

Department of Neuroscience Jikei University School of Medicine Minato Tokyo Japan

Department of Paediatrics 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Paediatrics Landeskrankenhaus Bregenz Bregenz Austria

Department of Paediatrics University Children's Hospital Frankfurt am Main Germany

Department of Paediatrics University of Cologne Cologne Germany

Department of Pediatrics Nutrition and Metabolic Diseases The Children's Memorial Health Institute Warsaw Poland

Department of Pediatrics Paracelsus Medical University Salzburg Austria

Department of Pediatrics Section of Paediatric Neurology University of Pisa Pisa Italy

Department of Pediatrics University of Heidelberg Heidelberg Germany

Division of Child Neurology and Children's Research Center University Children's Hospital Zürich Zürich Switzerland

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

Division of Metabolism Bambino Gesù Children's Hospital IRCCS Rome Italy

Edmond and Lilly Safra Pediatric Hospital Sheba Med Center and Sackler School of Medicine Tel Aviv Tel Aviv Israel

Institute of Genetic Medicine Newcastle University Newcastle upon Tyne UK

Istanbul Medical Faculty Children's Hospital Pediatric Nutrition and Metabolism Istanbul University Istanbul Turkey

Laboratori de Malalties Metabòliques Hereditàrias Hospital Sant Joan de Déu Barcelona Spain

Laboratory Metabolic Diseases University Medical Center Groningen Groningen The Netherlands

Neurology Department Hospital Universitario de Burgos Burgos Spain

radiz Rare Disease Initiative Zürich Clinical Research Priority Program University of Zürich Zürich Switzerland

Reference Center for Inborn Errors of Metabolism Hôpital Robert Debré APHP INSERM U1141 and Université Paris Diderot Sorbonne Paris Cité Paris France

Unit for rare metabolic diseases Department of Pediatrics Fondazione MBBM San Gerardo Hospital Monza Italy

University Childrens' Hospital Basel Basel Switzerland

University Hospital Southampton NHS Foundation Trust Southampton UK

Villa metabolica Center for Pediatric and Adolescent Medicine MC Johannes Gutenberg University Mainz Mainz Germany

Willink Unit Manchester Centre for Genomic Medicine Central Manchester University Hospitals Manchester UK

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