Martina Huemer1,2,3, Regina Mulder-Bleile4, Patricie Burda1, D Sean Froese1, Terttu Suormala1, Bruria Ben Zeev5, Patrick F Chinnery6, Carlo Dionisi-Vici7, Dries Dobbelaere8, Gülden Gökcay9, Mübeccel Demirkol9, Johannes Häberle1, Alexander Lossos10, Eugen Mengel10, Andrew A Morris11, Klary E Niezen-Koning12, Barbara Plecko2,13, Rossella Parini14, Dariusz Rokicki15, Manuel Schiff16, Mareike Schimmel17, Adrian C Sewell18,19, Wolfgang Sperl20, Ute Spiekerkoetter21, Beat Steinmann1, Grazia Taddeucci22, Jose M Trejo-Gabriel-Galán23, Friedrich Trefz24, Megumi Tsuji25, María Antònia Vilaseca26, Jürgen-Christoph von Kleist-Retzow27, Valerie Walker28, Jiri Zeman29, Matthias R Baumgartner30,31, Brian Fowler32,33. 1. Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland. 2. radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland. 3. Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria. 4. University Childrens' Hospital Basel (UKBB), Basel, Switzerland. 5. Edmond and Lilly Safra Pediatric Hospital, Sheba Med Center and Sackler School of Medicine Tel Aviv, Tel Aviv, Israel. 6. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. 7. Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 8. Centre de Référence Maladies Héréditaires du Métabolisme de l'enfant et de l'adulte, Hôpital Jeanne de Flandre, Lille, France. 9. Istanbul Medical Faculty, Children's Hospital, Pediatric Nutrition and Metabolism, Istanbul University, Istanbul, Turkey. 10. Villa metabolica, Center for Pediatric and Adolescent Medicine, MC Johannes-Gutenberg-University Mainz, Mainz, Germany. 11. Willink Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, Manchester, UK. 12. Laboratory Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands. 13. Division of Child Neurology and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. 14. Unit for rare metabolic diseases, Department of Pediatrics, Fondazione MBBM/San Gerardo Hospital, Monza, Italy. 15. Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland. 16. Reference Center for Inborn Errors of Metabolism, Hôpital Robert Debré, APHP, INSERM U1141 and Université Paris-Diderot, Sorbonne Paris Cité, Paris, France. 17. Children's Hospital Augsburg, Augsburg, Germany. 18. Department of Paediatrics, University Children's Hospital, Frankfurt am Main, Germany. 19. Bioscientia Institute for Laboratory Diagnostics, Ingelheim, Germany. 20. Department of Pediatrics, Paracelsus Medical University (PMU), Salzburg, Austria. 21. Department of General Pediatrics and Adolescent Medicine, University Children's Hospital, Freiburg, Germany. 22. Department of Pediatrics, Section of Paediatric Neurology, University of Pisa, Pisa, Italy. 23. Neurology Department, Hospital Universitario de Burgos, Burgos, Spain. 24. Department of Pediatrics, University of Heidelberg, Heidelberg, Germany. 25. Department of Neuroscience, Jikei University School of Medicine, Minato, Tokyo, Japan. 26. Laboratori de Malalties Metabòliques Hereditàrias, Hospital Sant Joan de Déu, Barcelona, Spain. 27. Department of Paediatrics, University of Cologne, Cologne, Germany. 28. University Hospital Southampton NHS Foundation Trust, Southampton, UK. 29. Department of Paediatrics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. 30. Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland. Matthias.baumgartner@kispi.uzh.ch. 31. radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zürich, Switzerland. Matthias.baumgartner@kispi.uzh.ch. 32. Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zürich, Switzerland. Brian.fowler@kispi.uzh.ch. 33. University Childrens' Hospital Basel (UKBB), Basel, Switzerland. Brian.fowler@kispi.uzh.ch.
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. 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.
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.
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