{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:43:04Z","timestamp":1790962984380,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100009553","name":"Agentura Pro Zdravotnick\u00fd V\u00fdzkum \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["NV19\u201001\u201000307"],"award-info":[{"award-number":["NV19\u201001\u201000307"]}],"id":[{"id":"10.13039\/501100009553","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>5,10\u2010Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late\u2010onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult\u2010onset forms of the disease, we included patients with a diagnosis established after the age of 10\u2009years. We included 14 patients (median age at diagnosis: 32\u2009years; range: 11\u201054). At onset (median age: 20\u2009years; range 9\u201038), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and\/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14\u2009years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55\u2009years. Upon treatment, median total homocysteine decreased (from 183\u2009\u03bcmol\/L, range 69\u2010266, to 90\u2009\u03bcmol\/L, range 20\u2010142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C\u2010terminal regulatory domain of the protein were over\u2010represented compared to early\u2010onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%\u201058%). This series of patients with late\u2010onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.<\/jats:p>","DOI":"10.1002\/jimd.12323","type":"journal-article","created":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T13:22:36Z","timestamp":1603372956000},"page":"777-786","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Clinical and molecular characterization of adult patients with late\u2010onset <scp>MTHFR<\/scp> deficiency"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9543-6311","authenticated-orcid":false,"given":"Cecilia","family":"Marelli","sequence":"first","affiliation":[{"name":"Expert Centre for Neurogenetic Diseases and Adult Mitochondrial and Metabolic Diseases Univ Montpellier, CHU  Montpellier France"},{"name":"MMDN, Univ Montpellier, EPHE, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Lavigne","sequence":"additional","affiliation":[{"name":"Internal Medicine Department Angers University Hospital  Angers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina M.","family":"Stepien","sequence":"additional","affiliation":[{"name":"Adult Inherited Metabolic Diseases, Salford Royal NHS Foundation Trust, Salford Care Organisation, Northern Care Alliance  Salford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirian C. H.","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Feillet","sequence":"additional","affiliation":[{"name":"Reference Center for Inborn Errors of Metabolism, Pediatric unit University Hospital of Nancy  Nancy France"},{"name":"INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE) Faculty of Medicine of Nancy  Nancy France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Ko\u017eich","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Disorders, Charles University\u2010First Faculty of Medicine and General University Hospital in Prague  Praha 2 Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Jesina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Disorders, Charles University\u2010First Faculty of Medicine and General University Hospital in Prague  Praha 2 Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Schule","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kessler","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Redonnet\u2010Vernhet","sequence":"additional","affiliation":[{"name":"lNSERM U1211, Universit\u00e9 de Bordeaux  Bordeaux France"},{"name":"Laboratoire de Biochimie Centre Hospitalier Universitaire de Bordeaux  Bordeaux France"},{"name":"Centre de r\u00e9f\u00e9rence pour les maladies mitochondriales de l'enfant \u00e0 l'adulte (CARAMMEL) Centre Hospitalier Universitaire de Bordeaux  Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline","family":"Regnier","sequence":"additional","affiliation":[{"name":"Department of General Practice Faculty of Medicine of Clermont\u2010Ferrand  Clermont\u2010Ferrand France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricie","family":"Burda","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Francois","family":"Benoist","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory Robert\u2010Debr\u00e9 University Hospital, APHP  Paris France"},{"name":"LYPSIS2, Universit\u00e9 Paris\u2010Saclay  Chatenay\u2010Malabry France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Huemer","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital  Z\u00fcrich Switzerland"},{"name":"Department of Paediatrics Landeskrankenhaus Bregenz  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Mochel","sequence":"additional","affiliation":[{"name":"APHP, La Piti\u00e9\u2010Salp\u00eatri\u00e8re University Hospital, Department of Genetics  Paris France"},{"name":"Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9s, UPMC Univ Paris 06 UMR S 1127 Institut du Cerveau et de la Moelle \u00e9pini\u00e8re, ICM  Paris France"},{"name":"APHP, La Piti\u00e9\u2010Salp\u00eatri\u00e8re University Hospital Reference Center for Adult Neurometabolic diseases  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the E\u2010HOD Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/7594"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-015-9860-6"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22779"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2013.4915"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-010-9120-8"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2007.02.012"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197503062921001"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.41.8.1313"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320450510"},{"key":"e_1_2_10_11_1","first-page":"1052","article-title":"Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype\/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency","volume":"56","author":"Goyette P","year":"1995","journal-title":"Am J Hum Genet."},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.57.6.765"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(200003)15:3<280::AID-HUMU9>3.0.CO;2-I"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2008.143677"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-008-0043-3"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2010.218586"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2014.04.005"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2014.116"},{"key":"e_1_2_10_19_1","first-page":"1735","article-title":"Adult\u2010onset severe methylenetetrahydrofolate reductase deficiency characterized by reversible spastic paraplegia with a novel mutation","volume":"37","author":"Lin N","year":"2016","journal-title":"Neurol Sci off J Ital Neurol Soc Ital Soc Clin Neurophysiol."},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2017.10.035"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0767-9"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurol.2017.06.028"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/bcr-2019-232241"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/48.6.835"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12041"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-016-9991-4"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurpub\/ckx143"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22970"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10193"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12323","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.12323","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,2]],"date-time":"2023-09-02T04:35:00Z","timestamp":1693629300000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,2]]},"references-count":28,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1002\/jimd.12323"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12323","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,2]]},"assertion":[{"value":"2020-08-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}