{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:57:34Z","timestamp":1781661454417,"version":"3.54.5"},"reference-count":30,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,1,30]],"date-time":"2015-01-30T00:00:00Z","timestamp":1422576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    In the folate cycle MTHFD1, encoded by\n                    <jats:italic>MTHFD1<\/jats:italic>\n                    , is a trifunctional enzyme containing 5,10\u2010methylenetetrahydrofolate dehydrogenase, 5,10\u2010methenyltetrahydrofolate cyclohydrolase and 10\u2010formyltetrahydrofolate synthetase activity. To date, only one patient with\n                    <jats:italic>MTHFD1<\/jats:italic>\n                    deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590\u20132, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C\u2009&gt;\u2009T, p.Thr296Ile) and a splice site mutation (c.1674G\u2009&gt;\u2009A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C\u2009&gt;\u2009T, p.Ser49Phe) and a premature stop mutation (c.673G\u2009&gt;\u2009T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [\n                    <jats:sup>14<\/jats:sup>\n                    C]\u2010formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.\n                  <\/jats:p>","DOI":"10.1007\/s10545-015-9810-3","type":"journal-article","created":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T03:07:30Z","timestamp":1422500850000},"page":"863-872","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment"],"prefix":"10.1002","volume":"38","author":[{"given":"P.","family":"Burda","sequence":"first","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Steinwiesstrasse 75 Zurich 8032 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Kuster","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology University Hospital of Nantes Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O.","family":"Hjalmarson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Gothenburg Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Suormala","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Steinwiesstrasse 75 Zurich 8032 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"B\u00fcrer","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Steinwiesstrasse 75 Zurich 8032 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Lutz","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Steinwiesstrasse 75 Zurich 8032 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Roussey","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology University Hospital of Nantes Nantes France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Christa","sequence":"additional","affiliation":[{"name":"Metabolic Biochemistry Department, Necker Hospital, AP\u2010HP University Paris Descartes Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Asin\u2010Cayuela","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Sahlgrenska University Hospital Gothenburg SE\u2010413 45 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Kollberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Sahlgrenska University Hospital Gothenburg SE\u2010413 45 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. A.","family":"Andersson","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology and Transfusion Medicine Sahlgrenska University Hospital Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. S.","family":"Rosenblatt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Montreal QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Fowler","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Steinwiesstrasse 75 Zurich 8032 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Holme","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Sahlgrenska University Hospital Gothenburg SE\u2010413 45 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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R.","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Steinwiesstrasse 75 Zurich 8032 Switzerland"},{"name":"Radiz \u2013 Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich Zurich Switzerland"},{"name":"Zurich Center for Integrative Human Physiology University of Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,30]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1086\/344213"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20830"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.22.10881"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100380200043"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.12.4158-4166.2002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13236"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199701000-00023"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0083-6729(08)00401-9"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg556"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","unstructured":"JusufiJ SuormalaT BurdaP FowlerB FroeseDS BaumgartnerMR(2014)Characterization of functional domains of the cblD (MMADHC) gene product.J Inherit Metab Dis.","DOI":"10.1007\/s10545-014-9709-4"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2012-0899"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808281200"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211199110"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201603"},{"key":"e_1_2_9_21_1","first-page":"3897","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Rosenblatt DS","year":"2001"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi992734y"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-10-49"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-06-1037"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/48.6.835"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407733200"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.012809.104810"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2293"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9418-1"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100286"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00295291"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-015-9810-3","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:49:40Z","timestamp":1694738980000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1007\/s10545-015-9810-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,30]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,9]]}},"alternative-id":["10.1007\/s10545-015-9810-3"],"URL":"https:\/\/doi.org\/10.1007\/s10545-015-9810-3","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725974804.793511917","asserted-by":"object"}]},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,30]]}}}