{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:28:51Z","timestamp":1791419331920,"version":"4.3.3"},"reference-count":17,"publisher":"American Academy of Pediatrics (AAP)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,2,1]]},"abstract":"<jats:p>Folate and vitamin B12 metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.<\/jats:p>","DOI":"10.1542\/peds.2012-0899","type":"journal-article","created":{"date-parts":[[2013,1,8]],"date-time":"2013-01-08T18:12:31Z","timestamp":1357668751000},"page":"e629-e634","source":"Crossref","is-referenced-by-count":61,"title":["Severe Combined Immunodeficiency Resulting From Mutations in\n                    <i>MTHFD1<\/i>"],"prefix":"10.1542","volume":"131","author":[{"given":"Michael D.","family":"Keller","sequence":"first","affiliation":[{"name":"Division of Allergy and Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaya","family":"Ganesh","sequence":"additional","affiliation":[{"name":"Section of Metabolic Disease,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Heltzer","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Paessler","sequence":"additional","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.G. Christina","family":"Bergqvist","sequence":"additional","affiliation":[{"name":"Division of Neurology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Jorge","family":"Baluarte","sequence":"additional","affiliation":[{"name":"Division of Nephrology, The Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University, Montreal, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Rosenblatt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University, Montreal, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan S.","family":"Orange","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2013,2,1]]},"reference":[{"issue":"1","key":"2021120903271218700_B1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/ajmg.c.30288","article-title":"Inborn errors of cobalamin absorption and metabolism.","volume":"157","author":"Watkins","year":"2011","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"4","key":"2021120903271218700_B2","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1007\/s10545-011-9418-1","article-title":"Update and new concepts in vitamin responsive disorders of folate transport and metabolism.","volume":"35","author":"Watkins","year":"2012","journal-title":"J Inherit Metab Dis"},{"issue":"12","key":"2021120903271218700_B3","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/BF01955004","article-title":"Transcobalamin II deficiency: case report and review of the literature.","volume":"150","author":"Kaikov","year":"1991","journal-title":"Eur J Pediatr"},{"issue":"6","key":"2021120903271218700_B4","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1111\/j.1651-2227.1987.tb17284.x","article-title":"Megaloblastic anemia and immune abnormalities in a patient with methionine synthase deficiency.","volume":"76","author":"Zittoun","year":"1987","journal-title":"Acta Paediatr Scand"},{"issue":"3","key":"2021120903271218700_B5","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.clim.2009.08.006","article-title":"Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter.","volume":"133","author":"Borzutzky","year":"2009","journal-title":"Clin Immunol"},{"issue":"9","key":"2021120903271218700_B6","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1136\/jmedgenet-2011-100286","article-title":"Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.","volume":"48","author":"Watkins","year":"2011","journal-title":"J Med Genet"},{"key":"2021120903271218700_B7","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1146\/annurev.immunol.22.012703.104614","article-title":"Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.","volume":"22","author":"Buckley","year":"2004","journal-title":"Annu Rev Immunol"},{"issue":"2","key":"2021120903271218700_B8","first-page":"83","article-title":"Severe combined immunodeficiencies.","volume":"3","author":"Fischer","year":"1992","journal-title":"Immunodefic Rev"},{"issue":"6","key":"2021120903271218700_B9","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1034\/j.1399-0004.2001.590608.x","article-title":"Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient patient.","volume":"59","author":"Dalal","year":"2001","journal-title":"Clin Genet"},{"issue":"6","key":"2021120903271218700_B10","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/ni0610-457","article-title":"20 years of gene therapy for SCID.","volume":"11","author":"Fischer","year":"2010","journal-title":"Nat Immunol"},{"issue":"8","key":"2021120903271218700_B11","doi-asserted-by":"crossref","first-page":"4209","DOI":"10.1182\/blood-2007-05-092429","article-title":"Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients.","volume":"111","author":"Cassani","year":"2008","journal-title":"Blood"},{"issue":"4","key":"2021120903271218700_B12","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1172\/JCI109367","article-title":"In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2\u2032-deoxyadenosine in adenosine deaminase-deficient patients.","volume":"63","author":"Hershfield","year":"1979","journal-title":"J Clin Invest"},{"issue":"31","key":"2021120903271218700_B13","doi-asserted-by":"crossref","first-page":"15946","DOI":"10.1016\/S0021-9258(18)37540-9","article-title":"Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase.","volume":"263","author":"Hum","year":"1988","journal-title":"J Biol Chem"},{"key":"2021120903271218700_B14","article-title":"Hereditary folate malabsorption","volume-title":"GeneReviews","author":"Mahadeo","year":"1993"},{"issue":"12","key":"2021120903271218700_B15","first-page":"868","article-title":"Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults.","volume":"5","author":"Teplitsky","year":"2003","journal-title":"Isr Med Assoc J"},{"issue":"4","key":"2021120903271218700_B16","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1097\/00043426-200205000-00023","article-title":"Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period.","volume":"24","author":"Kind","year":"2002","journal-title":"J Pediatr Hematol Oncol"},{"key":"2021120903271218700_B17","doi-asserted-by":"crossref","first-page":"S77","DOI":"10.1007\/PL00014307","article-title":"Remethylation defects: guidelines for clinical diagnosis and treatment.","volume":"157","author":"Ogier de Baulny","year":"1998","journal-title":"Eur J Pediatr"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/131\/2\/e629\/1087985\/peds_2012-0899.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/131\/2\/e629\/1087985\/peds_2012-0899.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T13:15:56Z","timestamp":1639055756000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/131\/2\/e629\/31919\/Severe-Combined-Immunodeficiency-Resulting-From"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2,1]]},"references-count":17,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2013,2,1]]},"published-print":{"date-parts":[[2013,2,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2012-0899","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725974803.793511915","asserted-by":"object"}]},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,2,1]]}}}