{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:40:27Z","timestamp":1790786427339,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,12,20]],"date-time":"2014-12-20T00:00:00Z","timestamp":1419033600000},"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><jats:sec><jats:title>Background<\/jats:title><jats:p>The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey\u2010based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow\u2010up. Eighteen\/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (<jats:italic>n<\/jats:italic>\u2009=\u20098) or stable (<jats:italic>n<\/jats:italic>\u2009=\u200915) in 96 % of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype\u2013 phenotype correlations evident.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10545-014-9803-7","type":"journal-article","created":{"date-parts":[[2014,12,19]],"date-time":"2014-12-19T12:26:55Z","timestamp":1418992015000},"page":"957-967","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data"],"prefix":"10.1002","volume":"38","author":[{"given":"M.","family":"Huemer","sequence":"first","affiliation":[{"name":"Division of Metabolic Diseases and Children's Research Center University Children's Hospital Z\u00fcrich Steinwiesstr. 75 Zurich Switzerland"},{"name":"radiz \u2013 Rare Disease Initiative Z\u00fcrich University of Z\u00fcrich Zurich Switzerland"},{"name":"Department of Paediatrics Landeskrankenhaus Bregenz Carl\u2010Pedenz\u2010Str. 2 Bregenz 6900 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"B\u00fcrer","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Children's Research Center University Children's Hospital Z\u00fcrich Steinwiesstr. 75 Zurich Switzerland"},{"name":"radiz \u2013 Rare Disease Initiative Z\u00fcrich University of Z\u00fcrich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Je\u0161ina","sequence":"additional","affiliation":[{"name":"Institute of Inherited Metabolic Diseases Charles University\u20101st Faculty of Medicine and General University Hospital Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Ko\u017eich","sequence":"additional","affiliation":[{"name":"Institute of Inherited Metabolic Diseases Charles University\u20101st Faculty of Medicine and General University Hospital Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. A.","family":"Landolt","sequence":"additional","affiliation":[{"name":"Department of Psychosomatics and Psychiatry University Children's Hospital Z\u00fcrich Zurich Switzerland"},{"name":"Department of Child and Adolescent Health Psychology, Institute of Psychology University of Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Suormala","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Children's Research Center University Children's Hospital Z\u00fcrich Steinwiesstr. 75 Zurich Switzerland"},{"name":"radiz \u2013 Rare Disease Initiative Z\u00fcrich University of Z\u00fcrich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Fowler","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Children's Research Center University Children's Hospital Z\u00fcrich Steinwiesstr. 75 Zurich Switzerland"},{"name":"radiz \u2013 Rare Disease Initiative Z\u00fcrich University of Z\u00fcrich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Augoustides\u2010 Savvopoulou","sequence":"additional","affiliation":[{"name":"1st Paediatric Department, Metabolic Laboratory Aristotle University of Thessaloniki Thessaloniki Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Blair","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Churchill Hospital, Oxford University Hospital NHS Trust Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Brennerova","sequence":"additional","affiliation":[{"name":"Ist Paediatric Clinic University Children's Hospital Bratislava Bratislava Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Broomfield","sequence":"additional","affiliation":[{"name":"Willink Biochemical Genetics Unit Manchester Centre for Genomic Medicine, St Mary's Hospital Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"De Meirleir","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology and Metabolics UZ Brussel l Brussel Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"G\u00f6kcay","sequence":"additional","affiliation":[{"name":"Istanbul Medical Faculty, Children's Hospital, Division of Nutrition and Metabolism, Istanbul Istanbul University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Hennermann","sequence":"additional","affiliation":[{"name":"Department of Paediatric and Adolescent Medicine, Villa Metabolica University Medical Center Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Jardine","sequence":"additional","affiliation":[{"name":"University of Bristol Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Paracelsus Medical University Salzburg Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Lorenzl","sequence":"additional","affiliation":[{"name":"Endowed Professorship for Interdisciplinary Research in Palliative Care Institute of Nursing Science and Practice Paracelsus Medical University Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. S.","family":"Lotz\u2010Havla","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children's Hospital Ludwig Maximilians University Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Noss","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Klinikum Dritter Orden Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Parini","sequence":"additional","affiliation":[{"name":"Rare Metabolic Diseases Unit Azienda Ospedaliera San Gerardo Monza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Peters","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Royal Children's Hospital Melbourne Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Plecko","sequence":"additional","affiliation":[{"name":"Division of Child Neurology University Children's Hospital Zurich Zurich Switzerland"},{"name":"Department of Paediatrics University Children's Hospital Graz Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. J.","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Neurology Hospital Sant Joan de Deu Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Schlune","sequence":"additional","affiliation":[{"name":"Department of General Paediatrics, Neonatology and Pediatric Cardiology University Children's Hospital, Heinrich\u2010Heine University D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"Tsiakas","sequence":"additional","affiliation":[{"name":"Departments of Paediatrics University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Zerjav Tansek","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolic Diseases University Children's Hospital, UMC Ljubljana Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. R.","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Division of Metabolic Diseases and Children's Research Center University Children's Hospital Z\u00fcrich Steinwiesstr. 75 Zurich Switzerland"},{"name":"radiz \u2013 Rare Disease Initiative Z\u00fcrich University of Z\u00fcrich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,20]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198806303182607"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-009-1257-y"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2013.05.013"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005372730310"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00381-007-0303-z"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19970905)71:4<384::AID-AJMG3>3.0.CO;2-U"},{"issue":"14","key":"e_1_2_15_8_1","first-page":"00161","article-title":"Cobalamin E defect, a rare inborn error of vitamin B12 metabolism: Value of early diagnosis and treatment","volume":"0967","author":"Kandula T","year":"2014","journal-title":"Clin Neurosci2014"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2012-2581"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004310050744"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004310051190"},{"key":"e_1_2_15_12_1","first-page":"361","article-title":"A rare inborn error of intracellular processing of cobalamin presenting with microcephalus and megaloblastic anemia: a report of 3 children","volume":"219","author":"M\u00fcller P","year":"2007","journal-title":"Klin P\u00e4diatr"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318260451b"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2012_161"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-004-1044-2"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24316"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(85)92433-X"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-010-9120-8"},{"key":"e_1_2_15_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198403153101104"},{"key":"e_1_2_15_20_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005382627986"},{"key":"e_1_2_15_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M407733200"},{"key":"e_1_2_15_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00014296"},{"key":"e_1_2_15_23_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1025159103257"},{"key":"e_1_2_15_24_1","doi-asserted-by":"publisher","DOI":"10.1086\/341354"},{"key":"e_1_2_15_25_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021299117308"},{"key":"e_1_2_15_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20131"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-014-9803-7","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T04:49:45Z","timestamp":1694753385000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1007\/s10545-014-9803-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,20]]},"references-count":25,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,9]]}},"alternative-id":["10.1007\/s10545-014-9803-7"],"URL":"https:\/\/doi.org\/10.1007\/s10545-014-9803-7","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,20]]}}}