{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:47:57Z","timestamp":1786978077297,"version":"build-2736575974"},"reference-count":14,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,4,6]],"date-time":"2022-04-06T00:00:00Z","timestamp":1649203200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["CHAFEA agreement no. 2012 12 02"],"award-info":[{"award-number":["CHAFEA agreement no. 2012 12 02"]}],"id":[{"id":"10.13039\/501100000780","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":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013\u20132016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B\n                    <jats:sub>6<\/jats:sub>\n                    nonresponsive (\n                    <jats:italic>N<\/jats:italic>\n                    \u00a0=\u00a054) and partially responsive (\n                    <jats:italic>N<\/jats:italic>\n                    \u00a0=\u00a07) cystathionine beta\u2010synthase (CBS) deficiency, as well as 5,10\u2010methylenetetrahydrofolate reductase (MTHFR;\n                    <jats:italic>N<\/jats:italic>\n                    \u00a0=\u00a021) deficiency and cobalamin C (\n                    <jats:italic>N<\/jats:italic>\n                    \u00a0=\u00a048) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0\u20139.8) years. The prescribed betaine dose exceeded the recommended maximum (6\u00a0g\/day) in 49% of individuals older than 10\u2009years because of continued dose adaptation to weight; however, with disease\u2010specific differences (minimum: 31% in B\n                    <jats:sub>6<\/jats:sub>\n                    nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease\u2010specific treatment decreased mean\u2009\u00b1\u2009SD total plasma homocysteine concentrations from 203\u2009\u00b1\u2009116 to 81\u2009\u00b1\u200951\u2009\u03bcmol\/L (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals \u2265 10\u2009years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well\u2010established structures and avoiding data duplication and fragmentation.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12499","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T12:40:54Z","timestamp":1648730454000},"page":"719-733","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Postauthorization safety study of betaine anhydrous"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4251-7257","authenticated-orcid":false,"given":"Ulrike","family":"M\u00fctze","sequence":"first","affiliation":[{"name":"Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7397-5640","authenticated-orcid":false,"given":"Florian","family":"Gleich","sequence":"additional","affiliation":[{"name":"Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7420-4757","authenticated-orcid":false,"given":"Sven F.","family":"Garbade","sequence":"additional","affiliation":[{"name":"Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Plisson","sequence":"additional","affiliation":[{"name":"Recordati Rare Diseases  Puteaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0687-6604","authenticated-orcid":false,"given":"Luis","family":"Ald\u00e1miz\u2010Echevarr\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Santiago de Compostela (IDIS)  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Arrieta","sequence":"additional","affiliation":[{"name":"Endocrinology &amp; Nutrition, Metabolic Congenital Disease, H.U. Ramon y Cajal  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2940-3439","authenticated-orcid":false,"given":"Diana","family":"Ballhausen","sequence":"additional","affiliation":[{"name":"Pediatric Unit for Metabolic Diseases, Woman\u2010Mother\u2010Child Department Lausanne University Hospital  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9653-2914","authenticated-orcid":false,"given":"Matthias","family":"Zielonka","sequence":"additional","affiliation":[{"name":"Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danijela","family":"Petkovi\u0107 Ramad\u017ea","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Hospital Centre Zagreb and University of Zagreb, School of Medicine  Zagreb Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9270-0826","authenticated-orcid":false,"given":"Matthias R.","family":"Baumgartner","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital, University of Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Cano","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies H\u00e9r\u00e9ditaires du M\u00e9tabolisme, CHU La Timone Enfants  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5563-3177","authenticated-orcid":false,"given":"Mar\u00eda Concepci\u00f3n","family":"Garc\u00eda Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Metabolic Department, University Children Miguel Servet Hospital  Aragon Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0007-3379","authenticated-orcid":false,"given":"Carlo","family":"Dionisi\u2010Vici","sequence":"additional","affiliation":[{"name":"Division of Metabolism Bambino Ges\u00f9 Children's Hospital IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Je\u0161ina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Inherited Metabolic Disorders Charles University\u2010First Faculty of Medicine and General University Hospital  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5202-9241","authenticated-orcid":false,"given":"Henk J.","family":"Blom","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center  Rotterdam Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luz","family":"Couce","sequence":"additional","affiliation":[{"name":"Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Service of Neonatology, Department of Pediatrics, Hospital Cl\u00ednico Universitario de Santiago, CIBERER, Health Research Institute of Santiago de Compostela (IDIS)  Santiago de Compostela Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Meavilla Olivas","sequence":"additional","affiliation":[{"name":"Pediatrics, Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de D\u00e9u  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Mention","sequence":"additional","affiliation":[{"name":"Centre de R\u00e9f\u00e9rence des Maladies H\u00e9r\u00e9ditaires du M\u00e9tabolisme, H\u00f4pital Jeanne de Flandre  Lille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Mochel","sequence":"additional","affiliation":[{"name":"Ap.HP, Sorbonne University, Reference Center for Adult Neurometabolic Diseases, La Piti\u00e9\u2010Salp\u00eatri\u00e8re University Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew A. M.","family":"Morris","sequence":"additional","affiliation":[{"name":"Alder Hey Children's NHS Foundation Trust  Liverpool UK"},{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Trust  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Mundy","sequence":"additional","affiliation":[{"name":"Evelina London Children's Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5102-3814","authenticated-orcid":false,"given":"Isabelle","family":"Redonnet\u2010Vernhet","sequence":"additional","affiliation":[{"name":"Endocrinology, Nutrition and Metabolic Diseases Haut\u2010L\u00e9v\u00eaque Hospital, Bordeaux University  Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saikat","family":"Santra","sequence":"additional","affiliation":[{"name":"Department of Clinical Inherited Metabolic Disorders Birmingham Women's and Children's NHS Foundation Trust  Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Schiff","sequence":"additional","affiliation":[{"name":"Necker Hospital, APHP, Reference Center for Inborn Error of Metabolism and Fili\u00e8re G2M, Pediatrics Department University of Paris  Paris France"},{"name":"Inserm UMR_S1163, Institut Imagine  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8165-8212","authenticated-orcid":false,"given":"Aude","family":"Servais","sequence":"additional","affiliation":[{"name":"Nephrology and Transplantation, MAMEA Reference Center, Necker hospital, APHP  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isidro","family":"Vitoria","sequence":"additional","affiliation":[{"name":"Unit of Metabolic Disorders, Universitary Hospital La Fe  Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0590-678X","authenticated-orcid":false,"given":"Martina","family":"Huemer","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital, University of Zurich  Zurich Switzerland"},{"name":"Department of Pediatrics Landeskrankenhaus Bregenz  Bregenz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5820-5277","authenticated-orcid":false,"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  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00f6lker","sequence":"additional","affiliation":[{"name":"Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010021\u201001726\u20103"},{"key":"e_1_2_10_3_1","unstructured":"Rodwell C Aym\u00e9 S. 2014 Report on the State of the Art of Rare Disease Activities in Europe.European Union; 2014.https:\/\/ec.europa.eu\/health\/sites\/health\/files\/rare_diseases\/docs\/2014report_rare_disease_activitieseu_1_en.pdf. Accessed March 24 2021."},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sdata.2016.18"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2015_408"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12041"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010016\u20109991\u20104"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12338"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010016\u20109979\u20100"},{"key":"e_1_2_10_10_1","unstructured":"EMACystadane: EPAR\u2014Sientific Discussion. 2007.https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010discussion\/cystadane\u2010epar\u2010scientific\u2010discussion_en.pdf. Accessed March 25 2021."},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010019\u20101036\u20102"},{"key":"e_1_2_10_12_1","unstructured":"EMACystadane: EPAR\u2014Product information. 2019.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/cystadane\u2010epar\u2010product\u2010information_en.pdf. Accessed March 25 2021."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545\u2010015\u20109830\u2010z"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12034"},{"key":"e_1_2_10_15_1","unstructured":"EMACystadane: EPAR\u2014procedural steps taken sientific information after authorisation. 2019.https:\/\/www.ema.europa.eu\/en\/documents\/procedural-steps-after\/cystadane-epar-procedural-steps-taken-scientific-information-after-authorisation_en.pdf. Accessed March 25 2021."}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12499","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jimd.12499","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jimd.12499","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T17:04:05Z","timestamp":1692551045000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jimd.12499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,6]]},"references-count":14,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1002\/jimd.12499"],"URL":"https:\/\/doi.org\/10.1002\/jimd.12499","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,6]]},"assertion":[{"value":"2022-01-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}