{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:41:44Z","timestamp":1792788104107,"version":"4.5.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":94,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Khalifa University and the United Arab Emirates University","award":["Award No. KU-UAEU-2023-068"],"award-info":[{"award-number":["Award No. KU-UAEU-2023-068"]}],"id":[{"id":"https:\/\/ror.org\/01km6p862","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Inborn errors of metabolism (IEMs) are among the most clinically actionable groups of rare genetic diseases, yet therapeutic knowledge remains distributed across multiple databases, complicating consistent identification of treatable IEMs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we performed a cross-database analysis to characterize the current therapeutic landscape of IEM genes using GeneReviews as a clinical reference. Gene symbols from GeneReviews, Metabolic Treatabolome, Treatable ID, and the Drug Database for Inborn Errors of Metabolism (DDIEM) were harmonized to HGNC nomenclature and mapped to the International Classification of Inherited Metabolic Disorders (ICIMD). IEM genes were categorized as associated with targeted or supportive treatment based on a GeneReviews-derived benchmark.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 656 ICIMD-defined IEM genes in GeneReviews, 155 (23.6%) were associated with targeted therapies and 501 (76.4%) with supportive treatment. Cross-database comparison demonstrated limited concordance, with only 36 genes associated with targeted therapy shared across Metabolic Treatabolome, Treatable ID, and DDIEM, reflecting heterogeneous representation of treatable IEMs across databases. Targeted therapies were more common in intermediary metabolic pathways, including fatty acid, tetrapyrrole, and vitamin\/cofactor metabolism, whereas mitochondrial and complex cellular disorders were predominantly associated with supportive management. Moreover, 53% of the ICIMD-defined IEM genes remain unrepresented in structured databases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study defines a set of IEM genes for which targeted therapies are available and demonstrates that treatment information is largely fragmented across databases. This set of IEM genes may facilitate the interpretation of genomic findings and aid the prioritization of IEMs for genomic screening and clinical decision-making.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-026-04486-0","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T16:55:13Z","timestamp":1783097713000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping the landscape of treatable inborn errors of metabolism: a systematic gene-level evaluation based on the ICIMD classification"],"prefix":"10.1186","volume":"21","author":[{"given":"Tabeer","family":"Fatima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalal","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Al-Jasmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiba","family":"Alblooshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"issue":"3","key":"4486_CR1","doi-asserted-by":"publisher","first-page":"e341","DOI":"10.1016\/S2214-109X(24)00056-1","volume":"12","author":"The Lancet Global Health","year":"2024","unstructured":"The Lancet Global Health. The landscape for rare diseases in 2024. Lancet Glob Health. 2024;12(3):e341. https:\/\/doi.org\/10.1016\/S2214-109X(24)00056-1.","journal-title":"Lancet Glob Health"},{"key":"4486_CR2","doi-asserted-by":"publisher","first-page":"701988","DOI":"10.3389\/fgene.2021.701988","volume":"12","author":"J Kruse","year":"2022","unstructured":"Kruse J, Mueller R, Aghdassi AA, Lerch MM, Salloch S. Genetic Testing for Rare Diseases: A Systematic Review of Ethical Aspects. Front Genet. 2022;12:701988. https:\/\/doi.org\/10.3389\/fgene.2021.701988.","journal-title":"Front Genet"},{"key":"4486_CR3","unstructured":"RARE Disease Facts - Global Genes. Accessed February 18. 2026. https:\/\/globalgenes.org\/rare-disease-facts\/"},{"key":"4486_CR4","unstructured":"EURORDIS NRP. 2005 undefined. Rare diseases: understanding this public health priority. myeloma.ro. Published online 2005. Accessed February 18, 2026. https:\/\/myeloma.ro\/documente\/european-organization-for-rare-diseases-november-2005.pdf"},{"issue":"2","key":"4486_CR5","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.pcl.2017.11.002","volume":"65","author":"JM Saudubray","year":"2018","unstructured":"Saudubray JM, Garcia-Cazorla \u00c0. Inborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management. Pediatr Clin North Am. 2018;65(2):179\u2013208. https:\/\/doi.org\/10.1016\/j.pcl.2017.11.002.","journal-title":"Pediatr Clin North Am"},{"issue":"1","key":"4486_CR6","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/s41436-018-0022-8","volume":"21","author":"CR Ferreira","year":"2019","unstructured":"Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Sci. 2019;21(1):102\u20136. https:\/\/doi.org\/10.1038\/s41436-018-0022-8.","journal-title":"Genet Sci"},{"key":"4486_CR7","doi-asserted-by":"publisher","first-page":"418333","DOI":"10.3389\/fneur.2018.01016","volume":"9","author":"CDM van Karnebeek","year":"2018","unstructured":"van Karnebeek CDM, Sayson B, Lee JJY, et al. Metabolic Evaluation of Epilepsy: A Diagnostic Algorithm With Focus on Treatable Conditions. Front Neurol. 2018;9:418333. https:\/\/doi.org\/10.3389\/fneur.2018.01016.","journal-title":"Front Neurol"},{"issue":"9","key":"4486_CR8","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1093\/pch\/19.9.469","volume":"19","author":"CDM Van Karnebeek","year":"2014","unstructured":"Van Karnebeek CDM, Stockler-Ipsiroglu S. Early identification of treatable inborn errors of metabolism in children with intellectual disability: The Treatable Intellectual Disability Endeavor protocol in British Columbia. Paediatr Child Health. 2014;19(9):469\u201371. https:\/\/doi.org\/10.1093\/pch\/19.9.469.","journal-title":"Paediatr Child Health"},{"issue":"8","key":"4486_CR9","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1001\/jamapediatrics.2015.0754","volume":"169","author":"HJ Vernon","year":"2015","unstructured":"Vernon HJ. Inborn Errors of Metabolism: Advances in Diagnosis and Therapy. JAMA Pediatr. 2015;169(8):778\u201382. https:\/\/doi.org\/10.1001\/jamapediatrics.2015.0754.","journal-title":"JAMA Pediatr"},{"key":"4486_CR10","unstructured":"Hivre M, Holkar SR, Vaishnav D, Chandankhede S, Vidhale D. Inborn Errors of Metabolism: A Comprehensive Clinical Review and Case-Based Analysis of Metabolic Disorders Across Multiple Biochemical Pathways. 15. 2025. www.jchr.org."},{"issue":"1","key":"4486_CR11","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/gim.2017.108","volume":"20","author":"JJY Lee","year":"2018","unstructured":"Lee JJY, Wasserman WW, Hoffmann GF, Van Karnebeek CDM, Blau N. Knowledge base and mini-expert platform for the diagnosis of inborn errors of metabolism. Genet Sci. 2018;20(1):151\u20138. https:\/\/doi.org\/10.1038\/gim.2017.108.","journal-title":"Genet Sci"},{"key":"4486_CR12","doi-asserted-by":"publisher","unstructured":"van Karnebeek CDM, Wortmann SB, Tarailo-Graovac M et al. The role of the clinician in the multi-omics era: are you ready? Journal of Inherited Metabolic Disease 2018 41:3. 2018;41(3):571\u2013582. https:\/\/doi.org\/10.1007\/s10545-017-0128-1","DOI":"10.1007\/s10545-017-0128-1"},{"issue":"1","key":"4486_CR13","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/JIMD.12348","volume":"44","author":"CR Ferreira","year":"2021","unstructured":"Ferreira CR, Rahman S, Keller M, et al. An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis. 2021;44(1):164\u201377. https:\/\/doi.org\/10.1002\/JIMD.12348.","journal-title":"J Inherit Metab Dis"},{"key":"4486_CR14","doi-asserted-by":"publisher","unstructured":"den Hollander B, van Hoytema EMM, Hewitson B, et al. The Metabolic Treatabolome and Inborn Errors of Metabolism Knowledgebase therapy tool: Do not miss the opportunity to treat! J Inherit Metab Dis John Wiley Sons Inc. 2025;48(1). https:\/\/doi.org\/10.1002\/jimd.12835.","DOI":"10.1002\/jimd.12835"},{"issue":"3","key":"4486_CR15","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1002\/ajmg.c.32137","volume":"199","author":"NB Adam","year":"2025","unstructured":"Adam NB, Amemiya AR, Wallace SE, Mahon CT, Mirzaa GM, Adam MP. Evaluation of Targeted Therapies Currently Available for Congenital Genetic Conditions Indexed in GeneReviews. Am J Med Genet C Semin Med Genet. 2025;199(3):143\u201350. https:\/\/doi.org\/10.1002\/ajmg.c.32137.","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"1","key":"4486_CR16","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1002\/ajmg.c.31874","volume":"187","author":"D Bick","year":"2021","unstructured":"Bick D, Bick SL, Dimmock DP, Fowler TA, Caulfield MJ, Scott RH. An online compendium of treatable genetic disorders. Am J Med Genet C Semin Med Genet. 2021;187(1):48\u201354. https:\/\/doi.org\/10.1002\/ajmg.c.31874.","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"4486_CR17","doi-asserted-by":"publisher","unstructured":"van Hoytema EMM, Wortmann SB, Koelewijn MJ, et al. Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app. Orphanet J Rare Dis BioMed Cent Ltd. 2021;16(1). https:\/\/doi.org\/10.1186\/s13023-021-01727-2.","DOI":"10.1186\/s13023-021-01727-2"},{"key":"4486_CR18","doi-asserted-by":"publisher","unstructured":"Abdelhakim M, Abdelhakim M, McMurray E, et al. DDIEM: Drug database for inborn errors of metabolism. Orphanet J Rare Dis. 2020;15(1). https:\/\/doi.org\/10.1186\/s13023-020-01428-2.","DOI":"10.1186\/s13023-020-01428-2"},{"key":"4486_CR19","doi-asserted-by":"publisher","unstructured":"R\u00e9dei GP. GeneReviews. In: Encyclopedia of Genetics, Genomics, Proteomics and Informatics. 2008. https:\/\/doi.org\/10.1007\/978-1-4020-6754-9_6624","DOI":"10.1007\/978-1-4020-6754-9_6624"},{"key":"4486_CR20","unstructured":"Home | HUGO Gene Nomenclature Committee. Accessed February 18. 2026. https:\/\/www.genenames.org\/"},{"key":"4486_CR21","doi-asserted-by":"publisher","unstructured":"Seal RL, Braschi B, Gray K, et al. Genenames.org: the HGNC resources in 2023. Nucleic Acids Res. 2023;51(D1). https:\/\/doi.org\/10.1093\/nar\/gkac888.","DOI":"10.1093\/nar\/gkac888"},{"key":"4486_CR22","doi-asserted-by":"publisher","unstructured":"Bruford EA, Braschi B, Haim-Vilmovsky L, Jones TEM, Seal RL, Tweedie S. The importance of being the HGNC. Hum Genomics. 2022;16(1). https:\/\/doi.org\/10.1186\/s40246-022-00432-w.","DOI":"10.1186\/s40246-022-00432-w"},{"issue":"6","key":"4486_CR23","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1002\/ajmg.a.61124","volume":"179","author":"CR Ferreira","year":"2019","unstructured":"Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179(6):885\u201392. 10.1002. \/AJMG.A.61124;JOURNAL:JOURNAL:10968628;PAGE:STRING:ARTICLE\/CHAPTER.","journal-title":"Am J Med Genet A"},{"issue":"1","key":"4486_CR24","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/jimd.12315","volume":"44","author":"S Stockler-Ipsiroglu","year":"2021","unstructured":"Stockler-Ipsiroglu S, Potter BK, Yuskiv N, Tingley K, Patterson M, van Karnebeek C. Developments in evidence creation for treatments of inborn errors of metabolism. J Inherit Metab Dis. 2021;44(1):88\u201398. https:\/\/doi.org\/10.1002\/jimd.12315.","journal-title":"J Inherit Metab Dis"},{"issue":"8","key":"4486_CR25","doi-asserted-by":"publisher","first-page":"1798","DOI":"10.1111\/bph.12456","volume":"171","author":"M Kanabus","year":"2014","unstructured":"Kanabus M, Heales SJ, Rahman S. Development of pharmacological strategies for mitochondrial disorders. Br J Pharmacol. 2014;171(8):1798\u2013817. https:\/\/doi.org\/10.1111\/bph.12456.","journal-title":"Br J Pharmacol"},{"issue":"6","key":"4486_CR26","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1007\/s11940-014-0292-7","volume":"16","author":"S Avula","year":"2014","unstructured":"Avula S, Parikh S, Demarest S, Kurz J, Gropman A. Treatment of Mitochondrial Disorders. Curr Treat Options Neurol. 2014;16(6):292. https:\/\/doi.org\/10.1007\/s11940-014-0292-7.","journal-title":"Curr Treat Options Neurol"},{"issue":"1","key":"4486_CR27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.4103\/0971-5916.154489","volume":"141","author":"NA Khan","year":"2015","unstructured":"Khan NA, Govindaraj P, Meena AK, Thangaraj K. Mitochondrial disorders: Challenges in diagnosis & treatment. Indian J Med Res. 2015;141(1):13. https:\/\/doi.org\/10.4103\/0971-5916.154489.","journal-title":"Indian J Med Res"},{"key":"4486_CR28","unstructured":"Gandhi G, Aliyev E, Syed N, Vempalli F, Saad C, Mbarek H, et al. Mapping the genetic landscape of treatable inherited metabolic disorders in a large Middle Eastern biobank. Elsevier. https:\/\/www.gimjournal.org\/article\/S1098-3600(24)00202-8\/fulltext. Accessed December 8, 2025."}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04486-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04486-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04486-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:02:25Z","timestamp":1791316945000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13023-026-04486-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4486"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04486-0","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-9355661\/v1","asserted-by":"object"}]},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]},"assertion":[{"value":"8 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors give consent for the publication of this article.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"335"}}