{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T03:46:55Z","timestamp":1787370415511,"version":"build-2736575974"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016062","name":"Stichting Metakids","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background\/Objectives<\/jats:title><jats:p>The timely diagnosis of inherited metabolic disorders (IMD) is essential for initiating treatment, prognostication and genetic testing of relatives. Recognition of IMD in adults is difficult, because phenotypes are different from those in children and influenced by symptoms from acquired conditions. This systematic literature review aims to answer the following questions: (1) What is the diagnostic yield of exome\/genome sequencing (ES\/GS) for IMD in adults with unsolved phenotypes? (2) What characteristics do adult patients diagnosed with IMD through ES\/GS have?<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A systematic search was conducted using the following search terms (simplified): \u201cWhole exome sequencing (WES),\u201d \u201cWhole genome sequencing (WGS),\u201d \u201cIMD,\u201d \u201cdiagnostics\u201d and the 1,450 known metabolic genes derived from ICIMD. Data from 695 articles, including 27,702 patients, were analyzed using two different methods. First, the diagnostic yield for IMD in patients presenting with a similar phenotype was calculated. Secondly, the characteristics of patients diagnosed with IMD through ES\/GS in adulthood were established.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The diagnostic yield of ES and\/or GS for adult patients presenting with unexplained neurological symptoms is 11% and for those presenting with dyslipidemia, diabetes, auditory and cardiovascular symptoms 10, 9, 8 and 7%, respectively. IMD patients diagnosed in adulthood (n = 1,426), most frequently portray neurological symptoms (65%), specifically extrapyramidal\/cerebellar symptoms (57%), intellectual disability\/dementia\/psychiatric symptoms (41%), pyramidal tract symptoms\/myelopathy (37%), peripheral neuropathy (18%), and epileptic seizures (16%). The second most frequently observed symptoms were ophthalmological (21%). In 47% of the IMD diagnosed patients, symptoms from multiple organ systems were reported. On average, adult patients are diagnosed 15 years after first presenting symptoms. Disease-related abnormalities in metabolites in plasma, urine or cerebral spinal fluid were identified in 40% of all patients whom underwent metabolic screening. In 52% the diagnosis led to identification of affected family members with the same IMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>ES and\/or GS is likely to yield an IMD diagnosis in adult patients presenting with an unexplained neurological phenotype, as well as in patients with a phenotype involving multiple organ systems. If a gene panel does not yield a conclusive diagnosis, it is worthwhile to analyze all known disease genes. Further prospective research is needed to establish the best diagnostic approach (type and sequence of metabolic and genetic test) in adult patients presenting with a wide range of symptoms, suspected of having an IMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic review registration<\/jats:title><jats:p><jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>, identifier: CRD42021295156.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2023.1206106","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T22:14:05Z","timestamp":1690323245000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Inherited metabolic disorders in adults: systematic review on patient characteristics and diagnostic yield of broad sequencing techniques (exome and genome sequencing)"],"prefix":"10.3389","volume":"14","author":[{"given":"Elise A.","family":"Ferreira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J. N.","family":"Buijs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Wijngaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost G.","family":"Daams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareen R.","family":"Datema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Engelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara D. M. van","family":"Karnebeek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Machteld M.","family":"Oud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric M.","family":"Vaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam M. C.","family":"Wamelink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia N. van der","family":"Crabben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Langeveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1002\/jimd.12348","article-title":"An international classification of inherited metabolic disorders (ICIMD)","volume":"44","author":"Ferreira","year":"2021","journal-title":"J Inherit Metab Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1007\/s10545-017-0128-1","article-title":"The role of the clinician in the multi-omics era: are you ready?","volume":"41","author":"van Karnebeek","year":"2018","journal-title":"J Inherit Metab Dis."},{"key":"B3","first-page":"20","article-title":"Recognition and diagnostic approach to acute metabolic disorders in the neonatal period","volume":"11","author":"Mohamed","year":"2011","journal-title":"Sudan J Paediatr."},{"key":"B4","doi-asserted-by":"publisher","first-page":"271","DOI":"10.4103\/0256-4947.65254","article-title":"Incidence and patterns of inborn errors of metabolism in the Eastern Province of Saudi Arabia, 1983-2008","volume":"30","author":"Moammar","year":"2010","journal-title":"Ann Saudi Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1053\/siny.2001.0083","article-title":"Clinical approach to inherited metabolic disorders in neonates: an overview","volume":"7","author":"Saudubray","year":"2002","journal-title":"Semin Neonatol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/8904_2015_435","article-title":"The frequencies of different inborn errors of metabolism in adult metabolic centres: report from the ssiem adult metabolic physicians group","volume":"27","author":"Sirrs","year":"2016","journal-title":"JIMD Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.ymgmr.2017.01.011","article-title":"Clinical characteristics of adult patients with inborn errors of metabolism in Spain: A review of 500 cases from university hospitals","volume":"10","author":"Perez-Lopez","year":"2017","journal-title":"Mol Genet Metab Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s13023-020-01471-z","article-title":"Clouds over IMD? perspectives for inherited metabolic diseases in adults from a retrospective cohort study in two swiss adult metabolic clinics","volume":"15","author":"Gariani","year":"2020","journal-title":"Orphanet J Rare Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"467","DOI":"10.21037\/atm.2018.11.36","article-title":"Inborn errors of metabolism in the 21(st) century: past to present","volume":"6","author":"Arnold","year":"2018","journal-title":"Ann Transl Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"102784","DOI":"10.1016\/j.ebiom.2020.102784","article-title":"Genetics of mitochondrial diseases: Identifying mutations to help diagnosis","volume":"56","author":"Stenton","year":"2020","journal-title":"EBioMedicine."},{"key":"B11","doi-asserted-by":"publisher","first-page":"100344","DOI":"10.1016\/j.lanwpc.2021.100344","article-title":"Prevalence of lysosomal storage disorders in Australia from 2009 to 2020","volume":"19","author":"Chin","year":"2022","journal-title":"Lancet Reg Health West Pac."},{"key":"B12","doi-asserted-by":"publisher","first-page":"106","DOI":"10.4103\/aian.aian_333_21","article-title":"Mutation spectrum of primary lipid storage myopathies","volume":"25","author":"Vengalil","year":"2022","journal-title":"Ann Indian Acad Neurol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1086\/302261","article-title":"Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency","volume":"64","author":"Andresen","year":"1999","journal-title":"Am J Hum Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1093\/brain\/awl260","article-title":"The adult form of Niemann-Pick disease type C","volume":"130","author":"Sevin","year":"2007","journal-title":"Brain."},{"key":"B15","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1212\/CPJ.0000000000000379","article-title":"\u201cThink metabolic\u201d in adults with diagnostic challenges: Biotinidase deficiency as a paradigm disorder","volume":"7","author":"Wolf","year":"2017","journal-title":"Neurol Clin Pract."},{"key":"B16","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan-a web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst Rev."},{"key":"B17","author":"Capture","year":"2019","journal-title":"CASTOR EDC"},{"key":"B18","doi-asserted-by":"publisher","first-page":"D865","DOI":"10.1093\/nar\/gkw1039","article-title":"The human phenotype ontology in 2017","volume":"45","author":"Kohler","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B19","first-page":"706","article-title":"Mutational screening of AGRN, SLC39A5, SCO2, P4HA2, BSG, ZNF644, and CPSF1 in a Chinese cohort of 103 patients with nonsyndromic high myopia","volume":"27","author":"Zheng","year":"2021","journal-title":"Mol Vis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"100653","DOI":"10.1016\/j.ymgmr.2020.100653","article-title":"The diagnosis of inborn errors of metabolism in previously undiagnosed adults referred for medical genetics evaluation","volume":"25","author":"Lee","year":"2020","journal-title":"Mol Genet Metab Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1007\/s00428-019-02633-6","article-title":"Update on polyglucosan storage diseases","volume":"475","author":"Cenacchi","year":"2019","journal-title":"Virchows Arch."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e86340","DOI":"10.1371\/journal.pone.0086340","article-title":"Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions","volume":"9","author":"Wedding","year":"2014","journal-title":"PLoS One."},{"key":"B24","doi-asserted-by":"publisher","first-page":"102320","DOI":"10.1016\/j.jbc.2022.102320","article-title":"The ARSACS disease protein sacsin controls lysosomal positioning and reformation by regulating microtubule dynamics","volume":"298","author":"Francis","year":"2022","journal-title":"J Biol Chem"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1056\/NEJMoa2035790","article-title":"100,000 genomes pilot on rare-disease diagnosis in health care\u2014preliminary report","volume":"385","author":"Investigators","year":"2021","journal-title":"n Engl J Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1002\/jimd.12507","article-title":"How to proceed after \u201cnegative\u201d exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques","volume":"45","author":"Wortmann","year":"2022","journal-title":"J Inherit Metab Dis."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1206106\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T22:14:13Z","timestamp":1690323253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1206106\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,25]]},"references-count":26,"alternative-id":["10.3389\/fneur.2023.1206106"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1206106","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,25]]},"article-number":"1206106"}}