{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:41:37Z","timestamp":1790329297182,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T00:00:00Z","timestamp":1620259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The identification of neurological disorders by next-generation sequencing (NGS)-based gene panels has helped clinicians understand the underlying physiopathology, resulting in personalized treatment for some rare diseases. While the phenotype of distinct neurogenetic disorders is generally well-known in childhood, in adulthood, the phenotype can be unspecific and make the standard diagnostic approach more complex. Here we present three unrelated adults with various neurological manifestations who were successfully diagnosed using NGS, allowing for the initiation of potentially life-changing treatments. A 63-year-old woman with progressive cognitive decline, pyramidal signs, and bilateral cataract was treated by chenodeoxycholic acid following the diagnosis of cerebrotendinous xanthomatosis due to a homozygous variant in CYP27A1. A 32-year-old man with adult-onset spastic paraplegia, in whom a variant in ABCD1 confirmed an X-linked adrenoleukodystrophy, was treated with corticoids for adrenal insufficiency. The third patient, a 28-year-old woman with early-onset developmental delay, epilepsy, and movement disorders was treated with a ketogenic diet following the identification of a variant in SLC2A1, confirming a glucose transporter type 1 deficiency syndrome. This case study illustrates the challenges in the timely diagnosis of medically actionable neurogenetic conditions, but also the considerable potential for improving patient health through modern sequencing technologies.<\/jats:p>","DOI":"10.3390\/genes12050695","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T11:10:27Z","timestamp":1620299427000},"page":"695","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["NGS-Based Diagnosis of Treatable Neurogenetic Disorders in Adults: Opportunities and Challenges"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9491-7597","authenticated-orcid":false,"given":"Jean-Marc","family":"Good","sequence":"first","affiliation":[{"name":"Division of Genetic Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isis","family":"Atallah","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4165-4804","authenticated-orcid":false,"given":"Mayte","family":"Castro Jimenez","sequence":"additional","affiliation":[{"name":"Division of Neurology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1049-9533","authenticated-orcid":false,"given":"David","family":"Benninger","sequence":"additional","affiliation":[{"name":"Division of Neurology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7788-1673","authenticated-orcid":false,"given":"Thierry","family":"Kuntzer","sequence":"additional","affiliation":[{"name":"Division of Neurology, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3543-7531","authenticated-orcid":false,"given":"Andrea","family":"Superti-Furga","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4158-536X","authenticated-orcid":false,"given":"Christel","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pediatrneurol.2016.07.010","article-title":"Treatment of Neurogenetic Developmental Conditions: From 2016 into the Future","volume":"65","author":"Bowden","year":"2016","journal-title":"Pediatr. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/mds.27140","article-title":"Treatable inherited rare movement disorders","volume":"33","author":"Jinnah","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1002\/mds.26158","article-title":"Treatable causes of cerebellar ataxia","volume":"30","author":"Zeigler","year":"2015","journal-title":"Mov. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/S0140-6736(53)90473-5","article-title":"Influence of phenylalanine intake on phenylketonuria","volume":"265","author":"Bickel","year":"1953","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/ncpneuro0494","article-title":"Therapy Insight: Inborn errors of metabolism in adult neurology\u2014A clinical approach focused on treatable diseases","volume":"3","author":"Sedel","year":"2007","journal-title":"Nat. Clin. Pr. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.neurol.2016.04.005","article-title":"Classifications of neurogenetic diseases: An increasingly complex problem","volume":"172","author":"Vallat","year":"2016","journal-title":"Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17154","DOI":"10.1038\/srep17154","article-title":"Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia","volume":"5","author":"Cho","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","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":"ref_9","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1055\/s-0032-1315433","article-title":"Glucose Transporter-1 (GLUT1) Deficiency Syndrome: Diagnosis and Treatment in Late Childhood","volume":"43","author":"Gramer","year":"2012","journal-title":"Neuropediatrics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1097\/WNF.0b013e318288076a","article-title":"Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: Early versus late diagnosis","volume":"36","author":"Yahalom","year":"2013","journal-title":"Clin. Neuropharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s10545-017-0093-8","article-title":"Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)","volume":"40","author":"Salen","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s10545-013-9674-3","article-title":"A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis","volume":"37","author":"Mignarri","year":"2014","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","first-page":"100719","article-title":"Spinal cerebrotendinous xanthomatosis: A case report and literature review","volume":"26","author":"Atallah","year":"2021","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1146\/annurev-genom-083118-014915","article-title":"Genomic Data Sharing for Novel Mendelian Disease Gene Discovery: The Matchmaker Exchange","volume":"21","author":"Azzariti","year":"2020","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/humu.22858","article-title":"The Matchmaker Exchange: A Platform for Rare Disease Gene Discovery","volume":"36","author":"Philippakis","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1055\/s-2005-872843","article-title":"Seizure Control and Acceptance of the Ketogenic Diet in GLUT1 Deficiency Syndrome: A 2- to 5-Year Follow-Up of 15 Children Enrolled Prospectively","volume":"36","author":"Klepper","year":"2005","journal-title":"Neuropediatrics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/mds.20660","article-title":"Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet","volume":"21","author":"Friedman","year":"2006","journal-title":"Mov. Disord."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1056\/NEJM199109053251006","article-title":"Defective Glucose Transport across the Blood-Brain Barrier as a Cause of Persistent Hypoglycorrhachia, Seizures, and Developmental Delay","volume":"325","author":"Trifiletti","year":"1991","journal-title":"New Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/ng0298-188","article-title":"GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier","volume":"18","author":"Seidner","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"270","DOI":"10.3109\/13816810.2015.1010736","article-title":"Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull\u2019s Eye Maculopathy","volume":"36","author":"Collison","year":"2013","journal-title":"Ophthalmic Genet."},{"key":"ref_21","first-page":"525","article-title":"Hereditary Spastic Paraplegia: Clinical and Genetic Hallmarks","volume":"16","author":"Bortholin","year":"2016","journal-title":"Cerebellum"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/brain\/awx016","article-title":"Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy","volume":"140","author":"Suarez","year":"2017","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.cell.2014.02.002","article-title":"A Genotype-First Approach to Defining the Subtypes of a Complex Disease","volume":"156","author":"Stessman","year":"2014","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1056\/NEJMe0806570","article-title":"Cytogenetic technology--genotype and phenotype","volume":"359","author":"Ledbetter","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s12471-019-1251-4","article-title":"Large next-generation sequencing gene panels in genetic heart disease: Challenges in clinical practice","volume":"27","author":"Christiaans","year":"2019","journal-title":"Neth. Hear. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1042\/CS20180436","article-title":"Recent developments in genetic\/genomic medicine","volume":"133","author":"Horton","year":"2019","journal-title":"Clin. Sci."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/5\/695\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:57:34Z","timestamp":1760162254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/5\/695"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,6]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["genes12050695"],"URL":"https:\/\/doi.org\/10.3390\/genes12050695","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,6]]}}}