{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T05:20:39Z","timestamp":1766726439027,"version":"3.48.0"},"reference-count":37,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Neurometabolic diseases encompass a diverse group of rare and often progressive genetic disorders affecting the nervous system due to abnormalities in metabolic pathways. These conditions, including mitochondrial disorders, lysosomal storage diseases, and others, can manifest in adults with a range of neurological symptoms, which will be reviewed here. Given their complexity and chronic nature, comprehensive management is crucial for improving patients\u2019 quality of life. In this Invited Perspective, we review the neurological signs and symptoms of the most commonly encountered inherited metabolic disorders in adult neurology. Furthermore, drawing on our clinical experience, we demonstrate that an integrated local care approach is fundamental for these patients, as it enables continuous monitoring, early intervention, and coordinated multidisciplinary support.<\/jats:p>","DOI":"10.3390\/jcm15010146","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T16:41:19Z","timestamp":1766594479000},"page":"146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Clinical Burden of Inherited Neurometabolic Disorders in Adults\u2014A Territorial Care Approach"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4847-7812","authenticated-orcid":false,"given":"Daniele","family":"Orsucci","sequence":"first","affiliation":[{"name":"Unit of Neurology, San Luca Hospital, 55100 Lucca, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Caldarazzo Ienco","sequence":"additional","affiliation":[{"name":"Unit of Neurology, San Luca Hospital, 55100 Lucca, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Giuntini","sequence":"additional","affiliation":[{"name":"Unit of Neurology, San Luca Hospital, 55100 Lucca, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Vista","sequence":"additional","affiliation":[{"name":"Unit of Neurology, San Luca Hospital, 55100 Lucca, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102587","DOI":"10.1016\/j.cpcardiol.2024.102587","article-title":"Cardiac manifestations in inherited metabolic diseases","volume":"49","year":"2024","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/jnnp-2021-328045","article-title":"Diagnostic approach in adult-onset neurometabolic diseases","volume":"93","author":"Carreau","year":"2022","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lopriore, P., Vista, M., Tessa, A., Giuntini, M., Caldarazzo Ienco, E., Mancuso, M., Siciliano, G., Santorelli, F.M., and Orsucci, D. (2024). Primary Coenzyme Q10 Deficiency-Related Ataxias. J. Clin. Med., 13.","DOI":"10.3390\/jcm13082391"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/j.numecd.2024.07.017","article-title":"Towards needed improvements in inherited metabolic medicine in adulthood: The SIMMESN adult metabolic working group and MetabERN Joint Position Statement","volume":"34","author":"Sechi","year":"2024","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","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":"ref_6","doi-asserted-by":"crossref","first-page":"115073","DOI":"10.1016\/j.expneurol.2024.115073","article-title":"Disease registries and rare disorders: The virtuous example of mitochondrial medicine","volume":"384","author":"Orsucci","year":"2025","journal-title":"Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1002\/jimd.12438","article-title":"Phenotype and genotype of 197 British patients with McArdle disease: An observational single-centre study","volume":"44","author":"Pizzamiglio","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ymgme.2022.09.004","article-title":"Clinical and biochemical footprints of inherited metabolic disorders: X. Metabolic myopathies","volume":"137","author":"Angelini","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Orsucci, D., Caldarazzo Ienco, E., Rossi, A., Siciliano, G., and Mancuso, M. (2021). Mitochondrial Syndromes Revisited. J. Clin. Med., 10.","DOI":"10.3390\/jcm10061249"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.jacc.2022.08.716","article-title":"Cardiac Outcomes in Adults With Mitochondrial Diseases","volume":"80","author":"Savvatis","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e18293","DOI":"10.1111\/jcmm.18293","article-title":"Charcot-Marie-Tooth type 2A in vivo models: Current updates","volume":"28","author":"Abati","year":"2024","journal-title":"J. Cell. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s10048-008-0168-7","article-title":"A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated","volume":"10","author":"Hornemann","year":"2009","journal-title":"Neurogenetics"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Cotrina, M.L., Morgenstein, B., Perez, M., Norcliffe-Kaufmann, L., Palma, J.A., and Kaufmann, H. (2023). Height, weight, and body mass index in patients with familial dysautonomia. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0293800"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Filosto, M., Cotti Piccinelli, S., Caria, F., Gallo Cassarino, S., Baldelli, E., Galvagni, A., Volonghi, I., Scarpelli, M., and Padovani, A. (2018). Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE-MTDPS1). J. Clin. Med., 7.","DOI":"10.3390\/jcm7110389"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1093\/brain\/awab056","article-title":"Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy","volume":"144","author":"Bonora","year":"2021","journal-title":"Brain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1136\/jnnp-2017-316961","article-title":"Beyond motor neurons: Expanding the clinical spectrum in Kennedy\u2019s disease","volume":"89","author":"Manzano","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ymgme.2022.02.002","article-title":"Clinical and biochemical footprints of inherited metabolic disorders. VII. Ocular phenotypes","volume":"135","author":"Garanto","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1093\/brain\/awp158","article-title":"Gene\u2013environment interactions in Leber hereditary optic neuropathy","volume":"132","author":"Kirkman","year":"2009","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.1016\/j.ajhg.2021.09.015","article-title":"Establishing risk of vision loss in Leber hereditary optic neuropathy","volume":"108","author":"Kearns","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1093\/brain\/awq007","article-title":"Multi-system neurological disease is common in patients with OPA1 mutations","volume":"133","author":"Griffiths","year":"2010","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ymgme.2022.09.005","article-title":"Clinical and biochemical footprints of inherited metabolic diseases. IX. Metabolic ear disease","volume":"137","author":"Bakhos","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1177\/0194599813482705","article-title":"The clinical and audiologic features of hearing loss due to mitochondrial mutations","volume":"148","author":"Yelverton","year":"2013","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3988\/jcn.2020.16.2.230","article-title":"Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia","volume":"16","author":"Zhan","year":"2020","journal-title":"J. Clin. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Giuntini, M., Picchi, L., Cafforio, G., Trovato, R., Santorelli, F.M., Vista, M., and Orsucci, D. (2025). A Novel Variant in GLRA1 Associated With Emotional Stimulus-Sensitive Hemichoreic Movements. Am. J. Med. Genet. A, e64297.","DOI":"10.1002\/ajmg.a.64297"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"109084","DOI":"10.1016\/j.ymgme.2025.109084","article-title":"Clinical and biochemical footprints of inherited metabolic diseases: Ia. Movement disorders, updated","volume":"145","author":"Peacock","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Vaisfeld, A., Bruno, G., Petracca, M., Bentivoglio, A.R., Servidei, S., Vita, M.G., Bove, F., Straccia, G., Dato, C., and Di Iorio, G. (2021). Neuroacanthocytosis Syndromes in an Italian Cohort: Clinical Spectrum, High Genetic Variability and Muscle Involvement. Genes, 12.","DOI":"10.3390\/genes12030344"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s00415-021-10697-1","article-title":"Adult-onset mitochondrial movement disorders: A national picture from the Italian Network","volume":"269","author":"Montano","year":"2021","journal-title":"J. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e200234","DOI":"10.1212\/NXG.0000000000200234","article-title":"Genetic and Phenotypic Variability in Siblings With Friedreich Ataxia","volume":"11","author":"Eshaghi","year":"2025","journal-title":"Neurol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Muthusamy, K., Sivadasan, A., Dixon, L., Sudhakar, S., Thomas, M., Danda, S., Wszolek, Z.K., Wierenga, K., Dhamija, R., and Gavrilova, R. (2023). Adult-onset leukodystrophies: A practical guide, recent treatment updates, and future directions. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1219324"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"122905","DOI":"10.1016\/j.jns.2024.122905","article-title":"Prevalence of Fabry disease and GLA variants in young patients with acute stroke: The challenge to widen the screening. The Fabry-Stroke Italian Registry","volume":"457","author":"Romani","year":"2024","journal-title":"J. Neurol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S1474-4422(21)00098-3","article-title":"Mitochondrial disease in adults: Recent advances and future promise","volume":"20","author":"Ng","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107690","DOI":"10.1016\/j.ymgme.2023.107690","article-title":"Clinical and biochemical footprints of inherited metabolic diseases. XV. Epilepsies","volume":"140","author":"Latzer","year":"2023","journal-title":"Mol. Genet. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s10048-019-00601-5","article-title":"Mitochondrial epilepsy: A cross-sectional nationwide Italian survey","volume":"21","author":"Ticci","year":"2020","journal-title":"Neurogenetics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108363","DOI":"10.1016\/j.ymgme.2024.108363","article-title":"Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency","volume":"142","author":"Latzer","year":"2024","journal-title":"Mol. Genet. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e70261","DOI":"10.1111\/cns.70261","article-title":"Neuronal Ceroid Lipofuscinosis\u2014Concepts, Classification, and Avenues for Therapy","volume":"31","author":"Zhang","year":"2025","journal-title":"CNS Neurosci. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1212\/CPJ.0000000000000266","article-title":"Neurometabolic disorders: Five new things","volume":"6","author":"Willemsen","year":"2016","journal-title":"Neurol. Clin. Pract."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1161\/01.STR.19.5.604","article-title":"Interobserver agreement for the assessment of handicap in stroke patients","volume":"19","author":"Koudstaal","year":"1988","journal-title":"Stroke"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/146\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T05:15:49Z","timestamp":1766726149000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/146"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,24]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["jcm15010146"],"URL":"https:\/\/doi.org\/10.3390\/jcm15010146","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2025,12,24]]}}}