{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:03:09Z","timestamp":1790863389101,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Neuronopathic lysosomal storage disorders remain difficult to treat because conventional enzyme replacement therapies generally do not reach therapeutically meaningful concentrations in the central nervous system. Miglustat (1,5-(butylimino)-1,5-dideoxy-D-glucitol; N-butyl-deoxynojirimycin) is an orally administered iminosugar that crosses the blood\u2013brain barrier and reduces glycosphingolipid synthesis through inhibition of glucosylceramide synthase. This narrative review evaluated the biological rationale, clinical evidence, and limitations of miglustat repurposing across neuronopathic lysosomal storage disorders. PubMed\/MEDLINE was searched from inception through 31 July 2026, with backward citation searching. Miglustat has established clinical benefit in Niemann\u2013Pick disease type C, whereas a randomized trial in Gaucher disease type 3 did not demonstrate neurological efficacy. Evidence in GM1 gangliosidosis, Sandhoff disease, mucolipidosis type IV, and CLN3 disease is encouraging but limited to preclinical studies, small uncontrolled series, or individual reports; controlled studies in late-onset Tay\u2013Sachs disease and mucopolysaccharidosis type III were negative. Central nervous system penetration and biochemical target engagement therefore cannot be equated with clinical disease modification. Future repurposing should require disease-specific mechanistic justification, pharmacodynamic biomarkers, natural-history comparators, and intervention before irreversible neurodegeneration.<\/jats:p>","DOI":"10.3390\/ijms27188336","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1849-8375","authenticated-orcid":false,"given":"Patryk","family":"Lipi\u0144ski","sequence":"first","affiliation":[{"name":"Third Department of Pediatrics, Center of Postgraduate Medical Education, 05-092 Dziekan\u00f3w Le\u015bny, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4042-7466","authenticated-orcid":false,"given":"Grzegorz","family":"W\u0119grzyn","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Biology, University of Gda\u0144sk, Wita Stwosza 59, 80-308 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1016\/B978-0-444-59565-2.00055-1","article-title":"Enzyme replacement therapy and substrate reduction therapy in lysosomal storage disorders with neurological expression","volume":"113","author":"Valayannopoulos","year":"2013","journal-title":"Handb. Clin. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1023\/A:1025902113005","article-title":"The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: A position statement","volume":"26","author":"Cox","year":"2003","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.2174\/157488906775245282","article-title":"Miglustat: Substrate reduction therapy for lysosomal storage disorders associated with primary central nervous system involvement","volume":"1","author":"Pastores","year":"2006","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1002\/ana.21491","article-title":"Randomized, controlled trial of miglustat in Gaucher\u2019s disease type 3","volume":"64","author":"Schiffmann","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8362","DOI":"10.1016\/S0021-9258(17)37202-2","article-title":"N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis","volume":"269","author":"Platt","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.ymthe.2022.11.015","article-title":"Targeting the central nervous system in lysosomal storage diseases: Strategies to deliver therapeutics across the blood\u2013brain barrier","volume":"31","author":"Critchley","year":"2023","journal-title":"Mol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1007\/s11011-017-0044-y","article-title":"The treatment of juvenile\/adult GM1 gangliosidosis with miglustat may reverse disease progression","volume":"32","author":"Deodato","year":"2017","journal-title":"Metab. Brain Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1371","DOI":"10.1002\/mgg3.1371","article-title":"Substrate reduction therapy with miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience","volume":"8","author":"Fischetto","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.2174\/138161208784705504","article-title":"Lysosomal storage diseases and the blood\u2013brain barrier","volume":"14","author":"Begley","year":"2008","journal-title":"Curr. Pharm. Des."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"26052","DOI":"10.1074\/jbc.M113.463562","article-title":"\u03b2-Glucosidase 2 (GBA2) activity and imino sugar pharmacology","volume":"288","author":"Ridley","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_11","unstructured":"(2026, August 19). Miglustat Dipharma 100 mg Hard Capsules. Summary of Product Characteristics. Electronic Medicines Compendium. Available online: https:\/\/www.medicines.org.uk\/emc\/product\/14618\/smpc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13023-015-0297-7","article-title":"A double-blind, randomized, placebo-controlled trial studying the effects of Saccharomyces boulardii on the gastrointestinal tolerability, safety, and pharmacokinetics of miglustat","volume":"10","author":"Remenova","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/S1474-4422(07)70194-1","article-title":"Miglustat for treatment of Niemann\u2013Pick C disease: A randomised controlled study","volume":"6","author":"Patterson","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.ymgme.2009.12.006","article-title":"Miglustat in adult and juvenile patients with Niemann\u2013Pick disease type C: Long-term data from a clinical trial","volume":"99","author":"Wraith","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.bbalip.2004.08.008","article-title":"Intracellular trafficking of Niemann\u2013Pick C proteins 1 and 2: Obligate components of subcellular lipid transport","volume":"1685","author":"Liscum","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1186\/s13023-023-02804-4","article-title":"Effects of miglustat therapy on neurological disorder and survival in early-infantile Niemann\u2013Pick disease type C: A national French retrospective study","volume":"18","author":"Freihuber","year":"2023","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.ymgme.2008.02.005","article-title":"Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis","volume":"94","author":"Speak","year":"2008","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nicoli, E.R., Annunziata, I., d\u2019Azzo, A., Platt, F.M., Tifft, C.J., and Stepien, K.M. (2021). GM1 gangliosidosis\u2014A mini-review. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.734878"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Leal, A.F., Benincore-Fl\u00f3rez, E., Solano-Galarza, D., Garz\u00f3n Jaramillo, R.G., Echeverri-Pe\u00f1a, O.Y., Suarez, D.A., Alm\u00e9ciga-D\u00edaz, C.J., and Espejo-Mojica, A.J. (2020). GM2 gangliosidoses: Clinical features, pathophysiological aspects, and current therapies. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints202007.0137.v2"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6388","DOI":"10.1073\/pnas.96.11.6388","article-title":"Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin","volume":"96","author":"Jeyakumar","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.nbd.2004.04.012","article-title":"Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease","volume":"16","author":"Andersson","year":"2004","journal-title":"Neurobiol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1097\/GIM.0b013e3181a1b5c5","article-title":"Miglustat in late-onset Tay\u2013Sachs disease: A 12-month, randomized, controlled clinical study with 24 months of extended treatment","volume":"11","author":"Shapiro","year":"2009","journal-title":"Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S355","DOI":"10.1007\/s10545-010-9186-3","article-title":"Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: Results of a 3-year follow-up","volume":"33","author":"Masciullo","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/cne.20355","article-title":"Differential subcellular localization of cholesterol, gangliosides, and glycosaminoglycans in murine models of mucopolysaccharide storage disorders","volume":"480","author":"McGlynn","year":"2004","journal-title":"J. Comp. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ymgme.2016.04.002","article-title":"N-butyldeoxynojirimycin treatment restores the innate fear response and improves learning in mucopolysaccharidosis IIIA mice","volume":"118","author":"Kaidonis","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.jpeds.2011.04.040","article-title":"Evaluation of miglustat treatment in patients with type III mucopolysaccharidosis: A randomized, double-blind, placebo-controlled study","volume":"159","author":"Guffon","year":"2011","journal-title":"J. Pediatr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.nbd.2017.06.003","article-title":"N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV","volume":"105","author":"Boudewyn","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"135944","DOI":"10.1016\/j.neulet.2021.135944","article-title":"Progress in elucidating pathophysiology of mucolipidosis IV","volume":"755","author":"Misko","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/ddrr.1118","article-title":"The neuronal ceroid-lipofuscinoses","volume":"17","author":"Bennett","year":"2013","journal-title":"Dev. Disabil. Res. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e214110","DOI":"10.1212\/WNL.0000000000214110","article-title":"Long-term open-label study evaluating oral miglustat treatment in patients with neuronal ceroid lipofuscinosis type 3","volume":"105","author":"Pietrafusa","year":"2025","journal-title":"Neurology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e214224","DOI":"10.1212\/WNL.0000000000214224","article-title":"Is miglustat an effective treatment for CLN3 (Batten) disease?","volume":"105","author":"Mink","year":"2025","journal-title":"Neurology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1177\/08830738251374538","article-title":"Visual recovery and neurological stabilization following miglustat treatment in pediatric CLN3 disease","volume":"41","author":"Dutton","year":"2026","journal-title":"J. Child Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Doccini, S., Marchese, M., Morani, F., Gammaldi, N., Mero, S., Pezzini, F., Soliymani, R., Santi, M., Signore, G., and Ogi, A. (2022). Lysosomal proteomics links disturbances in lipid homeostasis and sphingolipid metabolism to CLN5 disease. Cells, 11.","DOI":"10.3390\/cells11111840"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ejpn.2025.05.010","article-title":"Gene therapy in neuronopathic lysosomal storage disorders","volume":"57","author":"Donald","year":"2025","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Cyske, Z., Radzanowska-Alenowicz, E., Rintz, E., Gaffke, L., and Pierzynowska, K. (2025). The rare disease burden: A multidimensional challenge. Acta Biochim. Pol., 72.","DOI":"10.3389\/abp.2025.14777"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8336\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:31:43Z","timestamp":1790861503000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8336"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,19]]},"references-count":35,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188336"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188336","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,19]]}}}