Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of...

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-brain 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-Pick 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-Sachs 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.