Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.

• Keywords
• Farber disease, HSCT, Lysosomal storage disorders, central nervous system, ceramides, spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME),
• MeSH
• Ceramides metabolism   MeSH
• Farber Lipogranulomatosis * therapy   genetics   MeSH
• Acid Ceramidase * genetics   metabolism   MeSH
• Humans MeSH
• Spinal Cord metabolism   pathology   MeSH
• Disease Models, Animal MeSH
• Myoclonic Epilepsies, Progressive genetics   therapy   metabolism   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Hematopoietic Stem Cell Transplantation * methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Asah1 protein, mouse MeSH Browser
• Ceramides MeSH
• Acid Ceramidase * MeSH

Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1-/-), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans.

• Keywords
• Glycosphingolipids, Lysosomal storage disease, Miglustat, Mucolipidosis type IV, Mucolipin-1, Purkinje cells, Small molecule therapy,
• MeSH
• 1-Deoxynojirimycin analogs & derivatives   therapeutic use   MeSH
• Antigens, CD metabolism   MeSH
• Gliosis drug therapy   etiology   MeSH
• Enzyme Inhibitors therapeutic use   MeSH
• Transient Receptor Potential Channels genetics   metabolism   MeSH
• Lipid Metabolism drug effects   genetics   MeSH
• Disease Models, Animal MeSH
• Cerebellum pathology   MeSH
• Mucolipidoses * complications   genetics   pathology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Exploratory Behavior drug effects   MeSH
• Cell Count MeSH
• Movement Disorders drug therapy   etiology   MeSH
• Nerve Tissue Proteins metabolism   MeSH
• Psychomotor Performance drug effects   MeSH
• Purkinje Cells drug effects   pathology   MeSH
• Retina pathology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 1-Deoxynojirimycin MeSH
• Antigens, CD MeSH
• Enzyme Inhibitors MeSH
• Transient Receptor Potential Channels MeSH
• Mcoln1 protein, mouse MeSH Browser
• miglustat MeSH Browser
• Nerve Tissue Proteins MeSH