Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1P361R/P361R mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy-ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma-like accumulations of storage-laden CD68+ microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1P361R/P361R mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder.

• MeSH
• Time Factors MeSH
• Central Nervous System abnormalities   pathology   MeSH
• Behavior, Animal MeSH
• Farber Lipogranulomatosis complications   pathology   MeSH
• Phenotype MeSH
• Homozygote MeSH
• Hydrocephalus pathology   MeSH
• Acid Ceramidase metabolism   MeSH
• Nervous System Malformations etiology   pathology   MeSH
• Cerebellum pathology   ultrastructure   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neurons pathology   ultrastructure   MeSH
• Motor Activity MeSH
• Sphingolipids metabolism   MeSH
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization MeSH
• Cerebrum pathology   ultrastructure   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Asah1 protein, mouse MeSH Browser
• Acid Ceramidase MeSH
• Sphingolipids MeSH