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.

Department of Cell and Molecular Pharmacology Medical University of South Carolina Charleston South Carolina

Department of Pharmaceutical Sciences University of Toronto Toronto Ontario Canada

Dominick P Purpura Department of Neuroscience Rose F Kennedy Intellectual and Developmental Disabilities Research Center Albert Einstein College of Medicine Bronx New York

Dominick P Purpura Department of Neuroscience Rose F Kennedy Intellectual and Developmental Disabilities Research Center Albert Einstein College of Medicine Bronx New York; Institute of Inherited Metabolic Disorders Charles University 1st Faculty of Medicine Prague Czech Republic; Institute of Pathology Charles University 1st Faculty of Medicine Prague Czech Republic

INSERM UMR1037 Cancer Research Center of Toulouse Universite Toulouse 3 Paul Sabatier Toulouse France; Metabolic Biochemistry Laboratory Federative Institute of Biology Centre Hospitalier Universitaire de Toulouse Toulouse France

Institute of Medical Science University of Toronto Toronto Ontario Canada

Institute of Medical Science University of Toronto Toronto Ontario Canada; University Health Network Toronto Ontario Canada; Department of Medical Biophysics University of Toronto Toronto Ontario Canada; Medical College of Wisconsin Milwaukee Wisconsin

MetaToul Lipidomic Facility MetaboHUB INSERM UMR1048 Institute of Cardiovascular and Metabolic Diseases Université Paul Sabatier Toulouse 3 Toulouse France

Research Unit on Bioactive Molecules Department of Biomedicinal Chemistry Institute for Advanced Chemistry of Catalonia Spanish National Research Council Barcelona Spain

University Health Network Toronto Ontario Canada

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