Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1P361R/P361R mice. Asah1P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1P361R/P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Cell Biology Neurobiology and Anatomy Medical College of Wisconsin Milwaukee Wisconsin

Department of Cell Biology Neurobiology and Anatomy Medical College of Wisconsin Milwaukee Wisconsin; Department of Ophthalmology and Visual Sciences Medical College of Wisconsin Milwaukee Wisconsin

Department of Cell Biology Neurobiology and Anatomy Medical College of Wisconsin Milwaukee Wisconsin; Department of Ophthalmology and Visual Sciences Medical College of Wisconsin Milwaukee Wisconsin; Nuffield Laboratory of Ophthalmology University of Oxford Oxford United Kingdom

Department of Pediatrics Medical College of Wisconsin Milwaukee Wisconsin; Department of Medical Biophysics University of Toronto Toronto Ontario Canada

Institute of Medical Science University of Toronto Toronto Ontario Canada; Department of Pediatrics Medical College of Wisconsin Milwaukee Wisconsin

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

Rare Diseases Research Unit Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic; Institute of Pathology 1st Faculty of Medicine Charles University Prague Czech Republic

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