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Am J Pathol. 2018 Nov 22. pii: S0002-9440(18)30504-2. doi: 10.1016/j.ajpath.2018.10.018. [Epub ahead of print]

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment.

Author information

1
Institute of Medical Science, University of Toronto, Toronto Canada; Department of Pediatrics, Medical College of Wisconsin, Milwaukee USA.
2
Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee USA.
3
Rare Diseases Research Unit, Department of Pediatrics and Adolescent Medicine, Charles University, 1st Faculty of Medicine, Prague, Czech Republic; Institute of Pathology, Charles University, 1st Faculty of Medicine, Prague, Czech Republic.
4
Department of Pediatrics, Medical College of Wisconsin, Milwaukee USA; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
5
Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
6
Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee USA; Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin.
7
Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee USA; Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin; Nuffield Laboratory of Ophthalmology, University of Oxford, UK.
8
Institute of Medical Science, University of Toronto, Toronto Canada; Department of Pediatrics, Medical College of Wisconsin, Milwaukee USA; Department of Medical Biophysics, University of Toronto, Toronto, Canada; Department of Biochemistry, Medical College of Wisconsin, Milwaukee USA; University Health Network, Toronto, Canada. Electronic address: jmedin@mcw.edu.

Abstract

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 classical 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 non-invasive 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.

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