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Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment. Am J Pathol 2019 02;189(2):320-338

Date

11/26/2018

Pubmed ID

30472209

Pubmed Central ID

PMC6412726

DOI

10.1016/j.ajpath.2018.10.018

Scopus ID

2-s2.0-85060099082   10 Citations

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 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.

Author List

Yu FPS, Sajdak BS, Sikora J, Salmon AE, Nagree MS, Gurka J, Kassem IS, Lipinski DM, Carroll J, Medin JA

Authors

Joseph J. Carroll PhD Director, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Iris S. Kassem MD, PhD Associate Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Daniel M. Lipinski PhD Associate Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acid Ceramidase
Amino Acid Substitution
Animals
Ceramides
Disease Models, Animal
Farber Lipogranulomatosis
Inflammation
Mice
Mice, Mutant Strains
Mutation, Missense
Optic Nerve
Retina
Sphingolipids
Vision Disorders