1. Spinal muscular atrophy-like phenotype in a mouse model of acid ceramidase deficiency.
- Author
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Nagree MS, Rybova J, Kleynerman A, Ahrenhoerster CJ, Saville JT, Xu T, Bachochin M, McKillop WM, Lawlor MW, Pshezhetsky AV, Isaeva O, Budde MD, Fuller M, and Medin JA
- Subjects
- Distal Myopathies, Phenotype, Humans, Myoclonus congenital, Animals, Sphingolipids metabolism, Mice, Myoclonic Epilepsies, Progressive genetics, Myoclonic Epilepsies, Progressive pathology, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal pathology, Farber Lipogranulomatosis genetics, Farber Lipogranulomatosis metabolism, Farber Lipogranulomatosis pathology
- Abstract
Mutations in ASAH1 have been linked to two allegedly distinct disorders: Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). We have previously reported FD-like phenotypes in mice harboring a single amino acid substitution in acid ceramidase (ACDase), P361R, known to be pathogenic in humans (P361R-Farber). Here we describe a mouse model with an SMA-PME-like phenotype (P361R-SMA). P361R-SMA mice live 2-3-times longer than P361R-Farber mice and have different phenotypes including progressive ataxia and bladder dysfunction, which suggests neurological dysfunction. We found profound demyelination, loss of axons, and altered sphingolipid levels in P361R-SMA spinal cords; severe pathology was restricted to the white matter. Our model can serve as a tool to study the pathological effects of ACDase deficiency on the central nervous system and to evaluate potential therapies for SMA-PME., (© 2023. The Author(s).)
- Published
- 2023
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