Spinal muscular atrophy-like phenotype in a mouse model of acid ceramidase deficiency

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. Mice with the P361R mutation in the lysosomal ceramidase, Asah1, exhibit a spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME)-like phenotype and may be a valuable tool to evaluate future therapies for SMA-PME.

Automated summary

Mutations in the ASAH1 gene are associated with two distinct disorders, Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). This study describes a mouse model with an SMA-PME-like phenotype (P361R-SMA) caused by a specific mutation in the ASAH1 gene. The P361R-SMA mice show progressive ataxia, bladder dysfunction, demyelination, loss of axons, and altered sphingolipid levels in the spinal cords, providing a valuable tool for studying the effects of ASAH1 deficiency and evaluating potential therapies for SMA-PME.