New mouse model may help in study of rare SMA type with seizures
New, targeted treatments may come from model of SMA-PME
Researchers have developed a new mouse model that exhibits the features of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy, or SMA-PME — a rare type of the rare disorder characterized by seizures that typically start during childhood.
The mice, which exhibited motor and sensory impairments, were found to have significant spinal cord damage and inflammation, but minimal brain involvement.
Scientists believe the new model can be used to further study the mechanisms underlying SMA-PME — and may help in developing new targeted treatments for the genetic disease.
“Our model can serve as a tool to study the pathological [disease-causing] effects of [a certain enzyme] deficiency on the central nervous system and to evaluate potential therapies for SMA-PME,” the team wrote.
The study, “Spinal muscular atrophy-like phenotype in a mouse model of acid ceramidase deficiency,” was published in Communications Biology.
A lack of preclinical models in SMA-PME
SMA-PME is a very rare and severe form of SMA, characterized by seizures that usually manifest in childhood in addition to the progressive muscle weakness typically found with the disorder. In contrast to the more common forms of SMA, which occur due to mutations in the SMN1 gene, SMA-PME is caused by mutations in the ASAH1 gene.
ASAH1 is responsible for producing acid ceramidase, known as ACDase, an enzyme that works to break down certain families of molecules called ceramides. These ceramides are the precursors to complex fat molecules called sphingolipids.
Mutations in the gene that result in SMA-PME cause an ACDase deficiency, which also is the cause of Farber disease, a very rare condition in which ceramides and related molecules build to toxic levels inside cells. While SMA-PME mostly affects the central nervous system, comprised of the brain and spinal cord, the symptoms of Farber tend to involve the rest of the body, or the periphery.
Because SMA-PME is so rare, there is a lack of knowledge about the cellular and MRI features of the disease — and preclinical models of the condition are lacking. The few mouse models of ACDase deficiency that exist exhibit characteristics related to Farber disease and don’t seem to reflect SMA-PME.
Now, researchers from the U.S., Australia, and Canada developed a new mouse model of ACDase deficiency that would look more similar to SMA-PME.
The scientists believed that such a model would not only contribute to the understanding of how ACDase deficiency leads to distinct diseases affecting the brain or periphery, but would also “facilitate development of targeted diagnostic approaches, as well as treatments, including gene therapies, and provide a valuable resource to test them.”
The team previously had developed a mouse model of Farber disease, called P361R-Farber, that houses a mutation in ASAH1 known to drive the disease in humans. Here, the team modified those mice in certain ways to create a model of SMA-PME, called P361R-SMA.
Interestingly, the P361R-SMA mice lived significantly longer than the original P361R-Farber mice, with a lifespan averaging 145 days compared with an average of 52 days.
Still, the SMA model exhibited predominant signs of neurological dysfunction, including gait changes or different ways of walking, abnormal spine curvature, tremors, and eventually, lower limb paralysis and bladder dysfunction.
Investigating mechanisms underlying SMA-PME
A range of tests of sensory-motor function indicated that the SMA mice had progressive motor dysfunction and muscle wasting, or atrophy. Sensory deficits, namely a reduced responsiveness to painful stimuli, also were observed.
Relative to their healthy counterparts, P361R-SMA mice were sensitized to a type of chemically-induced seizure activity called a myoclonic jerk, which is a behavioral correlate of a type of seizure that SMA-PME patients experience.
[These mice] allow the testing of treatments targeting the various affected organs [in SME-PME], and they facilitate studies on how to ameliorate combinations of phenotypes [symptoms].
A closer look at the brain tissue indicated that the mice exhibited only mild brain tissue injury, which the researchers believe is “unlikely to result in the severe neuronopathic phenotype [neurological symptoms] observed in P361R-SMA mice.”
The minimal brain involvement observed in the mice also is consistent with imaging studies in human patients, the team noted.
That prompted the scientists to investigate whether the neurological deficits in the SMA mice might instead be driven by damage to the spinal cord.
Indeed, the P361R-SMA mice exhibited severe and progressive spinal cord damage, including a strong loss of myelin and degeneration of myelinated nerve cell projections, or axons. Myelin is the protective coating around nerve fibers that prevents damage and helps in sending electrical signals efficiently.
Markers of cell death, inflammation, and scar tissue buildup known as fibrosis all were significantly increased. The scientists also found evidence that an immune cell type called macrophages were infiltrating the spinal cord and contributing to inflammatory damage.
Sphingolipids and ceramides were found to accumulate in the spleen and liver of the P361R-SMA mice, although not to the same degree as reported in P361R-Farber mice. Various species of these molecules also accumulated in the brain and spinal cord.
Altogether, the P361R-SMA mice, along with the P361R-Farber model, “provide a way to study the various types of pathology caused by ACDase-deficiency,” the researchers wrote.
Moreover, these mice “allow the testing of treatments targeting the various affected organs, and they facilitate studies on how to ameliorate combinations of phenotypes [symptoms],” the team concluded.