Liver issues may be common, understudied in SMA: Study
Researchers say SMA in patients should be treated as 'multi-organ disease'
Liver issues may be an understudied manifestation of spinal muscular atrophy (SMA), according to a new study suggesting liver involvement in patients warrants greater consideration during disease management.
Among a small group of SMA patients, three-quarters showed signs of fat accumulation in the liver, with a few also showing elevations in markers of liver damage, per the study, led by researchers in Singapore. Cell culture experiments indicated that SMA liver cells exhibit disturbed fat metabolism and cellular energy production.
Together, the findings lend support to the idea that SMA is not just a disorder of the nervous system, but should instead be considered “a multi-cellular and multi-organ disease,” according to the authors.
In the clinic, it should be treated as such, the scientists noted. That includes liver health monitoring and the development of SMA therapies able to act in the liver and other organs.
The study, “Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy,” was published in The Journal of Clinical Investigation.
SMA historically thought to affect only nervous system
SMA has historically been considered a disease of the nervous system. A lack of the SMN protein leads to the degeneration of motor nerve cells involved in muscle control, causing symptoms of progressive muscle weakness and wasting.
However, SMN is also found across all of the body’s other major organs, where its function is not entirely understood. Limited evidence suggests that SMA patients have multiorgan dysfunction beyond the nervous system.
Scientists previously had not focused on these non-neuronal manifestations of SMA, given that the most severely affected patients with SMA type 1 typically did not survive past the first few years of life.
But now, as patients live longer with the advent of effective disease-modifying therapies, impairments in organ function may become more relevant to patient care. Moreover, according to the scientists, there may be a need for treatments that specifically target those impairments.
One such organ is the liver, which serves a number of critical functions in the body. Signs of liver dysfunction and related issues are evident in mouse SMA models, but the clinical importance of these observations is not entirely clear.
Here, the team of scientists set out to learn more about liver defects in SMA by examining liver ultrasound findings and blood biomarkers of liver function in a group of eight patients with SMA types 1-3 who received SMA therapies.
Three-quarters of the patients — six of eight individuals — showed abnormalities on an ultrasound suggestive of mild to moderate fat accumulation in the liver. Fatty liver disease often starts without any symptoms, but can eventually lead to more significant liver damage.
Three of those in the study also had blood markers indicative of liver damage, namely elevations in certain liver enzymes.
For some patients, there may have been other explanations for liver damage beyond SMA. One was taking a medication that can damage liver cells, another was obese, and a third was a heavy alcohol user.
More research needed to reduce liver issues with SMA therapies
Liver cell models were derived from SMA patient stem cells. These cells showed marked reductions in SMN protein relative to healthy cells and about a tenfold increase in fat accumulation.
Genetic and protein analyses identified key processes that seemed to be affected, including fat metabolism and the function of mitochondria, the cell compartments involved in energy production. Additional functional experiments further showed that mitochondria were not working normally in the diseased liver cells.
These faulty cellular processes may contribute to fatty liver and liver dysfunction in SMA patients, the researchers noted. Engineering the SMA cells to restore more normal SMN levels corrected the abnormalities.
Given the apparent liver involvement in SMA, the scientists believe their findings support suggestions that comprehensive liver screening and preventive treatment against fatty liver should be part of routine SMA care — particularly before patients start on SMA therapies.
[Future studies into poor treatment responses could] allow early identification of vulnerable patients so appropriate clinical management plans can be made.
The approved SMA gene therapy Zolgensma can cause liver toxicity in the weeks after treatment, and Evrysdi, an oral SMA therapy, is processed in the liver. Underlying liver dysfunction and related issues could mean that certain patients will react poorly to treatment or won’t respond to it, the researchers pointed out.
Future studies aimed at identifying the liver characteristics associated with poor treatment responses could “allow early identification of vulnerable patients so appropriate clinical management plans can be made,” the researchers wrote.
The fact that SMA patients exhibited signs of fatty liver despite treatment means that there is a need to develop SMN-boosting therapies that effectively target tissues outside the nervous system, according to the team.
The scientists noted that this will require more experiments to better understand the mechanisms underlying liver involvement in SMA and how liver issues correlate with clinical symptoms.
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