Fatty liver disease may be common complication of SMA: Small study
An abnormal buildup of fat in the liver, referred to as fatty liver disease, was found to be common in a small group of children and adults with spinal muscular atrophy (SMA), regardless of their disease type or severity.
Patient-derived liver cells confirmed that such accumulation was a result of altered fat metabolism due to mutations in the SMN1 gene, the underlying cause of SMA.
“Our findings show that SMA patients may be at higher risk of additional health problems over time, as the SMA gene mutation also affects other organs … including the liver,” Crystal Yeo, MD, PhD, the study’s lead researcher and director of the Agency for Science, Technology and Research in Singapore, said in a news release from the University of Aberdeen in Scotland.
The study, “Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy,” was published in The Journal of Clinical Investigation.
Fatty liver disease, marked by inflammation, seen in SMA animal models
Defects in the SMN1 gene disrupt production of the SMN protein, resulting in disease symptoms marked by progressive muscle weakness and atrophy (shrinkage). While loss of the SMN protein affects all cells in the body, the specialized nerve cells that control movement, called motor neurons, are particularly sensitive.
Recent advances in disease-modifying therapies (DMTs), designed to boost SMN protein levels, have improved motor outcomes, extended survival, and enhanced life quality for many SMA patients.
But studies demonstrate that a lack of SMN affects more than motor neurons, with organs including the heart, kidney, liver, pancreas, spleen, bone, and connective tissues also involved.
“As individuals with SMA live longer due to improved treatment options, understanding the long-term effects of the genetic mutation on various organs becomes crucial for screening for previously unknown problems, developing effective treatment strategies and improving patient outcomes,” said Yeo, who is also a practicing neurologist at the island country’s National Neuroscience Institute.
In particular, fatty liver disease, a condition marked by the buildup of fat in the liver causing inflammation and damage, has been detected in SMA animal models. However, whether fatty liver disease — which, when not due to alcohol consumption, is now known as metabolic dysfunction-associated steatotic liver disease — is common in people with an SMN protein deficiency is unknown.
Researchers at the Singapore agency, working with colleagues in Aberdeen and Boston, examined clinical data from eight SMA patients (five children, three adults) without a history of liver disease who had undergone a liver ultrasound and blood sampling for markers of liver health. Four of the children had SMA type 1, one child and two adults had type 2, and one adult had type 3.
All were using or had been given at least one of SMA’s three approved DMTs, and all were examined at a single center from 2020 to 2022.
Ultrasound images showed evidence of mild to moderate fat accumulation in the livers of six of these eight (75%) SMA patients. Three (37.5%) also had elevated blood markers for liver damage.
Abnormal fat buildup in the liver was detected regardless of a patient’s SMA type and severity of muscle weakness. This finding despite DMT use suggests “that current therapies may not be sufficient to target this [feature] for these patients at the time of treatment,” the researchers wrote.
Study supports SMA as being a ‘multicellular and multiorgan disease’
Liver cells derived from untreated SMA patients, with markedly reduced SMN protein, showed a 10-fold increase in fat-like lipid accumulation compared with liver cells derived from people without SMA. Again, this buildup was comparable across all SMA types. Further experiments found problems with lipid metabolism — liver cells’ ability to break down and effectively use fat — and in the function of mitochondria, the structures in cells that generate energy.
All defects in patient-derived liver cells were rescued by restoring SMN protein production using CRISPR/Cas9 gene-editing technology to create a functional SMN2 gene, a backup gene for SMN1.
“We provide evidence across the spectrum of SMA clinical [types] for susceptibility to [fatty liver disease] in an SMA patient cohort and [cell-based] human models of SMA,” the researchers concluded.
Study findings also support SMA being “considered and treated as a multicellular and multiorgan disease,” they added.
“Further research in this area could not only benefit those living with SMA but also provide insights into the treatment of other neurological conditions with similar disease mechanisms,” Yeo said.
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