SMN Depletion May Increase Risk of Liver Damage, Fatty Liver in SMA

Children and adults with spinal muscular atrophy (SMA) may be at a higher risk for developing fatty liver disease, according to a study published in The Journal of Clinical Investigation. Results from this small cohort study suggested that this complication can arise in SMA regardless of an individual’s disease type.¹

The SMN protein is expressed thoughout many body tissues types, including the liver | image credit: eddows - stock.adobe.com

Fatty liver disease is characterized by excess fat buildup in one’s liver. This condition can develop from heavy drinking habits (alcohol-associated fatty liver disease) or can be classified as nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of people worldwide.² NAFLD is more highly associated with prediabetes or type 2 diabetes, obesity, high blood pressure, metabolic disorders, intake of certain drugs or exposure to various infections and toxins, among other causes.

This disease is commonly asymptomatic and, therefore, difficult to diagnose. Physical examination, certain blood and imaging tests, or biopsy are the typical approach for diagnosing NAFLD as clinicians search for signs of enlarged liver, jaundice, and cirrhosis. While no medicines are currently approved for treating NAFLD, weight loss and management, whether through diet, exercise, or both, is frequently recommended to affected patients.

While SMA is an inherited disease of the motor neurons, the present authors point to a body of research that revealed affected patients also endure widespread, peripheral organ dysfunction.¹ The spinal motor neuron (SMN) protein, whose dysfunction lies at the root of SMA’s complications, is expressed throughout the body’s tissue types. Although SMA can be considered a disease of the motor neurons, prior autopsy observations showed that SMA is actually a “multisystem disorder” that affects patients’ skeletal muscle, kidney, hearth, pancreas, liver, bone, connective tissues, and immune systems.

“The liver is an important organ to study in SMA because of its many functions in detoxification, metabolism, immune regulation, hematopoiesis, and clotting, and its implications for SMA treatments,” the authors wrote, adding how hepatoxicity is a common consequence of onasemnogene abeparvovec therapy. They then pointed to previous stories where pediatric patients with SMA died from acute liver failure following the initiation of gene therapy, bringing about further concerns regarding the identification of patients who may react poorly to novel therapies in SMA, as well as understand the mechanisms of liver damage in this disease.

The goal of their study was to investigate hepatic defects in patients with SMA, the intrinsically cellular, SMA-related defects, and to what degree patients are affected by liver steatosis. They assessed patient-derived, induced, pluripotent stem cell-derived (iPSC-derived) hepatocyte-like cells (iHeps) and used CRISPR/Cas9 gene editing. Adult and pediatric patients who did not have liver disease were included in this analysis if they previously received a liver ultrasound and had clinical serum markers of liver function collected.

Clinical data on 8 patients were retrospectively collected; all patients were taking either nusinersen, risdiplam, or had gene therapy. Evidence of heighted hepatic echogenicity—indicating mild-to-moderate steatosis—was detected in 75% (n = 6) of this group, and liver damage (identified through serum markers) was found in 37.5% (n = 3). The authors noted that hepatic steatosis was observed regardless of a patient’s SMA genotype, neuromuscular phenotype, treatment or disease severity. These findings suggest that hepatic echogenicity could serve as both a sensitive and noninvasive biomarker of liver damage.

Patient-derived SMA iHeps also demonstrated reduced expression of the SMN protein. A quantitative proteome analysis of the liver revealed that 343 out of 657 proteins that are differentially expressed in an SMA phenotype were associated with disease severity. Additionally, SMA iHeps defects were found to play a role in hepatic function, metabolism, mitochondrial function, and more, with further analysis indicating that depletion of the SMN protein makes patients with SMA more vulnerable to liver dysfunction and the development of fatty liver disease.

“This work demonstrates that SMA patient hepatic steatosis is a cell-intrinsic metabolic phenotype, and highlights the critical need for further investigation of the liver in SMA and its clinical implications,” the authors wrote.

References

1. Leow DM, Ng YK, Wang LC, et al. Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy. J Clin Invest. 2024;134(12):e173702. doi:10.1172/JCI173702

2. Fatty Liver Disease. Medline Plus. Updated April 26, 2017. Accessed August 21, 2024. https://medlineplus.gov/fattyliverdisease.html