Conducted in collaboration with National University of Singapore, Duke-NUS Medical School, Harvard University, and Boston Children’s Hospital, the study was published in Muscle & Nerve and provides new insight into SMA as a condition that extends beyond the nervous system.

SMA is a leading genetic cause of infant mortality and a lifelong condition for survivors. While genetic therapies which restore the missing Survival Motor Neuron (SMN) protein have significantly improved outcomes, increasing survival has also revealed health challenges that extend beyond motor neuron degeneration. As more individuals with SMA live longer due to early interventions, understanding the full biological impact of the disease has become increasingly important.

To investigate these, Dr. Yeo and colleagues generated induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from an SMA patient, his clinically asymptomatic carrier parents, and genetically edited isogenic controls. The team found that carrier-derived liver cells, like patient-derived liver cells, exhibited increased lipid accumulation and altered metabolic gene expression compared with controls, indicating early disruptions in fat metabolism even in individuals who are traditionally considered clinically unaffected. 

Importantly, treatment with risdiplam, an approved Survival Motor Neuron 2 (SMN2) -splicing modulator used in SMA to increase SMN levels, partially reduced lipid accumulation in both patient-derived and carrier-derived hepatocytes. This provides the first in vitro evidence that SMA carrier–derived liver cells can display intrinsic cellular abnormalities, and that a therapy developed to protect motor neurons may also influence other tissues affected by reduced SMN levels.

“Our study shows that even in people who carry the SMA gene but have no symptoms, there may be subtle changes at the cellular level. Further studies will be needed to determine how these findings translate clinically, but this work highlights the importance of understanding SMA as a condition that can affect multiple tissues, not just the nervous system.” said Dr Crystal Yeo, clinician-scientist at A*STAR IMCB and consultant neurologist at NNI. 

Study citation: Sun, L. et al. Liver steatosis in induced hepatocytes from carriers of spinal muscular atrophy.
Muscle & Nerve (2025).