Spinal muscular atrophy (SMA) is typically characterized as a motor neuron disease, but extraneuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extraneuronal phenotypes were previously underappreciated, as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in SMA animal models, but generalizability to patients and whether this is due to hepatocyte-intrinsic survival motor neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN dependent and hepatocyte intrinsic, this suggests SMN-repleting therapies must target extraneuronal tissues and motor neurons for optimal patient outcome. Here, we showed that fatty liver is present in SMA patients and that SMA patient–specific induced pluripotent stem cell–derived hepatocyte-like cells were susceptible to steatosis. Using proteomics, functional studies, and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate the need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.


Damien Meng-Kiat Leow, Yang Kai Ng, Loo Chien Wang, Hiromi W.L. Koh, Tianyun Zhao, Zi Jian Khong, Tommaso Tabaglio, Gunaseelan Narayanan, Richard M. Giadone, Radoslaw M. Sobota, Shi-Yan Ng, Adrian Kee Keong Teo, Simon H. Parson, Lee L. Rubin, Wei-Yi Ong, Basil T. Darras, Crystal J.J. Yeo


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