{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T23:16:33Z","timestamp":1773098193367,"version":"3.50.1"},"reference-count":17,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001348","name":"Agency for Science, Technology and Research","doi-asserted-by":"publisher","award":["C210112024"],"award-info":[{"award-number":["C210112024"]}],"id":[{"id":"10.13039\/501100001348","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Muscle and Nerve"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction\/Aims<\/jats:title>\n                    <jats:p>Although classically characterized as a motor neuron disease, spinal muscular atrophy (SMA) is increasingly recognized as a multisystem disorder. We previously showed hepatocyte\u2010intrinsic steatosis in SMA, raising the question of whether SMA carriers, who are typically asymptomatic, may also exhibit subclinical hepatic abnormalities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated induced hepatocyte\u2010like cells (iHeps) from induced pluripotent stem cells (iPSCs) derived from an SMA Type 2 proband, his isogenic wild\u2010type (Iso\u2010WT) line, and both carrier parents, comprised of three carrier lines from the father and one from the mother. Steatosis was assessed by Oil Red O staining and image analysis. Survival motor neuron (SMN) expression was evaluated by immunoblotting. Proteotranscriptomic profiling and mitochondrial respiration assays were performed. Risdiplam, an\n                      <jats:italic>SMN2<\/jats:italic>\n                      splicing modulator, was used to assess reversibility of observed phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SMA and carrier iHeps demonstrated increased lipid accumulation compared to Iso\u2010WT. Risdiplam reduced steatosis by 65.9% in SMA patient\u2010derived iHeps and by 43.6% and 56.9% in father\u2010 and mother carrier\u2013derived iHeps, respectively. Carrier and SMA iHeps exhibited downregulation of genes involved in lipid metabolism and liver function, along with altered expression of lipid\u2010related proteins. Mitochondrial dysfunction was present only in SMA iHeps. Carrier\u2010derived induced motor neurons showed normal viability under oxidative stress, consistent with preserved neuromuscular function clinically.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our data reveal hepatocyte\u2010intrinsic lipid metabolic defects in SMA carriers, partially reversible with risdiplam. These findings suggest subclinical hepatic involvement in carriers and support further investigation into the systemic impact of SMN deficiency.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mus.70111","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T09:26:03Z","timestamp":1769073963000},"page":"675-682","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Liver Steatosis in Induced Hepatocytes From Carriers of Spinal Muscular Atrophy"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3407-553X","authenticated-orcid":false,"given":"Lingyu","family":"Sun","sequence":"first","affiliation":[{"name":"Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1996-4964","authenticated-orcid":false,"given":"Damien Meng Kiat","family":"Leow","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"},{"name":"National Neuroscience Institute  Singapore Singapore"},{"name":"Neurobiology Programme, Centre for Life Sciences National University of Singapore  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loo Chien","family":"Wang","sequence":"additional","affiliation":[{"name":"Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle Yating","family":"Eio","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6894-5129","authenticated-orcid":false,"given":"Hiromi W. L.","family":"Koh","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi Jian","family":"Khong","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunaseelan","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Duke\u2010NUS Medical School  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aloysius Kai Soon","family":"Teo","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"},{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Giadone","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology Harvard University  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-2526","authenticated-orcid":false,"given":"Radoslaw M.","family":"Sobota","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi Yan","family":"Ng","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian Kee Keong","family":"Teo","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"},{"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei Yi","family":"Ong","sequence":"additional","affiliation":[{"name":"Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"},{"name":"Neurobiology Programme, Centre for Life Sciences National University of Singapore  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee L.","family":"Rubin","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biology Harvard University  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Basil T.","family":"Darras","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children's Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-5965","authenticated-orcid":false,"given":"Crystal J. 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