Hepatic Steatosis in Spinal Muscular Atrophy: Evidence for a Primary Hepatic Defect and Implications
Crystal Yeo1, Damien Leow2, Yang Kai Ng 3, Wei Yi Ong 2, Basil Darras4
1Boston Children's Hospital, Northwestern University, University of Aberdeen, National Neuroscience Insitute, A*STAR, Lee Kong Chien School of Medicine, Duke-NUS Medical School, 2National University of Singapore, 3National University of Singapore, A*STAR, 4Boston Children's Hospital
Objective:
To investigate evidence of hepatic steatosis in patients with spinal muscular atrophy (SMA) and SMA patient-derived induced pluripotent stem cell (iPSC) models of disease.
Background:
SMA is generally regarded as a motor neuron disease but increasing evidence of extra-neuronal manifestations suggest that these may become future co-morbidities when lifespan is prolonged. Hepatocellular microsteatosis has been noted in mouse models and pediatric autopsies, but it is unclear whether this is a primary defect from hepatocyte Survival Motor Neuron (SMN) deficiency or secondary to muscle denervation.
Design/Methods:
We retrospectively analyzed clinical data from a single center cohort of pediatric and adult SMA patients without liver disease who received hepatic sonography or fibroscan. Sonographic/fibroscan steatosis grade and serum markers of liver function were reviewed. In parallel, we differentiated Type 0-3 SMA patient iPSCs into hepatocytes (iHeps) and analyzed lipid accumulation and markers of hepatocyte function compared to wild-type (WT). We CRISPR edited a SMA Type 1 iPSC line to derive isogenic carrier (1 SMN1, 1 SMN2) and isogenic WT lines (2 SMN1) and analyzed the isolated effect of SMN deficiency on iHeps.
Results:
Mild to moderate hepatic steatosis was present in 100% SMA patients regardless of age and therapy. Raised hepatic enzymes were found in 33% SMA patients, but serum albumin, protein and INR were normal. Compared to WT, SMA iHeps displayed significantly more lipid accumulation which did not differ by SMA Type. Isolated SMN rescue on the same genetic background by CRISPR editing ameliorated lipid accumulation.
Conclusions:
To our knowledge, this is the first study to present evidence that hepatic steatosis may be a primary defect in all SMA types. Imaging evidence of hepatic steatosis may be frequent and could be used as a clinical biomarker. Establishing currently lacking screening and treatment guidelines for primary extra-neuronal defects in treated SMA patients is important.