Hepatic Steatosis in Spinal Muscular Atrophy: Evidence for a Primary Hepatic Defect and Implications (S33.009)

Abstract

<h3>Objective:</h3> 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. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> 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. <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Dr. Yeo has nothing to disclose. Mr. Kiat has nothing to disclose. Mr. Ng has nothing to disclose. Prof. Ong has nothing to disclose. The institution of Dr. Darras has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Darras has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus. The institution of Dr. Darras has received research support from National Institutes of Health/National Institute of Neurological Disorders and Stroke,. The institution of Dr. Darras has received research support from Slaney Family Fund for SMA. The institution of Dr. Darras has received research support from Spinal Muscular Atrophy Foundation. The institution of Dr. Darras has received research support from CureSMA. The institution of Dr. Darras has received research support from Working on Walking Fund . The institution of Dr. Darras has received research support from CHERISH, CS2/CS12 . The institution of Dr. Darras has received research support from Biogen for CS11. The institution of Dr. Darras has received research support from AveXis. The institution of Dr. Darras has received research support from Sarepta Pharmaceuticals. The institution of Dr. Darras has received research support from PTC Therapeutics. The institution of Dr. Darras has received research support from Roche. The institution of Dr. Darras has received research support from Santhera. The institution of Dr. Darras has received research support from Scholar Rock. The institution of Dr. Darras has received research support from Fibrogen. The institution of Dr. Darras has received research support from Summit. Dr. Darras has received publishing royalties from a publication relating to health care. Dr. Darras has received publishing royalties from a publication relating to health care.