LAUSR

Abstract Background: Hypertriglyceridemia (HTG) is common, but familial chylomicronemia syndrome (FCS) is a very rare cause of severe HTG, associated with pancreatitis, which can be fatal. It is due to impaired lipoprotein lipase (LPL) function, typically caused by bi-allelic LPL loss-of-function mutations. Although FCS generally presents in childhood with acute pancreatitis and HTG, it should also be considered as a diagnosis in adults with severe HTG. Unlike polygenic HTG, dietary fat-restriction is the mainstay of treatment in FCS which is critical in preventing pancreatitis since traditional medications are ineffective. Several promising biologics currently under clinical development may provide novel therapeutic approaches in FCS. Clinical Case: 52-year-old fraternal twins and their 55-year-old brother born to consanguineous parents were recruited into an IRB-approved lipid genetic study. LPL activity and genetic analyses were performed to definitively diagnose FCS. Moreover, the twins participated in clinical trials which investigated novel therapies for HTG. The female twin seemed to have had undiagnosed pancreatitis since age 13, and was hospitalized at age 20 with HTG and severe pancreatitis for the first time. The male twin had multiple hospitalizations for pancreatitis and HTG. The older brother also had emergency room visits for pancreatitis. Misguidedly, all siblings had been on low-carbohydrate diet that lead to severe HTG. Their medical and family histories were consistent with FCS. The studies performed identified a previously unreported homozygous LPL variant, c.617T>C, p.V206A, corroborated by reduced LPL activities, and altered molecular dynamics, consistent with dysfunctional LPL and the diagnosis of FCS. A very low-fat diet was prescribed which facilitated in stabilizing their clinical picture with a reduction in TG and pancreatitis episodes. The female twin qualified to enroll in a clinical study for the treatment of HTG, receiving multiple doses of an experimental APOC3 inhibitor, which lowered her TG from 3,447 to 201 mg/dL (~94% reduction) within 90 days which persisted for several months. The result seemed to indicate that inhibiting APOC3 could effectively enhance the residual LPL lipolytic activity and lower TG. In addition, the twins qualified to participate in a double-blinded clinical trial with an experimental ANGPTL3 inhibitor whose results are forthcoming in the near future. Conclusion: Our case demonstrates the importance of elucidating FCS diagnosis even in adults with HTG for selecting the most appropriate therapy. This was the first reported case of this particular homozygous variant causing FCS. Particularly, the clinical trial result was encouraging that novel biologics may become an optional therapy in certain patients with FCS beyond dietary management in the future. Disclosure: permission to present the study result has been obtained.