Treatment With Evinacumab Links a New Pathogenic Variant in the LPL Gene to Persistent Chylomicronemia

Figures

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  Figure 1.. Spectrum and mechanisms of action of ANGPTL3 inhibition. ANGPTL3 inhibition decreases TG levels in a large spectrum of lipid disorders from homozygous familial hypercholesterolemia to persistent chylomicronemia provided that LPL is bioavailable (Fig. 1A). In patients with complete LPL deficiency and persistent chylomicronemia, ANGPTL3 inhibition does not decrease TG levels since it requires LPL to be effective (LPL-dependent). As illustrated in Fig. 1B, it is likely that following ANGPTL3 inhibition, TG-rich lipoproteins from both the exogenous or endogenous pathways (chylomicrons and VLDL) are secreted (1) and are rapidly hydrolyzed following LPL upregulation (2). IDL and chylomicrons remnants are then promptly removed from the bloodstream and internalized through endothelial lipase-dependent clearance mechanisms (3). Fewer LDL particles are formed, which allows evinacumab to be effective even in the absence of competent LDLRs (LDLR-independent pathway) (4). Abbreviations: ANGPTL3, angiopoietin-like protein 3; LPL, lipoprotein lipase; LDLR, lipoprotein lipase receptor; TG, triglycerides; VLDL, very low density lipoprotein.

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  Figure 2.. Exposure to evinacumab of 3 patients with proven LPL deficiency carrying known FCS-causing variants in the LPL gene and not responding to ANGPTL3 inhibition identified a new potentially pathogenic variant. In patients homozygotes for the P234L pathogenic variant (exon 5) completely lacking LPL activity due to defect at the catalytic site of the LPL protein, TG levels remain elevated and do not decrease below 10 mmol/L following evinacumab treatment (A, B, C). One homozygote carrier of the E282X variant did not respond either, and TG levels remained above 10 mmol/L (D). This variant is thus likely pathogenic and FCS-causing. It is located in exon 6 and surrounded by other documented variants associated with chylomicronemia. This region of the LPL gene codes for the enzyme catalytic site and affects lipoprotein binding. Abbreviations: ANGPTL3, angiopoietin-like protein 3; FCS, familial chylomicronemia syndrome; LPL, lipoprotein lipase; TG, triglycerides.