Management of autosomal recessive hypercholesterolemia in a patient with an LDLRAP1 mutation

Familial hypercholesterolemia (FH) is characterized by a lifelong elevation of low-density lipoprotein cholesterol (LDL-C), conferring an increased risk of premature atherosclerotic disease and its associated burden of morbidity and mortality. Autosomal recessive hypercholesterolemia (ARH) is a rare form of homozygous FH (HoFH) and is a distinct subset caused by mutations in the low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) gene. We present a 29-year-old South Asian male who visited the lipid clinic with a markedly elevated, untreated LDL-C level of 557 mg/dL. Clinical and genetic evaluation identified a homozygous pathogenic splice donor variant in the LDLRAP1 (c.344+1G>A), confirming the diagnosis of ARH. On examination, a grade III/VI systolic ejection murmur was appreciated, prompting further investigation that confirmed mild aortic stenosis. Achieving adequate LDL-C control for this patient required stepwise escalation of the lipid-lowering therapy comprising high-intensity statin therapy, proprotein convertase subtilisin/kexin type 9 inhibitor, bempedoic acid, and ultimately evinacumab. This case draws attention to the importance of appropriately diagnosing and treating individuals with ARH and initiating combination lipid-lowering therapy, including specialty medications indicated for this diagnosis, to effectively treat this disorder, as well as the importance of screening for valvular heart disease in this population.