Autosomal recessive hypercholesterolemia: update for 2020

Purpose of review This review summarizes the current knowledge regarding autosomal recessive hypercholesterolemia (ARH) and provides new insight into the natural history and therapeutic management of this lipid disorder. Recent findings Novel homozygous and compound heterozygous ARH-causing mutations have been reported in the literature, to date. The long-term follow-up of a cohort of ARH patients demonstrated that, despite intensive treatment with conventional lipid-lowering therapies, their low-density lipoprotein (LDL) cholesterol levels remain far from target and this translates into a poor cardiovascular prognosis. ARH is also associated with increased risk of developing aortic valve stenosis. However, lomitapide, a microsomal triglyceride transfers protein inhibitor, may represent a new opportunity for the effective treatment of ARH. Summary ARH is an ultrarare disorder of LDL metabolism caused by mutations in the LDLRAP1 gene. It is inherited as a recessive trait and causative mutations, though heterogeneous, are all predicted to be loss-of-function. Recent investigations have demonstrated that ARH can be considered a phenocopy of homozygous familial hypercholesterolemia, where the risk of atherosclerotic cardiovascular diseases and aortic valve stenosis remains elevated despite conventional therapies. The combination of lomitapide with the conventional LDL-C-lowering medications appears to be a promising approach to treat this condition.