PURPOSE OF REVIEW: Homozygous familial hypercholesterolemia (HoFH) is an orphan 
disease caused by biallelic mutations at the LDL receptor (LDLR) gene, with a 
prevalence estimated at 1 : 250 000 to 1 : 630 000. HoFH is characterized by 
extremely elevated plasma levels of LDL-C greater than 10 mmol/l (>387 mg/dl), 
tendinous and cutaneous xanthomas in youth and premature atherosclerotic 
cardiovascular disease (ASCVD). The expected prevalence varies from country to 
country depending on the presence of founder effects, genetic probability and 
life expectancy. Untreated, HoFH is a fatal condition before age 30. Plasma 
levels of LDL-C are the major cause of mortality and the therapeutic target. 
Statin therapy led to a remarkable improvement in survival but is of limited use 
in loss-of-function LDLR gene variants or 'null' mutations. Inhibitors of PCSK9 
are a useful adjunct in patients with LDLR mutations with residual activity. 
Extracorporeal LDL filtration has improved survival since its introduction three 
decades ago.
RECENT FINDINGS: Novel therapies, not dependent on a functioning LDLR include 
lomitapide and mipomersen, which decrease hepatic apolipoprotein B secretion, 
and evinacumab, directed at the angiopoietin like-3 protein (ANGPLT-3).
SUMMARY: Over the past 3-4 decades, the survival of patients with HoFH has 
increased markedly. New therapeutic options offer new hope.