**1. Introduction**

Familialhypercholesterolemia (FH)is anautosomal codominantgeneticdisorderoflipoprotein metabolism,usually causedbymutations inthe low‐density lipoprotein(LDL)receptor(*LDLR*) gene or other genes that affect LDLR function. Patients can be heterozygous (HeFH) with one mutatedallele,homozygous (HoFH) withtwo identicalmutations, or compoundheterozygous with different mutations in each allele [1]. Patients with HoFH have either a complete absence or marked impairment (i.e., 2–30% activity) in LDLR function [1]. There are a number of defects in lipid metabolism among patients with FH that include reduced LDLR‐mediated catabolism of LDL, impairment of apolipoprotein B (apo B)‐mediated clearance of LDL, and increased proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, which mediates posttranslational destruction of LDLRs [2, 3].

Since the reduction of LDLRs in HoFH is more pronounced than that seen with HeFH, hypercholesterolemia is usually more severe in HoFH than in HeFH and is characterized by very high serum levels of total cholesterol and LDL‐cholesterol (LDL‐C). Levels of LDL‐C are typically above 500 mg/dL and total cholesterol levels range from 650 to 1000 mg/dL when HoFH is untreated, whereas LDL‐C levels are typically greater than 300 mg/dL when treated [2–5]. High‐density lipoprotein cholesterol (HDL‐C) is often decreased and triglyceride levels are generally normal [4].

**Figure 1.** Cumulative LDL exposure in patients with FH [8, 9]. Modified from Horton et al. 2009 [9].

The severe lipid abnormalities associated with HoFH result in accelerated atherosclerosis, accelerated cardiovascular disease (CVD), and an increased risk of cardiac events and early death. It is estimated that CVD risk is increased by up to 20‐fold in untreated patients and still elevated approximately 10‐fold in patients receiving statins [5–7]. The lifelong exposure of highly elevated lipid levels means that signs/symptoms of CVD occur at an early age typically prior to 20 years of age and as early as preteen years with the highest risk in males [5, 8]. Females develop CVD about 10 years later than males [6]. Young patients often have severe and widespread atherosclerosis in all major arterial beds, including the carotid, coronary, femoral, and iliac, and there have been instances of acute myocardial infarction and sudden death in patients as young as 4 years of age [8]. The CVD risk is related to cumulative LDL‐C exposure. As seen in **Figure 1**, patients with HoFH exceed the theoretical threshold of LDL‐C exposure in early childhood compared with early middle age for patients with HeFH and after age 60 years for normal healthy individuals [8, 9]. Although, as with all individuals, the risk of developing CVD is also related to the presence of other genetic or environmental risk factors, the effect of each risk factor is amplified in the setting of dramatically elevated cholesterol levels [4].

The physical signs and symptoms of HoFH are characterized by accelerated atherosclerosis and the deposition of cholesterol. Atherosclerotic manifestations include vascular endothelial damage that produces premature coronary artery disease (CAD), peripheral artery disease, and valvular disease (e.g., aortic stenosis) [4]. Deposition of cholesterol results in the devel‐ opment of cutaneous or tendinous xanthomas and corneal arcus [8]. Xanthomas typically occur around the eyelids and tendons of the feet, hands, and elbows [5].

HoFH is substantially underdiagnosed and undertreated [7]. For example, it is estimated that less than 1% of patients with FH are diagnosed in most countries and that only 48% of patients with FH were receiving statin therapy in one Danish study [7]. Most patients with FH are not identified because of inconsistent screening and general unawareness [6]. Indeed, the disease is often not recognized until the initial cardiovascular (CV) event [6].
