Homozygous familial hypercholesterolemia: Current perspectives on diagnosis and treatment

Abstract

Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant disease resulting from mutations in both copies of the low-density lipoprotein receptor (LDLR) gene. Mutations in 3 other associated genes, proprotein convertase subtilisin/kexin type 9, apolipoprotein B (APOB), and, more rarely, the autosomal recessive hypercholesterolemia adaptor protein, may lead to a similar phenotype with varying severity. HoFH patients have aggressive cardiovascular disease that develops from birth due to severe LDLR defects, resulting, in turn, in excess production of Apo B-containing atherogenic lipoproteins (low-density lipoprotein [LDL] and lipoprotein(a)). The condition is characterized by exceptionally high LDL cholesterol levels, cutaneous and tendon xanthomas, and valvular and supravalvular stenosis, and accelerated atherosclerosis often manifests in the first 2 decades of life. Treatment typically involves lipid-modifying medical therapy as well as mechanical removal of plasma LDL by means of apheresis. Although statins have afforded survival into the third and fourth decades of life, further therapeutic advancements currently under investigation promise hope of further improvements in survival and improved quality of life. The purpose of this review is to provide current perspectives on diagnosis and therapy in an effort to encourage early recognition and treatment of this rare but severe disease.

Introduction

Homozygous familial hypercholesterolemia (HoFH) is an inherited disorder caused primarily by homozygous mutations in the low-density lipoprotein receptor (LDLR) gene. However, mutations in 3 other genes regulating sterol and lipoprotein pathways may lead to similar phenotypes with varying severity: apolipoprotein B-100 (Apo B-100), proprotein convertase subtilisin/kexin 9 (PCSK9), and, more rarely, the autosomal recessive hypercholesterolemia (ARH) adaptor protein [1]. Mutations in both LDLR alleles that result in reduced uptake and clearance of low-density lipoprotein (LDL)-cholesterol is the most common cause of HoFH. HoFH patients with mutations in the LDLR gene may be true homozygotes (having the same mutation in both LDLR alleles) or compound heterozygotes (having different mutations on each LDLR allele). Patients with HoFH present with severe hypercholesterolemia associated with accumulation of LDL-cholesterol in plasma, tendons, and skin, as well as present with accelerated atherosclerosis, particularly coronary heart disease (CHD), often within the first 2 decades of life. In addition, HoFH patients frequently develop either valvular or supravalvular aortic stenosis [2], [3].

Globally, the prevalence of HoFH is estimated to be 1 case per 1 million persons, whereas the heterozygous form of familial hypercholesterolemia (HeFH) is estimated at 1 case per 500 persons [2]. The prevalence of HoFH is greater in specific regions throughout the world, presumably due to founder effects and isolation of a population [1]. Among Afrikaners, the estimated prevalence of LDLR mutations is 1 case per 100 persons for heterozygous patients and 1 case per 30,000 for homozygous patients [4]. Among French Canadians, the prevalence of HeFH is 1 in 270 and of HoFH is 1 in 275,000 [5]. The prevalence of HoFH is 1 in 100,000 among Lebanese persons [6]. The Hokuriku district of Japan has a prevalence 1 in 208 for HeFH and of 1 in 171,167 for HoFH [7].

Although in recent years there have been many publications discussing FH, few have focused on HoFH and its unique clinical profile. Here, we review the definition, diagnosis, natural history, and recent and emerging therapies for HoFH.