Background: Familial Hypercholesterolaemia (FH) is an autosomal-dominant genetic disease and
represents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300, 000 births. FH is
characterized by high to very high low-density lipoprotein cholesterol (LDL-C), which is the main cause of increased
incidence of premature atherosclerotic Cardiovascular Disease (CVD) or aortic stenosis.
Objective: The aim of the review was to investigate the pathogenesis and the pathophysiology of FH.
Results: The most common (60-80%) FH cause is mutations of the LDL Receptor (LDLR) protein (6 classes with
a different number of receptors and functionality). Moreover, mutations in apolipoprotein B (APOB) (<5%) and
gain-of-function mutations of proprotein convertase subtilisin/kexin type 9 genes (PCSK9) (<1%) contribute to its
pathogenesis. An Autosomal Recessive Hypercholesterolaemia (ARH) is another cause, very rare (1/2.500
births), mainly in Sardinia. The remaining patients with a clinical diagnosis of monogenic hypercholesterolaemia
do not present any known genetic cause. Since FH is a significant public health problem, early diagnosis and
treatment are of utmost importance. Recent studies demonstrated the influence of the LDLR mutation type in the
FH phenotype, associating a more severe clinical phenotype and worse advanced CVD in patients with null mutation
than those with receptor-defective mutations. This analysis completes the adequate clinical diagnosis.
Conclusion: Both homozygous and heterozygous FH are related to mutations of LDLR (mainly), APOB, PCSK9,
while other rare forms exist. All aberrations lead to the impaired removal of LDL-C from the blood leading to its
accumulation and subsequent CVD earlier than in the general population.