Autosomal recessive hypercholesterolemia: update for 2020.

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Medicine
• Metabolic Disorders

Background:

• Autosomal recessive hypercholesterolemia (ARH) is an ultrarare genetic disorder of low-density lipoprotein (LDL) metabolism.
• Caused by loss-of-function mutations in the LDLRAP1 gene, it follows a recessive inheritance pattern.
• ARH is considered a phenocopy of homozygous familial hypercholesterolemia, presenting similar cardiovascular risks.

Purpose of the Study:

• To review current knowledge on autosomal recessive hypercholesterolemia (ARH).
• To provide new insights into the natural history and therapeutic management of ARH.
• To evaluate novel mutations and treatment strategies for ARH.

Main Methods:

• Review of recent literature on ARH-causing mutations.
• Long-term follow-up analysis of a cohort of ARH patients.
• Assessment of treatment efficacy with conventional lipid-lowering therapies and lomitapide.

Main Results:

• Novel homozygous and compound heterozygous mutations in ARH have been identified.
• Despite intensive conventional therapy, ARH patients exhibit persistently high LDL cholesterol levels.
• ARH is associated with a poor cardiovascular prognosis and an increased risk of aortic valve stenosis.

Conclusions:

• Conventional lipid-lowering therapies are often insufficient for managing ARH.
• Lomitapide, a microsomal triglyceride transfer protein inhibitor, shows potential as an effective treatment for ARH.
• Combining lomitapide with conventional medications may offer a promising therapeutic approach for ARH patients.