Primary hypoalphalipoproteinemia (HDL cholesterol <10 mg/dl) is caused by a disturbance in the formation, maturation or metabolism of HDL particles. The occurrence of immature HDL precursors in plasma and lipid deposits in parenchymatous organs and the cornea (corneal opacities, not to be confused with arcus lipoides) are typical of HDL deficiency states. Pathogenic variants in three genes are mostly responsible for the condition:
- Lecithin-cholesterol acyltransferase (LCAT), a glycoprotein formed and secreted by the liver, is responsible for the esterification of free cholesterol in plasma. Variants in the LCAT gene lead to LCAT deficiency or fish-eye disease. The coronary risk is probably increased in homozygous carriers.
- Apolipoprotein A-I (Apo A-I), a structural protein of HDL particles, is the most important cofactor for LCAT activation. Apo A-I deficiency is associated with a significantly increased risk of coronary heart disease.
- ATP-binding cassette transporter 1 (ABCA1), a membrane protein, is involved in the cholesterol efflux from the cell. Heterozygous variants in the ABCA1 gene lead to HDL deficiency; homozygous carriers suffer from the very rare autosomal recessive Tangier disease with orange colored tonsils, hepatosplenomegaly and neuropathy. The coronary risk is moderately increased.
Shapiro 2018, Endotext [Internet], https://www.ncbi.nlm.nih.gov/books/NBK326744/ / Ramasamy 2016, Clin Chim Acta 454:143 / Schaefer et al. 2016, Prog Cardiovasc Dis 59:97 / Santamarina-Fojo et al. in Scriver et al. 2001 (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th Ed, Chapter 118 / Tall in Scriver et al. 2001: The Metabolic and Molecular Bases of Inherited Disease, 8th Ed, Chapter 121