low HDL syndromes

Tangier disease
Tangier - 9q
- orange tonsils, hepatosplenomegaly, polyneuropathy (syringomyelia-like), premature CVS
- hypoHDL
- ABCA1 mutation, loss-off-function,
- cellular cholesterol efflux impaired

primary familial hypoalfalipoproteinemia OMIM 604091
-French Canadian
- lowHDL, normal TG
- ABCA1 mutation 9q

LCAT deficiency
lecithin-cholesterol acyltransferase OMIM 606967
- soluble enzyme that converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high density lipoproteins
'reverse cholesterol transport.' The enzyme is synthesized in the liver and circulates in blood plasma as a complex with components of high density lipoprotein (HDL).
- Cholesterol from peripheral cells is transferred to HDL particles, esterified through the action of LCAT on HDL, and incorporated into the core of the lipoprotein. The cholesterol ester is thereby transported to the liver (Jonas, 2000). A lack of LCAT activity would be expected to lead to accumulation of free cholesterol in the tissues. Most cholesterol esters present in plasma are the product of the reaction catalyzed by LCAT in which cholesterol is esterified with the sn-2 fatty acid of phosphatidylcholine. The resulting cholesteryl esters are packed into the hydrophobic core of lipoproteins.
In fish-eye disease (OMIM 136120), there is a specific inability of LCAT to esterify cholesterol in HDL, a deficiency of alpha-LCAT function. In Norum disease (245900), the deficient esterification is generalized (Kinoshita and Teramoto, 2001).
PATHOGENESIS
Carlson and Holmquist (1985) and Holmquist and Carlson (1987) demonstrated that the defect in fish-eye disease is deficiency of high density lipoprotein lecithin:cholesterol acyltransferase activity.

Alpha-LCAT, deficient in this condition, is specific for HDL, whereas beta-LCAT, also deficient in Norum disease (245900), is specific for combined VLDL and LDL (Carlson and Holmquist, 1985). Thus, fish-eye disease is one form of LCAT deficiency. In fish-eye disease, the HDL of plasma contains only about 20% cholesteryl esters relative to total cholesterol as compared to 75 to 80% in control HDL. In fish-eye disease plasma, however, there is a normal cholesteryl ester percentage as well as a normal plasma cholesterol esterification rate as a result of the activity of beta-LCAT.