Familial HDL deficiency

Considerable amounts of LCAT are carried by HDL therefore a-LCAT activity is also secondarily reduced in other forms of familial HDL deficiency. Notably, this partial LCAT deficiency has been repeatedly documented in forms of apoA-I deficiency due to structural defects in apoA-I. However, despite secondary LCAT deficiency these patients have a normal unesterified cholesterolitotal cholesterol ratio [35]. 

Eckardstein A von, Huang Y, Wu S, Funke H, Noseda G, Assmann G (1995) Reverse cholesterol transport in plasma of patients with different forms of familial HDL deficiency. Arterioscler Thromb Vase Biol 15 691-703... 

In familial HDL deficiency, HDL levels are very low they are almost undetectable in Tangier disease. Both genetic disorders are the result of mutations in the ABC1 protein. Cholesterol-depleted HDL cannot take up cholesterol from cells that lack ABC1 protein, and... 

A brief review of three papers in this journal issue that establish mutations in ABC1 as the cause of Tangier disease and familial HDL deficiency. 

Two genetically determined disorders, familial HDL deficiency and Tangier disease, result from mutations in the ATP-binding cassette 1 (ABC 1) protein. Cholesterol-depleted HDL cannot transport free cholesterol from cells that lack the ability to express this protein. As a consequence, HDL is rapidly degraded. These disorders have established a role for ABC 1 protein in the regulation of HDL levels in the blood. 

Apart from the hyperlipoproteinaemias that act as determinants of abnormal plasma lipoprotein concentrations, conditions with abnormally low concentrations of certain lipoproteins are also encountered and are generally referred to as the hypolipoproteinaemias. Tangier disease is one such condition that occurs as a rare inherited condition with autosomal recessive characteristics. The condition, a familial HDL deficiency, is characterized by cholesteryl ester accumulation in the reticuloendothelial system, which is similar in pattern to other lipid-storage diseases, such as gangliosidoses. Atheroma are substantially absent from the aorta and coronary vessels of such patients. The plasma cholesterol concentration is reduced and the triacylglycerol concentration is normal or increased in these cases. 

To date, the genetic origin of low HDL cholesterol has been unraveled only to a minor degree. Family studies in humans have identified at least 30 quantitative trait loci that cover almost all chromosomes. Most known mutations underlying monogenic forms of HDL deficiency have been found in genes that encode proteins involved in the formation, maturation, and catabolism of HDL. 

Familial apolipoproteinA-Iand C-IIIdeficiency is characterized by mild comeal opacification, coronary artery disease, marked HDL deficiency, and a normal ratio of free cholesterol to esterified cholesterol in plasma in all probands, also yellow orange, lipid-laden plaques on the tmnk, eyelids, neck, chest, anus, and backs of several affected individuals. The LDL is often found to be triacylglycerol-rich. The mode of inheritance is autosomal codominant. 

The significance of the complex sequence of events involved in the formation, transfer, and clearance of plasma lipoprotein CE is demonstrated dramatically by several inborn errors of metabolism. One such error is familial LCAT deficiency [67]. In this disease, as well as in diseases associated with acquired LCAT deficiency, LCAT activity in the plasma is abnormally low, and many hpoprotein and tissue abnormalities are observed. The content of UC and PC is abnormally high, and the molar ratio of UC to PC in the hpoproteins is also high, sometimes reaching a value of nearly 2 1. In association with these abnormahties, most lipoproteins show an abnormally low content of CE. In addition, there are abnormahties in the distribution and/or concentration of apolipoproteins AI, All, B, C, and E disc-shaped HDL and unusually small spherical HDL are seen and multilamehar vesicles containing UC and PC are usually present in the LDL fraction obtained by preparative ultracentrifugation. These abnormahties all seem to depend on the LCAT deficiency they are altered toward normal when patient plasma is incubated with LCAT in vitro. 

Familial lecithimcholesterol acyltransferase (LCAT) deficiency Absence of LCAT leads to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol. Plasma concentrations of cholesteryl esters and lysolecithin are low. Present is an abnormal LDL fraction, lipoprotein X, found also in patients with cholestasis. VLDL is abnormal ( 3-VLDL). 

Rare genetic disorders, including Tangier disease and LCAT (lecithin cholesterol acyltransferase) deficiency, are associated with extremely low levels of HDL. Familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45 mg/dL in women. These patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor. Management should include special attention to avoidance or treatment of other risk factors. Niacin increases HDL in many of these patients. Reductase inhibitors and fibric acid derivatives exert lesser effects. 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

Another factor that regulates HDL cholesterol levels is the plasma level of cholesteryl ester transfer protein (CETP). CETP, a hydrophobic glycoprotein (M.W. 741,000), facilitates the transfer of cholesteryl esters in HDL and triacylglycerols in LDL and VLDL (see above). In CETP deficiency due to a point mutation (G A) in a splice donor site that prevents normal processing of mRNA, the plasma HDL cholesterol levels of affected individuals are markedly high, with decreased LDL cholesterol. In the affected families, there was no evidence of premature atherosclerosis and, in fact, there was a trend toward longevity. These observations support the role of CETP and the antiatherogenic property of HDL. However, not all factors that elevate HDL levels may be... 

Hyperlipidaemias are conditions where levels of LDL cholesterol are raised relative to HDL levels. They can be primary or secondary to other conditions such as diabetes or hypothyroidism. About 5% of cases are due to a hereditary condition where there is a deficiency of LDL receptors on cell membranes (familial hyperlipidaemia). 

I Familial lipoprotein lipase deficiency Increased chylomicrons decreased HDL levels Absence of certain apoproteins... 

According to the above developed scheme of HDL and LDL structure, the molecular structure of cholesteryl esters is an important determinant to the size and internal arrangement of lipoproteins. This is further demonstrated by the structures of lipoprotein particles which lack cholesteryl esters. A natural system, where this is the case, is given by the abnormal lipoprotein Lp-X oc-curing abundantly in the serum of patients suffering from obstructive jaundice or from a familial deficiency in the enzyme lecithin-cholesterol-acyltransferase, which controls the conversion of cho-... 

Familial hypoalphalipoproteinemia A deficiency in HDL due to mutations at the ABCAl locus. 

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