Alpha High-Density Lipoprotein Deficiency(Tangier Disease)

Tangier disease (also known as Familial alpha-lipoprotein deficiency) or hypoalphalipoproteinemia is a rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein (HDL), often referred to as “good cholesterol”, in the bloodstream.

Tangier disease is an inherited disorder characterized by significantly reduced levels of high-density lipoprotein (HDL) in the blood. HDL transports cholesterol and certain fats called phospholipids from the body’s tissues to the liver, where they are removed from the blood. HDL is often referred to as “good cholesterol” because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease. Because people with Tangier disease have very low levels of HDL, they have a moderately increased risk of cardiovascular disease.

Additional signs and symptoms of Tangier disease include a slightly elevated amount of fat in the blood (mild hypertriglyceridemia); disturbances in nerve function (neuropathy); and enlarged, orange-colored tonsils. Affected individuals often develop atherosclerosis, which is an accumulation of fatty deposits and scar-like tissue in the lining of the arteries. Other features of this condition may include an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), clouding of the clear covering of the eye (corneal clouding), and type 2 diabetes.

Tangier Disease is an inherited blood disorder involving decreased concentrations of fat compounds in the blood called high-density lipoproteins (sometimes called “good cholesterol”). Large amounts of these compounds may accumulate in certain organs of the body causing tissue discoloration. In later stages, these accumulations may cause organ enlargement and/or blood circulation problems.

Synonyms

• Alpha High-Density Lipoprotein Deficieny
• Alphalipoproteinemia
• Analphalipoproteinemia
• Familial High-Density Lipoprotein Deficiency
• High density lipoproteindeficiency, type 1 (HDLDT1)
• Familial Alpha-Lipoprotein Deficiency
• Tangier Disease Neuropathy

Background

Low levels of high-density lipoprotein cholesterol (HDL), or hypoalphalipoproteinemia (HA), includes a variety of conditions, ranging from mild to severe, in which concentrations of alpha lipoproteins or high-density lipoprotein (HDL) are reduced. The etiology of HDL deficiencies ranges from secondary causes, such as smoking, to specific genetic mutations, such as Tangier disease and fish-eye disease.

HA has no clear-cut definition. An arbitrary cutoff is the 10th percentile of HDL cholesterol levels. A more practical definition derives from the theoretical cardioprotective role of HDL. The US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) redefined the HDL cholesterol level that constitutes a formal coronary heart disease (CHD) risk factor. The level was raised from 35 mg/dL to 40 mg/dL for men and women. A prospective analysis by Mora et al investigated the link between cholesterol and cardiovascular events in women and found baseline HDL-C level was consistently and inversely associated with incident coronary and CVD events across a range of LDL-C values.

For the metabolic syndrome in which multiple mild abnormalities in lipids, waist size (abdominal circumference), blood pressure, and blood sugar increase the risk of CHD, the designated HDL cholesterol levels that contribute to the syndrome are sex-specific. For men, a high-risk HDL cholesterol level is still less than 40 mg/dL, but for women, the high-risk HDL cholesterol level is less than 50 mg/dL.

A low HDL cholesterol level is thought to accelerate the development of atherosclerosis because of impaired reverse cholesterol transport and possibly because of the absence of other protective effects of HDL, such as decreased oxidation of other lipoproteins.

The common, mild forms of HA have no characteristic physical findings, but patients may have premature coronary heart or peripheral vascular disease, as well as a family history of low HDL cholesterol levels and premature CHD.

Therapy to raise the concentration of HDL cholesterol includes weight loss, smoking cessation, aerobic exercise, and pharmacologic management with niacin and fibrates.

This review addresses the pathogenesis and presenting features of, and the diagnostic tests, therapeutic interventions, and follow-up strategies for, low HDL cholesterol levels.

Pathophysiology

Plasma lipoproteins

Plasma lipoproteins are macromolecular complexes of lipids and proteins that are classified by density and electrophoretic mobility. The structure of all lipoproteins is the same. The nonpolar lipids (ie, cholesterol ester, triglycerides [TGs]) reside in a core surrounded by more polar components (eg, free cholesterol, phospholipids, proteins). The proteins, termed apolipoproteins, play an important role in lipoprotein metabolism.

The major apolipoproteins of high-density lipoprotein (HDL) are alpha lipoproteins (ie, apolipoprotein A-I [apo A-I], apo A-II, apo A-IV), which are soluble and can move between different classes of lipoproteins. The beta lipoproteins are structural, are never complexed with HDL, and remain throughout the metabolism of the lipoproteins with which they are associated. Apo B-450 is associated with chylomicrons and their remnants, and apo B-100 is associated with low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), VLDL remnants, and intermediate-density lipoprotein.

HDL plays a major role in reverse cholesterol transport, mobilizing cholesterol from the periphery to promote return to the liver. In the general population, lower-than-normal HDL cholesterol levels are closely correlated with coronary heart disease (CHD); the risk of a coronary event is thought to increase 2% for every 1% decrease in HDL cholesterol. However, extreme HDL deficiencies caused by rare autosomal recessive disorders, including familial hypoalphalipoproteinemia (HA), familial lecithin-cholesterol acetyltransferase (LCAT) deficiency, and Tangier disease, do not always correlate with more frequent CHD.

Results from the Framingham Heart Study offspring cohort, where 3590 individuals without known cardiovascular disease were studied from 1987 to 2011, found that cardiovascular risk was not only associated with high-density lipoprotein cholesterol but also was associated with a combination HDL levels and levels of low-density lipoprotein cholesterol and triglycerides.

Familial hypoalphalipoproteinemia or familial apo A-I deficiency

Criteria for the definition of familial HAs are (1) a low HDL cholesterol level in the presence of normal VLDL cholesterol and LDL cholesterol levels, (2) an absence of diseases or factors to which HA may be secondary, and (3) the presence of a similar lipoprotein pattern in a first-degree relative.

Familial HA is a relatively common disorder and is frequently associated with decreased apo A-I production or increased apo A-I catabolism. Severe HDL deficiency can also be associated with a heterogeneous group of rare, autosomal-recessive lipoprotein disorders. The underlying molecular defects involve apo A-I, apo C-III, or apo A-IV. HDL in plasma is almost undetectable in persons with the familial apo A-I deficiency caused by deletions of the APOA1 gene, the HDL level being less than 10 mg/dL. Heterozygotes tend to have less severe reductions in HDL.

Some patients with severe genetic HDL reductions manifest corneal opacities and xanthomas and have an increased risk of developing premature coronary atherosclerosis (ie, CHD).

The molecular diagnosis can be made by specialized analysis, including electrophoresis of the plasma apolipoproteins and deoxyribonucleic acid (DNA) analysis to determine the mutation. Because raising plasma apo A-I or HDL-C levels is usually difficult in persons with these disorders, treatment should be directed toward lowering the level of non-HDL cholesterol.

In some patients, this condition occurs as a result of certain nonsense mutations that affect the generation of the apo A-I molecule. These mutations are a very rare cause of low HDL cholesterol levels (usually 15-30 mg/dL). An example is APOA1 Milano, inherited as an autosomal dominant trait, which is not associated with an increased risk of premature CHD despite low HDL levels. Other than corneal opacities, most of these patients do not exhibit many clinical sequelae related to the APOA1 mutations. Certain other APOA1 mutations have been found in association with systemic amyloidosis, and the mutant APOA1 gene has been located within the amyloid plaque.

Causes

Tangier disease is an autosomal recessive genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for Tangier disease, the individual will be a carrier for the disease but will not show the classic characteristics. However, carriers of Tangier disease often are found to have relatively low levels of HDL-C.

The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

The gene that causes Tangier disease has been identified as ABCA1 (ATP-binding cassette transporter A1). ABCA1 codes for a cell surface protein that is important in the process of reverse cholesterol transport, which allows the movement of cholesterol from inside the cell to apolipoprotein AI (apoA-I), the major protein constituent of HDL. When two ABCA1 gene mutations are present, the cell is no longer able to efflux cholesterol out of the cell to ApoA-I.

Cholesterol is a soft, waxy substance found among the lipids (fats) in the bloodstream and in all the cells in our body. Cholesterol is essential to the formation of cell membranes, hormones, and other cellular functions. Cholesterol and other fats cannot dissolve in the blood and have to be transported to and from the cells by special carriers called lipoproteins.

There are several types of lipoproteins that vary in density, but the most clinically important types are low-density lipoprotein (LDL) and HDL. About one-third to one-fourth of blood cholesterol is carried by HDL. HDL is commonly called the “good” cholesterol because it may be involved with the removal of cholesterol from the artery walls and ultimate disposal to the liver. On the other hand, LDL deposits cholesterol in the artery walls, causing the formation of cholesterol plaque.

Patients with Tangier disease have been found to have a severe reduction in HDL levels. Without sufficient HDL to help clear arteries of plaques, individuals are more susceptible to having excess lipid deposits on organs of the body such as liver, heart, spleen, lymph nodes, and brain.

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency

This is a very rare autosomal recessive disorder characterized by corneal opacities, normochromic anemia, and renal failure in young adults. Approximately 30 kindreds and a number of mutations have been reported. LCAT deficiency results in decreased esterification of cholesterol to cholesteryl esters on HDL particles.

This in turn results in an accumulation of free cholesterol on lipoprotein particles and in peripheral tissues, such as the cornea, red blood cells, renal glomeruli, and vascular walls. At present, no effective method has been found to increase plasma LCAT levels; therefore, therapy is limited to (1) dietary restriction of fat to prevent the development of complications and (2) management of complications (eg, renal transplant for advanced renal disease).

Two kinds of genetic LCAT deficiencies have been reported. The first is complete (or classic) LCAT deficiency. Complete LCAT deficiency is manifested by anemia, increased proteinuria, and renal failure. The diagnosis can be made based on the results of LCAT quantification and cholesterol esterification activity in the plasma in certain specialized laboratories. The second type of deficiency is partial LCAT deficiency (fish-eye disease).

Components of plasma high-density lipoprotein

Plasma HDL is a small, dense, spherical lipid-protein complex, with the lipid and protein components each making up half. The major lipids are phospholipid, cholesterol, cholesteryl esters, and TGs. The major proteins include apo A-I (molecular weight, 28,000) and apo A-II (molecular weight, 17,000). Other minor, albeit important, proteins are apo E and apo C, including apo C-I, apo C-II, and apo C-III. HDL particles are heterogeneous. They can be classified into larger, less dense HDL2 and smaller, denser HDL3. Normally, most HDL is present as HDL3. However, individual variability in HDL levels in humans is usually due to different amounts of HDL2.

Reverse cholesterol transport system

HDL removes cholesterol from the peripheral tissues, such as fibroblasts and macrophages, and it is esterified by LCAT. The cholesteryl ester thus produced is transferred from the HDL to apo B – containing lipoproteins, such as VLDL, intermediate-density lipoprotein, and LDL, by a key protein termed cholesteryl ester transport protein in the liver. The HDL itself becomes enriched with TGs and subsequently becomes hydrolyzed by hepatic lipase. By this mechanism, the HDL finally becomes smaller again and is ready to scavenge more cholesterol. This pathway is called the reverse cholesterol transport system.

Familial Primary HypoAlphalipoproteinemia (FPHA) includes patients with a heritable genetic defect in one of the key genes involved in HDL particle production or maturation (apoA-I, ABCA-1, LCAT), which are individually very rare (prevalence: less than one in one million births in the homozygous form) but in both homozygous and heterozygous forms can act in an autosomal dominant manner to cause low apoA-I levels and low HDL particle numbers through either decreased production or increased clearance and premature destruction of HDL particles, and ultimately result in accelerated atherosclerosis from a single final common pathophysiology of impaired reverse lipid transport and accumulation of cholesterol throughout the body, in particular the vasculature.

FPHA caused by homozygous ABCA-1 deficiency is also known as Tangier’s disease. FPHA patients are at high risk of cardiovascular disease as a consequence of having inherited a virtually absent endogenous RLT system. Because of the specific characteristics of the disease and very limited available therapeutic approaches, FPHA remains an unmet medical need and a life-threatening condition.

Clinical Information

• A disorder of lipoprotein metabolism caused by mutations in the lcat gene. It is characterized by deficiency of the enzyme lecithin cholesterol acyltransferase. It is manifested with corneal opacity, hemolytic anemia, and proteinuria.
• A metabolic disorder characterized by deficiency of high density (alpha) lipoprotein in the blood.
• A rare, autosomal recessive inherited disorder of cholesterol transport, resulting in severe reduction of the amount of high density lipoprotein in the plasma and accumulation of cholesterol esters in the tissues. Signs and symptoms include large tonsils, hepatosplenomegaly, lymphadenopathy, and hypocholesterolemia.
• An autosomal recessive disorder characterized by defective absorption of dietary fat, cholesterol and fat-soluble vitamins. It results in multiple vitamin deficiencies. Signs and symptoms include failure to thrive, diarrhea, steatorrhea, acanthocytosis and ataxia.
• An autosomal recessive disorder of lipid metabolism. It is caused by mutation of the microsomal triglyceride transfer protein that catalyzes the transport of lipids (triglycerides; cholesterol esters; phospholipids) and is required in the secretion of beta-lipoproteins (low density lipoproteins or ldl). Features include defective intestinal lipid absorption, very low serum cholesterol level, and near absent ldl.
• An autosomal recessively inherited disorder caused by mutation of atp-binding cassette transporters involved in cellular cholesterol removal (reverse-cholesterol transport). It is characterized by near absence of alpha-lipoproteins (high-density lipoproteins) in blood. The massive tissue deposition of cholesterol esters results in hepatomegaly; splenomegaly; retinitis pigmentosa; large orange tonsils; and often sensory polyneuropathy. The disorder was first found among inhabitants of tangier island in the chesapeake bay, md.

An autosomal recessively inherited disorder caused by mutation of lecithin cholesterol acyltransferase that facilitates the esterification of lipoprotein cholesterol and subsequent removal from peripheral tissues to the liver. This defect results in low hdl-cholesterol level in blood and accumulation of free cholesterol in tissue leading to a triad of corneal opacity, hemolytic anemia (anemia, hemolytic), and proteinuria.

Autosomal recessive disorder of lipoprotein and lipid metabolism characterized by absence in plasma of normal high-density lipoprotein, deficiency of apolipoproteins ai and aii, low to normal low-density lipoproteins, high triglycerides and accumulation in body tissues of cholesteryl esters.

Conditions with abnormally low levels of alpha-lipoproteins (high-density lipoproteins) in the blood. Hypoalphalipoproteinemia can be associated with mutations in genes encoding apolipoprotein a-i; lecithin cholesterol acyltransferase; and atp-binding cassette transporters.

Conditions with abnormally low levels of lipoproteins in the blood. This may involve any of the lipoprotein subclasses, including alpha-lipoproteins (high-density lipoproteins); beta-lipoproteins (low-density lipoproteins); and prebeta-lipoproteins (very-low-density lipoproteins).

Disease characterized by abnormally low levels of plasma lecithin cholesterol acyl transferase; clinical manifestations include corneal opacity, anemia, and proteinuria.

Disorder of lipid metabolism inherited as an autosomal recessive trait characterized by the near absence of apolipoprotein b and apob containing lipoproteins in plasma; microsomal triglyceride transfer protein is deficient or absent in enterocytes; clinical and laboratory findings include acanthocytosis, hypocholesterolemia, peripheral neuropathy, posterior column degeneration, ataxia, and steatorrhea; intellectual abilities may also be impaired.

Presence of abnormally low levels of lipoproteins in the serum.

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