Hypercholesterolemia familial , defective

In a large population study Goldstein et al. discussed three frequent lipid disorders, familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia. Ascorbate deficiency unmasks these underlying genetic defects and leads to an increased plasma concentration of lipids (e.g. cholesterol, triglycerides) and Hpoproteins (e.g. LDL, VLDL) as well as to their deposition in the impaired vascular wall. As with Lp(a), this deposition is a defense measure counteracting the increased permeability. It should, however, be noted that the deposition of lipoproteins other than Lp(a) is a less S[>ecific defense mechanism and fre-... 

Tybiaerg-Hansen, A. and Humphries, S. (1992) Familial defective apolipoprotein B-100 a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis, 96, 91. 

Defects in the LDL receptor have been particularly well explored as a basis of the disease familial hypercholesterolemia (93,111). A number of defects that collectively impair LDL receptor trafficking, binding, or deUvery underHe this disease where LDL and semm cholesterol rise to levels that mediate early cardiovascular mortaUty. Studies of the population distribution of this defect can determine the source of the original mutation. Thus, in Quebec, about 60% of the individuals suffering from familial hypercholesterolemia have a particular 10-kdobase deletion mutation in the LDL gene (112). This may have arisen from an original founder of the French Canadian settiement in the seventeenth century. 

The hver and many extrahepatic tissues express the LDL (B-lOO, E) receptor. It is so designated because it is specific for apo B-IOO but not B-48, which lacks the carboxyl terminal domain of B-lOO containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E. This receptor is defective in familial hypercholesterolemia. Approximately 30% of LDL is de-... 

The primary defect in familial hypercholesterolemia is the inability to bind LDL to the LDL receptor (LDL-R) or, rarely, a defect of internalizing the LDL-R complex into the cell after normal binding. This leads to lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL cholesterol (LDL-C) being inversely proportional to the deficit in LDL-Rs. 

In patients with familial hypercholesterolemia caused by defective LDL-receptor function, Lp(a) concentration in plasma is reported to be 2.5-3.0 times higher than in matched controls (HI 1, U8). In cultured fibroblasts of these patients, catabolism of Lp(a) and LDL is diminished as compared to controls. In fibroblasts of controls, the catabolism of Lp(a) is slower than that of LDL (F13, HI 1, Ml). 

Familial hypercholesterolemia (FH), an autosomal dominant disorder of lipoprotein metabolism, is caused by absent or defective LDL receptors. Several studies indicated that Lp(a) levels were approximately doubled in FH heterozygotes, compared to their unaffected family members or non-FH controls (H30, L14, M20, M21, U8, W13, W14). 

The number of active LDL receptors is also affected by a condition called familial hypercholesterolemia, in which there is a defective gene coding for the receptor. In either case, the reduction of active receptors means that the LDL carrying cholesterol is unable to enter the cell interior instead, it is deposited in the arteries leading to the heart or brain. These deposits build up over time and may block blood supply to the heart muscle or brain, resulting in a heart attack or stroke. In contrast, HDL transports cholesterol from other parts of the body to the liver, where it is degraded to bile acids. 

D. Reduced hepatic LDL-receptor activity. Familial hypercholesterolemia is most often due to dehcient LDL-receptor activity. A less likely possibility, although not considered in this question, is reduced LDL clearance from the circulation due to defective apolipoprotein Bioo. 

Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholesterolemia of moderate severity. Tendon xanthomas may occur. These disorders are as prevalent as familial hypercholesterolemia. Response to reductase inhibitors is variable. Up-regulation of LDL receptors in liver increases endocytosis of LDL precursors but does not increase uptake of ligand-defective LDL particles. Niacin often has beneficial effects by reducing VLDL production. 

A proper balance of cholesterol in the bloodstream requires having an adequate balance of receptors to process the amount of cholesterol in the blood. Receptors are continually regenerated, produced, and disappear in the cell in response to blood biochemistry. The liver contains the greatest concentration of receptors. Too few receptors or excess dietary cholesterol intake can lead to elevated blood cholesterol. A genetic disorder called familial hypercholesterolemia results when a person inherits a defective gene from one parent resulting in the inability to produce sufficient receptors. A diet with too much cholesterol represses the production of LDL receptors and leads to high blood cholesterol and Apo B. 

Familial hypercholesterolemia (FH) is one of the most common genetic disorders in lipoprotein metabolism, and causes elevated cholesterol levels. This autosomal dominant disorder with a prevalence of about 1/500 in Western countries is caused by mutations in the LDLR gene. The LDLR defect impairs the catabolism of LDL and results in elevation of plasma LDL-cholesterol. Untreated heterozygous FH patients have 2-3 times elevated cholesterol levels and have a 100-fold increased risk to die... 

The best understood cause of atherosclerosis is the genetic defect familial hypercholesterolemia,... 

Familial hypercholesterolemia results from a defective LDL receptor. As a result, the cholesteryl ester in the LDL of the bloodstream cannot be cleared by the normal process, hence, high cholesterol levels occur in the plasma of these patients. Somehow, the high levels of cholesterol lead to the formation of the atherosclerotic lesions, the underlying cause of premature heart disease in these patients. 

G22. Goldstein, J. L., Kita,T., and Brown, M. S., Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N. Engl. ]. Med. 309, 288-296 (1983). 

Type I lipoproteinemia is generally caused by the inability of the organism to clear chylomicrons. The problem may be defective ApoC-II or a defective lipoprotein lipase. Very often, chylomicron clearance may be affected by injection of heparin, which apparently releases hepatic lipase from the liver into the circulation. ApoE disorders may be associated with type III lipoproteinemia, in which clearance of IDL is impeded. Increases in circulatory LDL are usually caused by a decrease in tissue receptors specific for ApoB-100. An extreme case of type Ha hyperlipoproteinemia is familial hypercholesterolemia, in which serum cholesterol levels may be as high as 1000 mg/dL and the subjects may die in adolescence from cardiovascular disease. There is total absence of ApoB-100 receptors. Mild type Ila and lib lipoproteinemias are the most commonly occurring primary lipoproteinemias in the general population. 

Four classes of LDL receptor mutations have been identified. Class 1 mutations are characterized by the failure of expression of the receptor protein. It is possible, however, that a modified protein is produced but it is not recognized as an LDL receptor protein. Class 2 mutations involve a nonsense mutation (premature termination of protein synthesis Chap. 17), and result in a defect in the transfer of the receptor from the endoplasmic reticulum to the cell membranes. This class of mutation is common in Afrikaners and Lebanese. The Watanabe heritable hyperlipidemic rabbit (WHHL) is an animal model which has a Class 2 defect and has been used extensively for the study of familial hypercholesterolemia. Class 3 mutations result in abnormal binding of LDL. This can be caused by alterations in the amino acid sequence of Domain 1. Class 4 mutations are those with defective internalization due to the receptor s inability to be located in coated pits. This is the result of mutations in the fifth, C-terminal domain. 

In the congenital disease familial hypercholesterolemia, the high circulating level of cholesterol is due to the complete absence of LDL receptors or to the presence of defective receptors on cell surfaces. 

B. Familial hypercholesterolemia (Type Ila or lib pattern). Elevation of LDL (sometimes VLDL, too). This involves a defect in the ceil LDL receptor site. 

The molecular defect in most cases of familial hypercholesterolemia is an absence or deficiency of functional receptors for LDL. Receptor mutations that disrupt each of the stages in the endocytotic pathway have been identified. Homozygotes have almost no functional receptors for LDL, whereas heterozygotes have about half the normal number. Consequently, the entry of LDL into liver and other cells is impaired, leading to an increased plasma level of LDL. Furthermore, less IDL enters liver cells because IDL entry, too, is mediated by the LDL receptor. Consequently, IDL stays in the blood longer in familial hypercholesterolemia, and more of it is converted into LDL than in normal people. All deleterious consequences of an absence or deficiency of the LDL receptor can be attributed to the ensuing elevated level of LDL cholesterol in the blood. 

Familial hypercholesterolemia (FH) (common) is characterised by elevation of total and LDL-cholesterol in plasma. In the more severe heterozygous form, this affects about 1 500 of the population (one copy of the LDL-receptor protein is absent or defective). LDL-cholesterol is elevated from childhood. Untreated, half the males will be dead by 60 years, females 10 years later. The principal consequence is coronary heart, but occasionally also peripheral and cerebrovascular disease. 

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