Lipoprotein inherited disorders

In chylomicron retention disease (Anderson s disease) the secretory defect is restricted to intestinal apoB-containing lipoproteins (i.e., chylomicrons). This very rare recessively inherited disorder results from defects in a GTPase, Sarlb, which plays a critical role in the intracellular assembly and trafficking of chylomicrons. The affected patients present with fat malabsorption resulting in steatorrhea and deficiency of fat-soluble vitamins [46, 52, 54]. 

Reichl D, Miller NE. Pathophysiology of reverse cholesterol transport. Insights from inherited disorders of lipoprotein metabolism. Arteriosclerosis. 1989, 9 785-797. 

Of the many disorders of lipoprotein metabolism (Tables 5.2 and 5.3), familial hypercholesterolaemia type II may be the most prevalent in the general population. It is an autosomal dominant disorder that results from mutations affecting the structure and function of the ceU-surface receptor that binds plasma LDLs and removes them from the circulation. The defects in LDL-receptor interaction result in lifelong elevation of LDL cholesterol in the blood. The resultant hypercholesterolaemia leads to premature coronary artery disease and atherosclerotic plaque formation. Familial hypercholesterolaemia was the first inherited disorder recognised as being a cause of myocardial infarction (heart attack). 

The normal function of lipoproteins is to distribute and recycle cholesterol. The pathways of lipid metabolism and transport and their primary (inherited) disorders appear in Figure 25.1 and can be summarised thus ... 

The genetic level is characterized by the fact that inherited disorders assoeiated with CVD became the most frequent among all genetic predispositions. Among those predispositions lipid and lipoprotein disorders occur particularly often. 

Genest J. Lipoprotein disorders and cardiovascular risk. J Inherit Metab Dis 2003 26 267-287. 

Mixed hyperlipidemia is one of the most common lipid disorders, but only a minor fraction of the affected patients has a monogenic inherited disease. Most patients with mixed hyperlipidemia have a familial combined hyperlipidemia, a multifactorial disease for which the causative factors are not known. Patients have elevated remnant lipoproteins with elevated triglycerides > 3.0 mmol/1 and total cholesterol > 5.0 mmol/1. Two rare monogenic disorders lead to such a lipoprotein pattern,... 

Patients with HL deficiency present with hypercholesterolemia and hypertriglyceridemia, and accumulate VLDL remnants, triglyceride-rich LDL, and HDL [84]. These remnants mainly derive from a reduced catabolism of apoB-containing lipoproteins [82]. The disorder appears to be inherited in an autosomal recessive trait and is associated with an increased risk for coronary artery disease [8]. 

Kane JP, Havel RJ (2001) Disorders of the biogenesis and secretion of lipoproteins containing the apolipoproteins. In Scriver C, Beaudet A, Sly E, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, pp 2717-2752... 

Scriver, C. R A. L. Beaudet, W. S. Sly, and D. Valle, The Metabolic Basis of Inherited Disease, 7th ed., vol. 1, New York McGraw-Hill, 1995. This book has an introductory chapter on lipoprotein structure and metabolism followed by many excellent chapters on disorders of cholesterol and lipoprotein metabolism. 

In this article we shall review recent advances in plasma lipoproteins, apolipoproteins, and those proteins concerned with lipoprotein lipid metabolism. This is a rapidly growing field, far too large to enable all aspects to be covered in a single paper. In order to keep to a manageable size, we shall focus on areas in which there have been recent major advances. Our treatment of other areas will be brief, as adequate reviews are in most cases available. Clinical details of primary disorders of plasma lipid metabolism are very well covered in a series of reviews in The Metabolic Basis of Inherited Disease (5th Ed., J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds.) (B52, G13, G20, H24, N8, S3, S56). Disordered lipid metabolism, and especially secondary disorders of lipid metabolism, are equally well covered in Metabolic Control and Disease (8th Ed., P. K. Bondy and L. E. Rosenberg, eds.) (H16). 

N8. Nikkila, E. A., Familial lipoprotein lipase deficiency and related disorders of chylomicron metabolism. In The Metabolic Basis of Inherited Disease 0. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, eds.), 5th Ed., pp. 622-642. McGraw-Hill, New York, 1983. 

Three disorders of lipoprotein metabolism share these characteristics familial hypobetal-ipoproteinemia, chylomicron retention disease, and ABL (Table 27-2). The presence or absence of specific plasma apoB lipoproteins, as well as their mode of inheritance, can be useful when attempting to differentiate between these disorders. Symptoms associated with familial hypo-betalipoproteinemia are usually milder than for the other two and are inherited as dominant traits, that is, symptoms are observed in at least one parent of an affected offspring. Chylomicron retention disease is an autosomal recessive disorder with a severe phenotype commonly presenting soon after birth. Plasma lipoprotein analysis from affected individuals shows a specific absence of chylomicrons (apoB48) but normal amounts of VLDL and LDL (apoB 100). In our patient, evidence of recessive inheritance and absence of all apoB-containing lipoproteins implicates ABL as the most likely diagnosis. 

There are five primary inherited lipoprotein disorders which disturb lipid matabolism at the points indicated in Figure 25.1. These are ... 

Type II hyperlipoproteinemia has been divided inlutyrc I la and Ilb. Type I la is characterized by elevated levels LDL (j3-lipoproteins) and nomral levels of triglyceiiilr This subtype disorder is very common and may be ciusx by disturbed catabolism of LDL. Type Ilb differs ffomiyp lla. in that this hyperlipidemia has elevated VLDL Mdietary restrictions on eholcsteml and. saturated fuLs Tlii type of hyperlipoproteinemia responds to some fomi i ... 

The diagnosis is made by the documentation of low LPL activity in postheparin plasma in the absence of added apo C-II. Normal enzymatic activity is restored by the addition of norm apo C-II to the assay mixture. In another approach, the absence of apo C-II can be recognized using an immunoassay for apo C-II. However, the latter approach may not distinguish between normal subjects and those with normal levels of a nonfunctional form of apo C-II. The defective apo C-II disorder is inherited in an autosomal recessive mode, but at a lower frequency than LPL deficiency. More than 10 structural defects in the apo C-II gene that lead to the absence of apo C-II or the production of a defective apo C-II molecule have been described. Subjects heterozygous for a defective apo C-II gene have normal lipid and lipoprotein profiles, because a sufficient amount of normal apo C-II is usually present to activate LPL. 

Lipoprotein lipase (LPL) deficiency is inherited as an autosomal recessive disorder. Hyperchylomicronemia is present from birth. Upon fat ingestion, triacylglycerol levels may rise to 5000-10,000 mg/dL. Chylomicron levels are greatly elevated but not the VLDL levels (type I hyperlipoproteinemia). Type I hyperlipoproteinemia can also be... 

Beside lipoprotein disorders many other inherited metabolic diseases are associated with CVD. Generally these disorders lead to an increased concentration of plasma constituents that directly or indirectly damage the integrity of the vascular wall. Consequently these diseases lead to peripheral angiopathies as observed in diabetes, homocystinuria, sickle-cell anemia (the first molecular disease described, and man/ other genetic disorders. Similar to lipoproteins the deposition of various plasma constituents as well as proliferative thickening provided a certain stability for the ascorbate-deficient vascular wall. We illustrate this principle for diabetic and homocystinuric angiopathy. 

Another frequent inherited lipoprotein disorder is hypoalphalipoproteinemia. The frequency of this disorder again reflects its usefulness during evolution. The metabolic upregulation of HDL synthesis by ascorbate became an important mechanism to reverse and decrease existing lipid deposits in the vascular wall. 

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