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There are three major types of mutations: (1) genome mutations, which involve loss or gain of an entire chromosome; (2) chromosomal mutations, which involve alterations in one or more chromosomes that are usually identifiable by karyotyping; and (3) gene mutations, which are partial or complete deletion of the gene or alteration of the base. Genome mutations usually result in death of the fetus, or death during infancy or early childhood.

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Many diseases have a genetic component, albeit without a specific identifiable gene mutation. Such conditions are said to have a multifactorial inheritance pattern. Examples of such diseases include coronary artery disease, hypertension, gout, and diabetes mellitus.

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When discussing genetic diseases, some definitions are important to remember: (1) hereditary or familial, a condition derived from parents (i.e., a condition that is transmitted in the germ line); and (2) congenital, a condition that is present at birth. Not all hereditary conditions are congenital, and not all congenital conditions are hereditary. Some hereditary conditions are manifested at the time of birth or shortly thereafter, and many manifest later in life.

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The overall effects of the mutation of a single gene include (1) an enzyme defect; (2) defects in membrane receptors and/or transport system; (3) alterations in structure, function, or quantity of nonenzymatic protein; or (4) mutations resulting in unusual reactions to drugs. An enzyme defect can cause accumulation of substrate, a metabolic block resulting in a decreased amount of needed end product, or failure to inactivate a tissue-damaging substrate.

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Overview: In general, autosomal dominant disorders have reduced penetrance and variable expressivity. They usually do not encode enzymes because a loss of up to 50% of an enzyme's activity can be compensated for by activity of the enzyme encoded by the normal allele (Table 6-1).

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Table Graphic Jump Location
Table 6-1. Autosomal Dominant Neoplasia Syndromes 
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Familial Hypercholesterolemia

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Mutation: Low-density lipoprotein receptor gene (LDL); there are more than 100 known mutations.

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Mechanism: The LDL receptor recognizes apolipoprotein B100 or apolipoprotein E; therefore, a mutation of the receptor results in impaired uptake of cholesterol into cells.

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Manifestations of familial hypercholesterolemia

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  • Elevated cholesterol level: Heterozygotes have half the normal amount of LDL receptors and two to three times the normal level of cholesterol; homozygotes have five or more times the normal level of cholesterol.
  • Tendon sheath xanthomas, corneal arcus, and xanthelasma.
  • Early atherosclerosis and its consequences; homozygotes usually die of cardiovascular disease before the age of 30 years.

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Familial ...

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