Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

Autosomal Dominant Disorders In autosomal dominant disorders, a single mutant allele from an affected parent is transmitted to an off- spring regardless of sex. The affected parent has a 50% chance of transmitting the disorder to each offspring 1–4 (Fig. 6-1). The unaffected relatives of the parent or unaffected siblings of the offspring do not transmit the disorder. In many conditions, the age of onset is delayed, and the signs and symptoms of the disorder do not appear until later in life, as in Huntington disease (see Chapter 37). In some cases, the person with an autosomal domi- nant disorder does not have an affected parent. Such persons owe their disorder to new mutations involving either the ovum or sperm from which they were derived. Their siblings are neither affected nor at increased risk of developing the disease. Whether the mutation is passed on to the next generation depends on the affected person’s reproductive capacity. Many new autosomal dominant mutations are accompanied by reduced repro- ductive capacity; therefore, the defect is not perpetuated in future generations. If an autosomal defect is accom- panied by a total inability to reproduce, essentially all new cases of the disorder will be due to new mutations. If the defect does not affect reproductive capacity, it is more likely to be inherited. Although there is a 50% chance of inheriting a domi- nant genetic disorder from an affected parent, there can be wide variation in gene penetration and expres- sion. When a person inherits a dominant mutant gene but fails to express it, the trait is described as having reduced penetrance . Penetrance is expressed in mathe- matical terms: a 50% penetrance indicates that a person who inherits the defective gene has a 50% chance of expressing the disorder. The person who has a mutant gene but does not express it is an important exception to the rule that unaffected persons do not transmit an autosomal dominant trait. These persons can transmit the gene to their descendants and so produce a skipped generation. Autosomal dominant disorders also can display variable expressivity , meaning that they can be expressed differently among individuals. Polydactyly or supernumerary digits, for example, may be expressed in either the fingers or the toes.

The gene products of autosomal dominant disorders usually are regulatory proteins involved in rate-limiting components of complex metabolic pathways or key components of structural proteins such as collagen. 2,3 Two disorders of autosomal inheritance, Marfan syn- drome and neurofibromatosis (NF), are discussed here. Marfan Syndrome. Marfan syndrome is an autoso- mal dominant disorder with an estimated prevalence of 1 per 20,000. 3 Approximately 75% of cases are of familial origin, with the rest arising from new muta- tions in the germ cells of parents. The pathogenesis of Marfan syndrome is related to mutations in a gene on chromosome 15 that codes for fibrillin , a major compo- nent of microfibrils found in the extracellular matrix. 3–5 Microfibrils serve as scaffolding for deposition of elastin and are considered integral components of elastic fibers. These fibers are essential for maintaining the tissue architecture of various body structures, most notably tendons and other elastin tissue–rich structures, such as heart valves and blood vessels. Marfan syndrome affects several organ systems, including the ocular system (eyes), the cardiovascular system (heart and blood vessels), and the skeletal sys- tem (bones and joints). 3–6 There is a wide range of varia- tion in the expression of the disorder. Persons may have abnormalities of one or all three systems. The skeletal deformities, which are the most obvious features of the disorder, include a long, thin body with exceptionally long extremities and long, tapering fingers, sometimes called arachnodactyly or spider fingers ; hyperextensible joints; and a variety of spinal deformities, including kyphosis and scoliosis (Fig. 6-2). Chest deformities, pec- tus excavatum (i.e., deeply depressed sternum), or pectus carinatum (pigeon chest) deformity often is present and may require surgery. The most common eye disorder is bilateral dislocation of the lens due to weakness of the suspensory ligaments. Myopia and predisposition to ret- inal detachment also are common, the result of increased optic globe length due to altered connective tissue sup- port of ocular structures. The most life-threatening aspects of the disorder, however, are the cardiovascular defects, which include mitral valve prolapse, progressive dilation of the aortic valve ring, and weakness of the aorta and other arteries. Dissection and rupture of the aorta may lead to premature death. In women, the risk of aortic dissection is increased in pregnancy. Treatment plans for Marfan syndrome include echo- cardiograms and electrocardiograms to assess the status of the cardiovascular system, periodic eye examinations, and evaluation of the skeletal system, especially in chil- dren and adolescents. Low to moderate activity levels are usually well tolerated. Strenuous activities such as contact sports, weight training, high-impact aerobics, and scuba diving should usually be avoided. Surgical treatment may become necessary in cases of progressive aortic dilation or acute aortic dissection. Neurofibromatosis. Neurofibromatosis is a condition involving neurogenic tumors that arise from Schwann cells and other elements of the peripheral nervous system. 2,3,7–12

FIGURE 6-1. Simple pedigree for inheritance of an autosomal dominant trait.The blue-colored square (male) or circle (female) represents an affected persons with a mutant gene. An affected parent with an autosomal dominant trait has a 50% chance of passing the mutant gene on to each child regardless of sex.