Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

Neurofibromatosis-2,which is characterizedby tumors of the acoustic nerve and multiple meningiomas, is much less common than NF-1. 10–12 The disorder is often asymptomatic through the first 15 years of life. The most frequent symptoms are headaches, hearing loss, and tin- nitus (i.e., ringing in the ears). There may be associated intracranial and spinal meningiomas. The condition is often made worse by pregnancy, and oral contracep- tives may increase the growth and symptoms of tumors. Persons with the disorder should be warned that severe disorientation may occur during diving or swimming underwater, and drowning may result. Surgery may be indicated for debulking or removal of the tumors. Autosomal Recessive Disorders Autosomal recessive disorders are manifested only when both members of the gene pair are affected. In this case, both parents may be unaffected but are carriers of the defective gene. Autosomal recessive disorders affect both sexes. The occurrence risks in each pregnancy are one in four for an affected child, two in four for a carrier child, and one in four for a normal (noncarrier, unaf- fected) homozygous child 1–4 (Fig. 6-4). Consanguineous mating (mating of two related individuals), or inbreed- ing, increases the chance that two people who mate will be carriers of an autosomal recessive disorder. With autosomal recessive disorders, the age of onset is frequently early in life; the symptomatology tends to be more uniform than with autosomal dominant disor- ders; and the disorders are characteristically caused by loss-of-function mutations, many of which impair or eliminate the function of an enzyme. In the case of a heterozygous carrier, the presence of a mutant gene usu- ally does not produce symptoms because equal amounts of normal and defective enzymes are synthesized. This “margin of safety” ensures that cells with half their usual amount of enzyme function normally. By con- trast, the inactivation of both alleles in a homozygote results in complete loss of enzyme activity. Although new mutations for recessive disorders do occur, they are

rarely detected clinically because the affected person is an asymptomatic heterozygote. Several generations may pass before the descendants of such a person mate with other heterozygotes and produce affected offspring. 3 Autosomal recessive disorders include almost all inborn errors of metabolism. Enzyme disorders that impair catabolic pathways result in an accumulation of dietary substances (e.g., phenylketonuria) or cellular constituents (e.g., lysosomal storage diseases). Other disorders result from a defect in the enzyme-mediated synthesis of an essential protein (e.g., the cystic fibrosis transmembrane conductance regulator in cystic fibrosis [see Chapter 23]). Two examples of autosomal recessive disorders that are not covered elsewhere in this book are phenylketonuria and Tay-Sachs disease. Phenylketonuria. Phenylketonuria (PKU, hyperphenyl- alaninemia) is a metabolic disorder caused by elevated levels of phenylalanine that are toxic to the brain. The incidence of PKU and hyperphenylalaninemia is 1 per 10,000 in the white and Asian population, but varies widely across geographic areas (e.g., 1 per 4500 in Ireland to less than 1 per 100,000 in Finland). 2 In most cases, the hyperphenylalaninemia results from a deficiency of phenylalanine hydroxylase (PAH), a liver enzyme that converts the amino acid phenylalanine to tyrosine. 1–3,13,14 Phenylalanine is an essential amino acid derived solely from the diet. In normal children, less than 50% of the phenylalanine consumed in the diet is used for protein synthesis. The remainder is converted to tyro- sine by PAH. When breakdown of phenylalanine is blocked because of a lack of PAH, other minor meta- bolic pathways are used, yielding several intermediates that are excreted in large amounts in the sweat and urine. These metabolites impart an unpleasant, strong, musty odor to affected infants. It is believed, however, that phenylalanine rather than its metabolites contrib- utes to the brain damage in PKU. The lack of tyrosine, a precursor of melanin, is responsible for the light color of the hair and skin. At the molecular level, approximately 400 mutant alleles for the PAH gene have been identified, some of which produce only mild deficiency while others pro- duce severe deficiency. 3 The severity of hyperphenylal- aninemia depends on the degree of PAH deficiency and can be classified as classic PKU , mild PKU , or mild hyperphenylalaninemia based on blood concentrations of phenylalanine. 13,14 Infants and children with classic and mild PKU require dietary protein restrictions to pre- vent intellectual impairment, microcephaly, and other signs of impaired neurologic development. Affected infants are normal at birth but within a few weeks begin to develop a rising phenylalanine level and signs of impaired brain development. Seizures, other neurologic abnormalities, decreased pigmentation of the hair and skin, and eczema often accompany the mental retarda- tion in untreated infants. Because the symptoms of untreated PKU develop grad- ually andwouldoftengoundetecteduntil irreversible intel- lectual impairment had occurred, newborns are routinely screened for abnormal levels of serum phenylalanine. 13–15

FIGURE 6-4. Simple pedigree for inheritance of an autosomal recessive trait.The half blue-colored square (male) and circle (female) represent a mutant gene. When both parents are carriers of a mutant gene, there is a 25% chance of having an affected child (full blue-colored circle or square), a 50% chance of a carrier child, and a 25% chance of an unaffected or noncarrier child, regardless of sex. All children (100%) of an affected parent are carriers.