Porth's Essentials of Pathophysiology, 4e

111

Genetic and Congenital Disorders

C h a p t e r 6

Infants with hyperphenylalaninemia are treated with a special diet that restricts phenylalanine intake. The results of dietary therapy of children with PKU have been impressive. The diet can prevent intellectual impairment as well as other neurodegenerative effects of untreated PKU. However, dietary treatment must be started early in neonatal life to prevent brain damage. Infants with ele- vated phenylalanine levels should begin treatment by 7 to 10 days of age, indicating the need for early diagno- sis. The duration of the dietary restriction remains con- troversial. Women with PKU who wish to have children require careful attention to their diet, both before concep- tion and during pregnancy, as a means of controlling their phenylalanine levels. Tay-Sachs Disease. Tay-Sachs disease is a variant of a class of lysosomal storage diseases, known as the gan- gliosidoses, in which there is failure of lysosomes to break down the GM 2 ganglioside of cell membranes. Tay-Sachs disease is inherited as an autosomal reces- sive trait and is predominantly a disorder of Eastern European (Ashkenazi) Jews, in whom a carrier rate of 1 in 30 has been reported. 1–3 The GM 2 ganglioside accumulates in the lysosomes of all organs in Tay-Sachs disease, but is most promi- nent in the brain neurons and retina. Microscopic examination reveals neurons ballooned with cytoplas- mic vacuoles, each of which constitutes a markedly dis- tended lysosome filled with gangliosides. In time, there is progressive destruction of neurons within the brain substance, including the cerebellum, basal ganglia, brain stem, spinal cord, and autonomic nervous system. Involvement of the retina is detected by ophthalmos- copy as a cherry-red spot on the macula. Infants with Tay-Sachs disease appear normal at birth but begin to manifest progressive weakness, muscle flac- cidity, and decreased attentiveness at approximately 6 to 10 months of age. This is followed by rapid deteriora- tion of motor and mental function, often with develop- ment of generalized seizures. Retinal involvement leads to visual impairment and eventual blindness. The disease is invariably fatal, and death usually occurs before 4 to 5 years of age. Although there is no cure for the disease, analysis of the blood serum for the lysosomal enzyme hexosaminidase A, which is deficient in Tay-Sachs dis- ease, allows for accurate identification of genetic carriers for the disease. X-Linked Disorders Sex-linked disorders are almost always associated with the X, female, chromosome, and the inheritance pattern is predominantly recessive. 1–4 Because of the presence of a normal paired X gene, female heterozygotes rarely experience the effects of a defective gene, whereas all males who receive the gene are typically affected. The common pattern of inheritance is one in which an unaf- fected mother carries one normal and one mutant allele on the X chromosome. This means that she has a 50% chance of transmitting the defective gene to her sons, and her daughters have a 50% chance of being carriers

of the mutant gene (Fig. 6-5). When the affected son procreates, he transmits the defective gene to all of his daughters, who become carriers of the mutant gene. Because the genes of the Y chromosome are unaffected, the affected male does not transmit the defect to any of his sons, and they will not be carriers or transmit the disorder to their children. X-linked recessive disorders include glucose-6-phosphate dehydrogenase deficiency (see Chapter 13), hemophilia A (see Chapter 12), and X-linked agammaglobulinemia (see Chapter 16). FIGURE 6-5. Simple pedigree for inheritance of an X-linked recessive trait. X-linked recessive traits are expressed phenotypically in the male offspring. A small blue-colored circle represents the X chromosome with the defective gene in the female and the larger blue-colored square represents the affected male.The affected male passes the mutant gene to all of his daughters, who become carriers of the trait and have a 50% chance of passing the gene to their sons and daughters, who in turn have a 50% chance of being carriers of the gene. Single-Gene Disorders with Atypical Patterns of Inheritance Several genetic disorders do not follow the mendelian pattern of inheritance. These include diseases caused by genomic imprinting, triplet repeat mutations, and muta- tions in mitochondrial genes. 3 Genomic Imprinting According to the mendelian pattern of inheritance, a mutant allele of an autosomal gene is equally likely to be transmitted from a parent to an offspring of either sex; similarly, a female is equally likely to transmit a mutated X-linked gene to either sex. 2 Originally, little attention was paid to whether the sex of the parent had any effect on expression of the genes each parent transmits. It is now known that in some genetic disor- ders, such as Prader-Willi and Angelman syndromes, the expression of the disease phenotype depends on whether the mutant allele was inherited from the father or the mother, a phenomenon known as genomic imprint- ing . Both syndromes exhibit intellectual disability as a common feature, and both involve the same deletion in chromosome 15. However, when the deletion is inher- ited from the mother, the infant presents with Angelman