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classical example is hemophilia A, in which one of the serum factors necessary for normal blood clotting is inactive or lack- ing. (The disease can now be controlled by repeated substitu- tion of the deficient blood factor; this is a good example for phenotypic therapy of a hereditary disease by substitution of a deficient gene product.) As shown in Fig. 9a , male family members are affected, whereas their sisters and daughters, while being unaffected themselves, transmit the mutant gene to half their sons. Only in very rare instances, when a hemo- philic patient marries a heterozygous carrier, are homozygous females observed (Fig. 9b). Multifactorial diseases There are thousands of hereditary diseases with simple, men- delian modes of inheritance, but most common anomalies and diseases are influenced by genetic variability at more than one gene locus. Most congenital malformations, including congeni- tal heart disease, cleft lip and palate, and neural tube defects, fall into this category, as do the constitutional diseases, such as diabetes mellitus, coronary heart disease, anomalies of the immune response, and many mental diseases, including schizo- phrenia and affective disorders. All of these conditions are common and often increase in frequency with advanced age. Moreover, the environment usually contributes significantly to the disease risk. Biochemical genetics Research dealing with biochemical genetics began with the study of inborn errors of metabolism. These are diseases of the body chemistry in which a small molecule, such as a sugar or amino acid, accumulates in body fluids because an enzyme re- sponsible for its metabolic breakdown is deficient. This molecu- lar defect is the result of a mutation (or mutations) in the gene coding for the enzyme protein. The accumulated molecule, dependent on its nature, is responsible for the causation of a highly specific pattern of disease. In addition, similar heritable defective enzymes have been found to interfere with the break- down of very large molecules, including mucopolysaccharides and the complex lipids that are such prominent components of brain substance. The resultant storage disorders present with extreme alterations in morphology and bony structure and with neurodegenerative disease. Inheritance mechanism Most hereditary disorders of metabolism are inherited in an autosomal-recessive fashion. In these families, each par- ent carries a single mutant gene on one chromosome and a normal gene on the other. Typically, these mutations are rare. In populations where consanguinity is common, rare recessive diseases are seen with relative frequency, and affected indi- viduals are homozygous for the same mutation. In populations with more genetic diversity, most affected individuals carry two different mutations in the same gene. Some metabolic diseases are coded for by genes on the X chromosome. Most of these disorders are fully recessive; thus, affected individuals are all males, whereas females carrying the gene are clinically normal. The disorders that result from mutations in the mitochondrial genome are inherited in nonmendelian fashion because mi- tochondrial DNA is inherited only from the mother. Those that carry a mutation are heteroplasmic; that is, each carries a mixed population of mitochondria, some with the mutation and some without the mutation. Inborn errors of amino acid metabolism Phenylketonuria (PKU) is a prototypic biochemical genetic disorder. It is an autosomally recessive disorder in which muta- tions demonstrated in a sizable number of families lead, when present in the genes on both chromosomes, to defective activ- ity of the enzyme that catalyzes the first step in the metabolism of phenylalanine. This results in the accumulation of phenylala- nine and a recognizable clinical disease whose most prominent feature is severe intellectual disability of mental development. Human Genetics (continued) + ward ' s science Fig. 9 Typical pedigree patterns of a sex-linked recessive trait: hemophilia A. (a) Only males are affected and usually come from unaffected mothers, who often have affected fathers or brothers. (b) An affected female can result from an affected father and a carrier woman. (c) All daughters of affected males are carriers. (Copyright © McGraw Hill)