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Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to discovery of the usual law of Nature by careful investigation of cases of rarer forms of disease. For it has been found, in almost all things, that what they contain of useful or applicable is hardly perceived unless we are deprived of them, or they become deranged in some way. (Taken from Garrod1 quoting a letter written by William Harvey in 1657 to emphasize the value of studying human variants.)

Abstract  The medical model of disease holds that manifestations are the result of a process that has a cause. The manifestations of disease are assembled in diagnosis and they constitute a taxonomy. The process which underlies them is the pathogenesis of disease. The cause of disease comprises either an event that overwhelms homeostatic mechanisms (an extrinsic cause) or one that undermines them (an intrinsic cause). Most diseases involve a combination of both (a multifactorial cause).

Abstract  This text has three unifying themes. The first, and central, theme is that the causes of the diseases described are mutations (intrinsic). Because these mutations are often expressed as disadaptive phenotypes (i.e., clinical manifestations) in the universal environment, they may cause diseases that are simply inherited and classified as Mendelian or single-gene disorders. Some chapters describe more complex causes with non-Mendelian inheritance, as in the cases of Down syndrome (Chap. 63, a chromosomal disease) and diabetes mellitus (Chaps. 6 and 67 to 69, a multifactorial disease). The discussion of LDL-receptor deficiency (Chap. 120) and other lipoprotein disorders illustrates how a disease of heterogeneous etiology (coronary artery disease) is being broken down into its component causes, some cases being caused primarily by a defect in a single gene, and some cases being of multifactorial etiology. The text is now greatly expanded to encompass cancer, in which somatic mutation and environmental exposures play a more prominent role along with germ line mutations. Any of these three factors—germ line mutation, somatic mutation, or environmental factors—may predominate in a single individual or type of cancer. Germ line mutation is the major contributor in retinoblastoma (Chap. 36) and polyposis of the colon or hereditary nonpolyposis colon cancer (Chaps. 32 and 48). Somatic mutations and environment are usually entwined, but stochastic somatic mutation independent of environment may be more prominent, as perhaps is true for many cases of breast cancer (Chap. 47) or pancreatic cancer (Chap. 50), while environmental factors causing somatic mutations may be more obvious, as in the case of smoking and lung cancer or asbestosis and mesothelioma (Chap. 58). Each recent edition of this text, when compared with the previous edition, reveals an enormous increase in our knowledge about genetic cause at the molecular level. This knowledge is applied increasingly through the use of recombinant DNA methods in clinical diagnosis and counseling. Although the study of single-gene disorders has been the traditional focus of this book, the understanding of the molecular and biochemical basis of common, multifactorial disorders is increasing rapidly and will have a growing impact on the practice of medicine.

Abstract  This text’s second unifying theme deals with pathogenesis in great detail. Knowledge of the pathophysiology of a disease explains its manifestations, is necessary for rational treatment, and may even suggest that treatment is not feasible.2, 3 It can be taken for granted that at least partial knowledge of pathogenesis is important for the treatment of most inborn errors of metabolism. The successive editions of this book document the expansion of knowledge about cause and about pathogenesis of inherited diseases. In due course, this book, or one like it, should become a fundamental textbook for the theory and practice of medicine, because most diseases in developed societies have genetic determinants. Every individual is a deviant in terms of biochemical individuality, 4 meaning that every person has an inherited predisposition to disease (diathesis) in a particular circumstance. This is not a new idea; Garrod expounded it thoroughly and clearly in his second book.5 The difference between then and now is simply that molecular methods have made it possible to see in our DNA, our inherited predispositions. We can either avoid the occurrence of serious disease genotypes through genetic counseling procedures or ameliorate symptoms through treatment.

Abstract  Therapy of inherited diseases constitutes the third unifying theme of this text as outlined in Chap. 5 and in chapters throughout the book for specific diseases. In the metabolic context, we think first of dietary therapy as in phenylketonuria, but therapy for genetic disease is now very broad, encompassing organ transplantation, enzyme replacement, pharmacologic intervention, avoidance of genotype-specific risk factors, surgical correction or amelioration, and a multitude of other strategies. Attempts to provide treatment through somatic gene therapy have barely begun, but there is hope that this approach could provide dramatic new therapeutic avenues as discussed in recent reviews68 and texts, 911 despite the unfortunate, gene therapy-related death of a patient with an inborn error of metabolism in late 1999.12

Abstract  The power of current cellular, molecular, and metabolic techniques is that they provide a vast amount of new information. There is the astounding prospect of identifying the biochemical defects for most or all of the thousands of disease phenotypes catalogued by McKusick in Mendelian Inheritance in Man 13 and its electronic version, OMIM ( A detailed map of the human genome is now a reality (see Chap. 10), and about half of human genes were reported to be identified by late 1998.14 Efforts are underway to develop a full set of human full-length cDNA clones and sequences.15

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