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ABSTRACT

Archibald Garrod recognized that alkaptonuria was a disorder reflecting Mendelian inheritance in the human population. In 1902, that was an observation with remarkable insight. Garrod called this and three other Mendelian disorders (cystinuria, pentosuria, and albanism) examples of human biochemical individuality. Another 50 years would elapse before our understanding of the inborn errors of metabolism would lead to a field of inquiry called “human biochemical genetics.” The growth of knowledge in this field, in the latter half of the 20th century, is reflected in the expansion of information in The Metabolic and Molecular Bases of Inherited Disease.

INTRODUCTION

In Chap. 7, we emphasized the prominence in disease of the protein gene products that serve as unit steps of homeostasis. Variant proteins are salient proximate causes of disease, impairing the function of the homeostatic devices they serve. It is characteristic of an integrated whole that no single element stands out, but when the harmony is disrupted by the failure of one of its parts, the specificity of the variant unit step is likely to be reflected by the nature of the failed function. However, other qualities may be distinguishing, too: age at onset of symptoms, burden as measured by threat of life, impaired reproduction or permanent disability, or frequency in populations.

Physicians characterize and classify diseases according to the most prominent expressions, principally of organ systems. Hospitals and specialties have been organized accordingly. But molecular biology and medicine have shifted our attention to molecular causes and their role in pathogenesis, so that some diseases, particularly monogenic disorders, are both characterized and classified according to the homeostatic system or molecules involved in proximate cause, as for example lysosomal storage diseases (see Part 16 of this text) or disorders of oxidative phosphorylation (see Part 10). Some are named for the variant molecule, as is G6PD deficiency (see Chap. 220). These designations do not contravene the old classification, which is likely to persist. Rather they represent subclasses, revealing of cause in their names.

Table 9-1 documents the exponential rate of increase in our recognition of classical inborn errors over the history of this book. Chapters in the current edition also tell of the discovery of variant gene products engaged in the pathogenesis of disorders of more complex etiology. Moreover, the once distant rumble of the promise of the Human Genome Project has given way to a roar with a crescendo to come in 2 to 3 years, or sooner. With the sequence in hand, attention will turn to describing the protein products of the sequenced genes, their function, and their homeostatic position. Proteomics1,2 will uncover increasing levels of complexity resulting from amplification of the encoded information by alternative splicing, transcriptional regulation, a myriad of posttranslational modifications, and by the intricate roles the proteins play in what Goldstein calls the “dialectic” between molecules and integrating physiology.3 Anomalies of this discourse ...

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