a problem if their health would be placed at risk under circumstances conferring benefits to the health of most of the population.
Nutritional factors may have played a role in human evolution by selecting for certain genotypes (Neel, 1984). Thus, periods of starvation may have favored genotypes predisposing to hyperlipidemia and non-insulin-dependent diabetes by allowing more ready mobilization of lipids and glucose that provided a slightly better chance of survival and reproduction. A similar reasoning applies to genotypes predisposing to obesity. Such a hypothesis would explain the relatively high frequency of these traits.
Even though inborn errors of metabolism are rare, their mechanisms may illustrate the role that more common genes may play in nutrition. The intrinsic processes required for proper nutrition, such as digestion, absorption, and excretion, are affected selectively by many different inborn errors of nutrient metabolism (Rosenberg, 1984). More than 200 such disorders have already been described. Among them are lactose intolerance (the inability to digest lactose); glucose-galactose malabsorption (the inability to absorb these nutrients); familial hypercholesterolemia, which develops in people who lack the receptors necessary to remove low-density lipoproteins (LDLs) from plasma; ornithine transcarbamylase deficiency, in which people lack an enzyme involved in the detoxification of ammonia; and hypophosphatemic rickets, in which the renal reabsorption of phosphorus and the intestinal absorption of phosphorus are impaired (Rosenberg, 1980). These disorders vary with regard to nutrients involved, frequency of occurrence, ethnic distribution, clinical severity, and disease manifestations (Holtzman et al., 1980). They may produce an internal or functional deficiency of an essential macro- or micronutrient despite adequate dietary intake; they may lead to chemical toxicity by blocking a catabolic pathway needed to metabolize an ingested nutrient; they may interfere with the formation of a needed product from an ingested nutrient; they may disrupt feedback regulatory pathways; or they may lead to pathological accumulation of macromolecules. Many of these metabolic disorders can be managed by modifying nutrient intake. For example, deficient intestinal absorption of a nutrient can be remedied by high oral intakes or parenteral administration; toxicity resulting from a blocked catabolic pathway of an essential amino acid can be relieved by restricting intake; vitamin supplementation may help to ameliorate a disturbance due to deficiency of an enzyme that requires the vitamin as a cofactor (Rosenberg, 1980).
Uptake of a variety of nutrients and other critical metabolites by cells is carried out by receptor-mediated endocytosis. The receptor that facilitates the uptake of LDLs (LDL receptor) has been studied in detail in the normal state and is an excellent model for receptor function in general (Goldstein and Brown, 1985). Some mutations of this receptor lead to defective transfer of LDLs into cells and increased LDL and cholesterol levels in the blood; this in turn predisposes to coronary heart disease (CHD). Mutations for the heterozygote state of familial hypercholesterolemia are found in approximately 1 in 500 people and predispose to premature coronary arteriosclerosis. Homozygotes are very rare (one in a million) and often develop CHD before 20 years of age (Goldstein and Brown, 1983).
These rare genetic disorders affecting enzymes and receptors illustrate how a severe genetic defect may lead to malnutrition or specific damage to a given organ system. They can serve as models for the study of milder but more common genetic variations in their effect on nutrition.
The expression of most inborn errors of metabolism requires the presence of two identical mutant geneseach contributed by the carrier parent of an affected patient. The most common genetic disease of this sort is phenylketonuria, an autosomal recessive disease with a maximum frequency of 1 in 10,000 births. Most other inborn errors of metabolism have frequencies between 1 in 40,000 and 1 in 250,000 (Vogel and Motulsky, 1986). These rare inborn errors are not usually considered in making nutritional recommendations for the population as a whole, but carriers of the relevant mutant gene are quite common in the population. For example, 2% of the population are carriers of the mutant gene for phenylketonuria. In patients with inborn errors of metabolism, the involved enzyme has very little normal activity. Normal people have approximately 100% activity; carriers have about 50%. Under most conditions, a 50% level of enzyme activity is sufficient for adequate function. Thus, carriers are in good health. Under conditions of growth, stress, illness, or malnutri-