Metabolism genetic diseases

Genetic Diseases of Sulfur Metabolism in Humans (F. Skovby, S. H. Mudd)... 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Table 48-10. Some metabolic and genetic diseases affecting bone and cartilage.

A much more serious genetic disease, first described by Foiling in 1934, is phenylketonuria. Here the disturbance in phenylalanine metabolism is due to an autosomal recessive deficiency in liver phenylalanine hydroxylase (Jervis, 1954) which normally converts significant amounts of phenylalanine to tyrosine. Phenylalanine can therefore only be metabolized to phenylpyruvate and other derivatives, a route which is inadequate to dispose of all the phenylalanine in the diet. The amino acid and phenylpyruvate therefore accummulate. The condition is characterized by serious mental retardation, for reasons which are unknown. By the early 1950s it was found that if the condition is diagnosed at birth and amounts of phenylalanine in the diet immediately and permamently reduced, mental retardation can be minimized. The defect is shown only in liver and is not detectable in amniotic fluid cells nor in fibroblasts. A very sensitive bacterial assay has therefore been developed for routine screening of phenylalanine levels in body fluids in newborn babies. 

There are now thought to be several thousand different genetic diseases, about 10% of which have known biochemical lesions. As has already been seen with the thyroid diseases and diabetes, the phenotypic manifestation, hemophilia, for example, may have genetically, biochemically or clinically different causes. Some of the biochemically identified disturbances, such as those affecting glycogen or galactose, have been important in establishing metabolic pathways (see Chapter 4). 

A successful tool in the early studies of metabolic pathways was blocking the pathway at some specific point. This could be done by the use of either mutants or inhibitors. Schekman et al have isolated a number of yeast mutants with blocks in their secretion pathway (Schekman, 1982). It is not yet known which proteins these mutations affect, but this is clearly a most promising approach for identifying those components involved in transport. In animal cells there are no cellular mutants with blocks in the intracellular transport of protein from the ER to the cell surface. There are, however, genetic diseases which affect the routing of lysosomal enzymes to the lysosomes (Neufeld et al, 1975 Sly and Fischer, 1982). For viruses it has been possible to isolate temperature-sensitive mutants in which a mutation in the viral glycoprotein arrests... 

Other Genetic Diseases Associated With Amino Acid Metabolism... 

The propionyl-CoA derived from these three amino acids is converted to succinyl-CoA by a pathway described in Chapter 17 carboxylation to methylmalonyl-CoA, epimerization of the methylmalonyl-CoA, and conversion to succinyl-CoA by the coenzyme B independent methylmalonyl-CoA mutase (see Fig. 17-11). In the rare genetic disease known as methylmalonic acidemia, methylmalonyl-CoA mutase is lacking—with serious metabolic consequences (Table 18-2 Box 18-2). 

Examples of other important genetic diseases associated with amino acid metabolism Other important genetic diseases associated with amino acid metabolism include albinism, homocystinuria, methylmalonyl CoA mutase deficiency, alkaptonuria, histidinemia, and cystathioninuria. 

Roehrig, K. L., Carbohydrate Biochemistry and Metabolism. Westport, Ct. Avi Publishing Co., 1984. Carbohydrate metabolism discussed at a rather elementary level. Covers several topics that are not included in this book, such as disorders of carbohydrate metabolism with brief discussions of many types of human genetic diseases in which carbohydrate metabolism is impaired. 

Most Human Genetic Diseases Associated with Amino Acid Metabolism Are Due to Defects in Their Catabolism... 

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