Inborn errors of metabolism

Extract

[...] Inborn errors affecting proteins of the cytosolic compartment within a cell are the more "traditional" inborn errors of metabolism. They impair the catalytic reactions of anabolic or catabolic pathways and usually are classified by the class of biochemical involved. Classifications of disorders are of glucose, lipid fatty acid, amino acid, purine, organic acid, vitamin, and drug metabolism. Phenylalanine is essential for growth, and its anabolic products include tyrosine, thyroid hormone, adrenergic neurotransmitters, and melanin. Phenylketonuria (PKU) ( Chapter 217 ) is caused by mutations in the gene encoding phenylalanine hydroxylase, the first enzyme in this anabolic flow that catalyzes tyrosine production. [...]

[...] The phenotype (clinical outcome) also is affected not only by the specific genetic block, but also by alternate metabolic pathways (epigenetic phenomena) that may remove toxic precursors or supply deficient products of a blocked reaction. Outcome may be affected adversely by an alternate pathway, and a pathophysiologic mechanism may differ among organs. In galactosemia, the accumulation of galactose can produce excess intracellular galactitol through the alternate pathway catalyzed by aldose reductase and consequently cell death owing to the osmotic effect of intracellular galactitol. [...]

[...] Among these inborn errors of DNA repair are rare disorders, such as xeroderma pigmentosum, Bloom syndrome, ataxia-telangiectasia, Fanconi's anemia, and diseases associated with early aging such as progeria and Werner syndrome, and more common adult-onset nonpolyposis colon cancer. Collectively the disorders show an increased sensitivity and delayed repair of damaged DNA owing to ultraviolet, x-ray, alkylating cross-links, or "normal" DNA report requirements. Many inborn errors involve proteins that circulate in blood. Stable circulating proteins in blood perform a variety of functions, including immunologic, hemostatic, regulatory, hormonal, and interorgan transport of trace metals, lipids, and other nutrients. [...]

[...] Phenobarbital and several other drugs induce hepatic uridine diphosphate glucuronyl transferase gene expression and reduce the accumulation of unconjugated bilirubin in Gilbert's syndrome. In tyrosinemia type a drug NTBC blocks the catabolic pathway by which tyrosine produces the toxin succinylacetone and successfully prevents hepatotoxicity. Treatment of Inherited Disease If the specific protein or enzyme has been purified and engineered to function in its specified organ or subcellular organelle, it can be used to treat an inherited metabolic disease. One good example is glucocerebrosidase, the enzyme that is impaired in Gaucher's disease. [...]

[...] Many principles of diagnosis and therapy for inborn errors of metabolism are exemplified by disorders of the urea cycle. A group of inborn errors of metabolism is caused by mutations in nuclear genes that encode mitochondrial proteins. Collectively, they are considered disorders of organic acid metabolism. Branched-chain a-ketoacid dehydrogenase is a multienzyme complex located on the matrix side of the mitochondrial inner membrane in all tissues. When any of these proteins is impaired, the autosomal recessive disorder maple syrup urine disease may result. [...]