Proteins Inborn errors

Erythrocyte Entrapment of Enzymes. Erythrocytes have been used as carriers for therapeutic enzymes in the treatment of inborn errors (249). Exogenous enzymes encapsulated in erythrocytes may be useful both for dehvery of a given enzyme to the site of its intended function and for the degradation of pathologically elevated, diffusible substances in the plasma. In the use of this approach, it is important to determine that the enzyme is completely internalized without adsorption to the erythrocyte membrane. Since exposed protein on the erythrocyte surface may ehcit an immune response following repeated sensitization with enzyme loaded erythrocytes, an immunologic assessment of each potential system in animal models is required prior to human trials (250). 

Sanjuijo P., Ruiz J. I., and Montejo M. (1997). Inborn errors of metabolism with a protein-restricted diet effect on polyunsaturated fatty acids. J. Inherited Metab. Dis. 20 783-789. 

Since D-amino acids are poorly utilized, diets containing sufficient quantities of D-enanticmers will result in elevated levels of plasma and urinary amino acids. Urinary excretion of D-methionine by infants fed a formula supplemented with DD-methionine has led to misdiagnosis of inborn errors of metabolism (77). D-Amino acids derived from processed food proteins may confuse medical diagnoses. Determining D-amino acid contents of caimon foods would estimate the significance of this problem. Some preliminary results are shown in Table VI. 

An experimental approach that avoids concerns about the quality of brain tissue is to study in available peripheral tissues genes or gene products that are identical to those in neural tissues. Examples include blood cells and cultured skin fibroblasts, and to a lesser extent biopsies of other tissues such as muscle (Bubber et al., 2005). Most workers assume that genes are identical in all tissues examined from an individual but worry about epigenetic modifications, to DNA as well as to post-translational and posttranscriptional products. However, extensive data indicate that study of proteins in peripheral tissues can often give critical information about those molecules in the brain the standard A striking example is the use of white blood cells and cultured skin fibroblasts to elucidate enzyme defects in inborn errors of metabolism. A well-known example is Tay-Sachs disease (GM2-gangliosidosis) (Roe and Shur, 2007). 

Aminoacidurias may be primary or secondary. Primary disease is due to an inherited enzyme defect, also called an inborn error of metabolism. The defect is located either in the pathway by which a specific amino acid is metabolized or in the specific renal tubular transport system by which the amino acid is reabsorbed. Secondary aminoaciduria is due to disease of an organ, such as the liver, which is an active site of amino acid metabolism, or to generalized renal tubular dysfunction, or to protein-energy malnutrition. Specific inborn errors of metabohsm are discussed in more detail in Chapter 55. 

Hypo-IgG-globulinemia is also associated with myotonic dystrophy where the FOR can be 14% with a of 11 days (W12). This inborn error of IgG metabolism may be a loss of Brambell s protective intracellular carrier of IgG (B20) and some half of affected patients have subnormal serum levels of IgG. Rarely, similar endogenous hypercatabolism is found on a genetic basis and can affect several proteins (Rll). It is therefore clear that a subnormal serum level of IgG may be the result of increased catabolism or decreased synthesis. 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

Familial hypercholesterolemia (FH) is an inborn error of metabolism due to a defective LDL-receptor protein. Five classes of mutations have been identified consisting of more than 150 different alleles. The defects in the receptor function can be grouped into five types ... 

Protein degradation and the inflammatory response (p. 664) Inherited defects of the urea cycle (hyperammonemia) (p. 664) Inborn errors of amino acid degradation (p. 672)... 

The feature of all inherited disorders is a genetic defect, often the result of a single base substitution or deletion in the DNA. which results in the reduced synthesis of a particular protein or in the synthesis of a protein with an altered amino acid coniposiiion. A classical inborn error of metaholisni involves a missing or defective en/yme which causes a block on a metabolic pathway and the production of toxic metabolites. More than four thousand disorders involving single genes have been identified. 

The potential utility of enzymes as pharmaceuticals was noted many decades ago, and since then, nearly two dozen enzymes have been developed to treat a variety of diseases. Almost all enzyme therapies developed to date are used to deal with a loss of function defect (a mutation that diminishes activity, a low level of production, a deletion). Hence, most enzyme drugs are used as enzyme replacement therapies (ERT) for relatively rare, inborn errors of metabolism (lEMs). As a result, many enzyme therapeutics fall under the FDA s Orphan Drug Designation. However, a few enzyme therapies can also be used to treat much more common conditions such as cancer, heart attacks, and stroke. In the United States, the first enzyme to receive FDA approval was a tissue plasminogen activator called alteplase. This protein, which is now commonly used to treat strokes, was introduced in 1987 as Activase. Since then at least 16 other enzyme drugs have been introduced into the marketplace. Some of these are described in more detail below and in Table 6.1-3. 

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