Metabolic Disease

The causes of enzyme defects are genetic mutations that affect the structure or regulation of the enzyme protein or create problems with the transport, processing, or binding of cofactors. In general, the consequences of an enzyme deficiency are due to perturbations of cellular chemistry, because of either a reduction in the amount of an essential product, the buildup of a toxic intermediate, or the production of a toxic side-product, as shown in Figure 1.

Except as noted below, most metabolic disorders are inherited as auto-somal recessive conditions. In this inheritance pattern, two defective gene copies are needed (one from each parent) to develop the disease. The parents, each of whom almost always has only one gene copy, will not have the disease but are carriers. The chance that two carrier parents will have a child who inherits two defective gene copies is 25 percent for each birth.

Metabolic disorders tend to be recessive, because they are due to inactivating, or "loss-of-function," mutations. One working copy of the gene is Figure 1. Left: Normal sequence of metabolism, in which precursor A is converted to intermediate B, and then into final product C. The B-to-C conversion is catalyzed by the enzyme. The side-product D is made in very small amounts. Right: Metabolic disease, resulting in altered enzyme*, resulting in decrease of product C, and/or buildup of precursor A and/or side-product D. The enzyme defect may be due to either an abnormality of the gene (DNA), a problem with production of messenger RNA (mRNA), a defect in the production or stability of the protein, or a deficiency or abnormal interaction with an enzyme cofactor. usually enough to maintain sufficient levels of the enzyme, and so with one copy present, no disease develops.