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Most disorders of amino acid catabolism are rare, but if left untreated, they can result in irreversible brain damage and early mortality. Pre or early postnatal detection of metabolic disorders and timely initiation of treatment thus are essential. The ability to detect the activities of enzymes in cultured amniotic fluid cells facilitates prenatal diagnosis by amniocentesis. In the US, all states conduct screening tests of newborns for up to 40 metabolic diseases, including disorders associated with defects in the catabolism of amino acids. The most reliable screening tests use tandem mass spectrometry to detect, in a few drops of neonate blood, catabolites suggestive of a given metabolic defect, and thereby implicate the absence or lowered activity of one or more specific enzymes.
Mutations either of a gene or of associated regulatory regions of DNA can result either in the failure to synthesize the encoded enzyme or in synthesis of a partially or completely nonfunctional enzyme. Mutations that affect enzyme activity, those that compromise its catalytic or regulatory sites, can have severe metabolic consequences. Low catalytic efficiency of a mutant enzyme can result from impaired positioning of residues involved in catalysis, or in binding a substrate, coenzyme, or metal ion. Mutations may also impair the ability of certain enzymes to respond appropriately to the signals that modulate their activity by altering an enzyme’s affinity for an allosteric regulator of activity. Since different mutations can have similar effects on
any of the above factors, various mutations may give rise to the same clinical signs and symptoms. At a molecular level, these, therefore, are distinct molecular diseases. Present treatment of metabolic disorders of amino acid metabolism consists primarily of feeding diets low in the amino acid whose catabolism is impaired. Ultimately, however, genetic engineering may be able to permanently correct a given metabolic defect
