Enzyme deficiencies, genetic diseases

Leptospermone (34), a representative of an important new class of herbicides from the bottlebrush plant, Callistemon citrinus (Curtis) Skeels, has been found to have an inhibitory effect on the enzyme, -hydroxyphenylpyruvate dioxygenase (HPPD), involved in the synthesis of plastoquinone in plants. Nitisinone (35), a synthetic derivative of (34), has recently been introduced to the market for the treatment of hereditary tyrosinemia type 1 (HT-1), a severe genetic disease caused by a deficiency of fumaryl acetoacetate hydrolase (FAH). ... 

The study of enzymes has immense practical importance. In some diseases, especially inheritable genetic disorders, there may be a deficiency or even a total absence of one or more enzymes. For other disease conditions, excessive activity of an enzyme may be the cause. Measurements of the activities of enzymes in blood plasma, erythrocytes, or tissue samples are important in diagnosing certain illnesses. Many drugs exert their biological effects through interactions with enzymes. And enzymes are important practical tools,... 

Enzyme deficiency causing chronic granulomatosis hydroxyl radicals. Myeloperoxidase is an important enzyme in this pathway. A genetic defect in NADPH oxidase causes chronic granulomatosis, a disease characterized by severe, persistent, chronic pyogenic infections. 

Definition of porphyrias, their modes of genetic inheritance, and their treatment Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. Porphyrias are classified as erythropoietic or hepatic, depending where the enzyme deficiency occurs. With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all the porphyrias are inherited as autosomal dominant disorders. All porphyrias result in a decreased synthesis of heme and, therefore, ALA synthase is dere-pressed. The severity of symptoms of the porphyrias can be diminished by intravenous injections of hemin. Because some porphyrias result in photosensitivity, avoidance of sunlight is helpful. 

Thus, it has been found that genetic diseases run the gamut of time and of severity. In Pompc s disease, a deficient enzyme (alpha-1,4-glucosidasc) may range from death (total deficiency) to the progressive manifestation of cardiac or peripheral myopathy in later life (mild deficiency). 

Thus, knowledge of the structure of the oligosaccharides that accumulate in the urine and tissues of patients suffering from glycopro-teinoses has allowed the definition of the nature of the enzymic deficiencies that are a consequence of grave genetic diseases, and has led... 

Genetic diseases can be divided into two main groups based on whether they are caused by relatively few common mutations or by many unique mutations. Tay-Sachs disease, a fatal neurodegenerative disorder caused by a deficiency of hexosaminidase A, is common in the Ashkenazi Jewish population. Three hexosaminidase mutations account for 96% of the disease in the Ashkenazi Jewish population (9). In contrast most patients with Fabry disease, a metabolic disorder caused by deficiency of the enzyme galactosi-dase A, have unique mutations in the galactosidase A gene (10). This... 

Some diseases are caused by enzyme deficiencies. The congenital disease phenylketonuria is caused by the deficiency of the enzyme phenylalanine hydroxylase, resulting in a build-up of compounds that cause brain damage and mental retardation. This damage can be lessened and prevented by a diet containing a low amount of the amino acid phenylalanine. The complaint is caused by a genetic mutation. 

Thiamin-Responsive Pyruvate Dehydrogenase Deficiency Genetic deficiency of pyruvate dehydrogenase Ela (which is on the X chromosome) leads to potentially fatal lactic acidosis, with psychomotor retardation, central nervous system damage, atrophy of muscle fibers and ataxia, and developmental delay. At least some cases respond to the administration of high doses (20 to 3,000 mg per day) of thiamin. In those cases where the enzyme has been studied, there is a considerable increase in the of the enzyme for thiamin diphosphate. Female carriers of this X-linked disease are affected to a variable extent, depending on the X-chromosome inactivation pattern in different tissues (Robinson et al., 1996). 

Table I. Some Genetic Diseases Caused by Enzyme Deficiencies...

Purines are degraded to urate in human beings. Gout, a disease that affects joints and leads to arthritis, is associated with the excessive accumulation of urate. The Lesch-Nyhan syndrome, a genetic disease characterized by self-mutilation, mental deficiency, and gout, is caused by the absence of hypoxanthine-guanine phosphoribosyltransferase. This enzyme is essential for the synthesis of purine nucleotides by the salvage pathway. 

Biotinidase deficiency is an autosomal recessive disorder with an estimated incidence of 1 in 72,000-126,0(X). Many newborn-screening programs of genetic diseases include testing for this enzyme. Prompt treatment with oral biotin administration of 5-20 mg/d in affected infants will prevent clinical consequences. If the treatment is delayed, neurological manifestations (e.g., hearing loss and optic atrophy) and developmental delay occur and may not revert to normal. 

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