Enzyme Deficiency States

A metamorphosis has occurred in medical thinking since the landmark discovery by Pauling et al. in 1949 that a defect in the hemoglobin molecule was the basis for sickle cell anemia. With the accumulated knowledge regarding metabolic pathways and the description of the 

As classically viewed, the inborn errors of metabolism involve a mutation in a structural gene, causing an amino acid substitution or deletion affecting the active site of the protein. Defects in enzyme regulation can lead to a loss of modulation of metabolic pathways, with an overproduction of the terminal product without gross accumulation of 

Maintenance of function to provide structural and functional integrity 

Metabolic functions secretion of essential metabolite or its precursors 

Liver protein synthesis (albumin, coagulation proteins), synthesis of cholesterol, triglycerides, and bile salts 

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In 1955, Fritz determined that carnitine plays an essential role in fatty acid -oxidation (FAO), and in 1973 the first two clinically relevant disorders affecting this pathway were described primary carnitine deficiency by Engel and Angelini, and carnitine palmitoyltransferase (CPT) type II (CPT-II) deficiency by DiMauro and DiMauro [6, 7]. To date, more than 20 different enzyme deficiency states affecting fatty acid transport and mitochondrial / -oxidaLion have been described [8] and additional enzymes involved in this pathway are still being discovered [9, 10]. 

Sialidosis with isolated neuraminidase deficiency occurs in at least two clinical phenotypes a severe form with HuRLER-like appearance, myoclonus, cherry-red spots of the retina, mental retardation and, sometimes, with renal disease, and a mild form with or without mental retardation, with myoclonus and with cherry-red spots. Quite likely, the two forms originate from allelic mutations of the same neuraminidase gene, giving rise to enzyme deficiency states of varying degrees. 

The water-soluble vitamins comprise the B complex and vitamin C and function as enzyme cofactors. Fofic acid acts as a carrier of one-carbon units. Deficiency of a single vitamin of the B complex is rare, since poor diets are most often associated with multiple deficiency states. Nevertheless, specific syndromes are characteristic of deficiencies of individual vitamins, eg, beriberi (thiamin) cheilosis, glossitis, seborrhea (riboflavin) pellagra (niacin) peripheral neuritis (pyridoxine) megaloblastic anemia, methyhnalonic aciduria, and pernicious anemia (vitamin Bjj) and megaloblastic anemia (folic acid). Vitamin C deficiency leads to scurvy. 

There are no proven pharmacotherapies for treatment of cocaine or amphetamine dependence. Disulfiram, however, shows some promise in randomized controlled trials for treating cocaine dependence at doses of 250 mg daily, especially in combination with CBT.45 Its mechanism of action for treating cocaine dependence is not known, but may be due to its inhibition of the dopamine P-hydroxylase enzyme that converts DA to NE in the brain. The resulting increase in DA levels may counter the DA-deficient state that is believed to underlie cocaine withdrawal and craving. 

Native Americans may be more susceptible to MCS because of a P450 enzyme deficiency this enzyme is needed to break down toxic chemicals in the body. Another factor that contributes to poor health in Indian communities is that more toxic wastes are dumped on reservations than anywhere else in the United States. 

The rates of metabolism are also impaired in vitamin deficiency states (especially vitamin A, vitamin B, C and E). Starvation in mice leads to decrease in the rates of metabolism of certain drugs like pethidine, acetanilide, hexobarbitone etc. Ethanol increases the hepatic content of monooxygenase enzymes and cytochrome P450 on chronic ingestion. 

Amino acid metabolism in vertebrates contrasts sharply with amino acid metabolism in plants and microorganisms. Most striking is the fact that plants and microorganisms can synthesize all twenty amino acids required for protein synthesis whereas vertebrates can only synthesize about half this number. This leads to complex nutritional needs for vertebrates, which are discussed in chapter 22, Amino Acid Metabolism in Vertebrates. Vertebrate amino acid degradation pathways are also discussed in chapter 22 along with the existence of many pathological states that result from enzyme deficiencies in the degradative pathways. 

Non-Se GSH-Px activity is associated with one or more forms of the glutathioine S-transferases. In these experiments, we have measured the total GSH-Px activity associated with these multifunctional enzymes employing CHP as substrate. As shown in Table V, Non-Se GSH-Px activity of liver, kidney, and lung were significantly (P < 0.05) increased under Se-deficient states. 

Table VI summarizes total GSH-Px activity toward LHP and 15-HPETE in tissues from rats fed on vitamin E and/or Se deficient diets. GSH-Px activity toward fatty acid hydroperoxides was reduced markedly in liver and lung under Se-deficient states whereas kidney enzyme levels were only marginally affected. It should be noted that these total enzyme activities were contributed by both Se-GSH-Px and non-Se GSH-Px in crude cytosols of Se supplemented animals. However, in Se-deficient...

Reduced activity of carbonic anhydrase, another zinc metalloenzyme, has been reported in gastric and intestinal tissues and in erythrocytes when the activity of the enzyme was expressed per unit of erythrocytes (91), Recently in sickle-cell-disease patients, an example of a conditioned zinc-deficient state, the content of carbonic anhydrase in the red cells was found to be decreased, correlating with the zinc content of the red cells (10,75). Inasmuch as the technique measured the apoenzyme content, it appears that zinc may have a specific eflFect on the synthesis of this protein by some mechanism yet to be understood. 

FECH (also known as heme synthase) is an iron-sulfur protein located in the inner mitochondrial membrane. This enzyme inserts ferrous iron into protoporphyrin to form heme During this process, two hydrogens are displaced from the ring nitrogens. Other metals in the divalent state will also act as substrate, yielding the corresponding chelate (e.g., incorporation of Zn into protoporphyrin to yield zinc protoporphyrin). In iron-deficient states Zn successfully competes with Fe in developing red cells so that the concentration of zinc protoporphyrin in erythrocytes increases. Furthermore, other dicarboxylic porphyrins will also serve as substrates (e.g., mesoporphyrin). 

Examination of the urine of subjects receiving EATDA showed that several, if not all, of the urinary purines were excreted in increased amounts. There was, furthermore, no change in the mode of excretion of urates or in the proportion disposed of extrarenally (S12). The suggestion has been made (K18) that the fundamental mechanism of action of these compounds is the blocking of the incorporation of newly synthesized adenine into polynucleotides and/or coenzymes, with the production of an undefined deficiency state. This block could stimulate a compensatory increase in purine biosynthesis. The excess purines would not be utilizable and, therefore, would be excreted from the cells, and the normal degradation by enzymes would convert this material to uric acid. 

When the enzyme deficiency is severe, symptoms appear within the first 3-5 months of life. Eventually symptoms include upper and lower motor neuron deficits, visual difficulties that can progress to blindness, seizures, and increasing cognitive dysfunction. By the second year of life, the patient may regress into a completely vegetative state, often succumbing to bronchopneumonia caused by aspiration or an inability to cough. 

Psychiatric disorders (in so far as they can be explained by imbalances in neurochemicals) that accompany some of the porph)oias may be caused by a build-up in levels of ALA, which bears a structural resemblance to the neurotransmitter GABA (y-aminobutyric acid), and so could act as a neurotoxin. The heme deficiency that is brought on by the porphyrias, can lead to a reduction in the activity of hepatic (liver) enzymes that require heme. For example, reduction in the level of hepatic tryptophan pyrrolase activity leads to a build-up in levels of the amino acids tryptophan and 5-hydroxy-tryptophan. Thus, a heme-deficient state in the liver could produce biochemical abnormalities capable of leading to neurological dysfunction, while heme deficiency in nerve tissue could directly alter nerve function. This has led to the treatment of severe neurological dysfunction by intravenous administration of heme compounds. 

Other such enzyme deficiencies have been revealed through an individual s adverse reaction to drugs. More than 90% of Orientals are genetically rapid N-acetylators of isoniazid (6.12), whereas only 40% of black or white citizens of the United States showed this trait (Kalow, 1962). Rapid acetylators produce acetylhydrazine, which can cause liver damage. The same inheritance controls the acetylation (deactivation) of the sulphonamide antibacterials. The rise of intraocular pressure when glucocorticoids are placed in the eye is another pharmacogenetic effect. Low and high responses are shown by 66% and 5%, respectively, of a sample white population. 

In 1956 selenium was identified (123) as an essential micronutrient iu nutrition. In conjunction with vitamin E, selenium is effective iu the prevention of muscular dystrophy iu animals. Sodium selenite is adrninistered to prevent exudative diathesis iu chicks, a condition iu which fluid leaks out of the tissues white muscle disease iu sheep and infertility iu ewes (see Eeed ADDITIVES). Selenium lessens the iacidence of pneumonia iu lambs and of premature, weak, and stillborn calves controls hepatosis dietetica iu pigs and decreases muscular inflammation iu horses. White muscle disease, widespread iu sheep and cattle of the selenium-deficient areas of New Zealand and the United States, is insignificant iu high selenium soil areas. The supplementation of animal feeds with selenium was approved by the U.S. EDA iu 1974 (see Eeed additives). Much of selenium s metaboHc activity results from its involvement iu the selenoproteia enzyme, glutathione peroxidase. 

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