Enzyme defects

Disruption of the Uronic Acid Pathway Is Caused by Enzyme Defects Some Drugs... 

GSH-S deficiency is a more frequent cause of GSH deficiency (HI7), and more than 20 families with this enzyme deficiency have been reported since the first report by Oort et al. (05). There are two distinct types of GSH-S deficiency with different clinical pictures. In the red blood cell type, the enzyme defect is limited to red blood cells and the only clinical presentation is mild hemolysis. In the generalized type, the deficiency is also found in tissues other than red blood cells, and the patients show not only chronic hemolytic anemia but also metabolic acidosis with marked 5-oxoprolinuria and neurologic manifestations including mental retardation. The precise mechanism of these two different phenotypes remains to be elucidated, because the existence of tissue-specific isozymes is not clear. Seven mutations at the GSH-S locus on six alleles—four missense mutations, two deletions, and one splice site mutation—have been identified (S14). 

B10. Baughan, M. A., Valentine, W. N., Paglia, D. E., Ways, P. O., Simon, E. R and DeMarsh, Q. B Hereditary hemolytic anemia associated with glucosephosphate isomerase (GPI) deficiency—A new enzyme defect of human erythrocytes. Blood 32,236-249 (1969). 

B15. Beutler, E., Carson, D., Dannawi, H., Forman, L., Kuhl, W., West, C., and Westwood, B., Metabolic compensation for profound erythrocyte adenylate kinase deficiency A hereditary enzyme defect without hemolytic anemia. J. Clin. Invest. 72,648-655 (1983). 

VI. Valentine, W. N Tanaka, K. R., and Miwa, S A specific erythrocyte glycolytic enzyme defect (pyruvate kinase) in three subjects with congenital non-spherocytic hemolytic anemia. Trans. Assoc. Am. Physicians 74, 100-110 (1961). 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

Bifunctional protein deficiency. The enzyme defect involves the D-bifunctional protein. This enzyme contains two catalytic sites, one with enoyl-CoA hydratase activity, the other with 3-hydroxyacyl-CoA activity [13]. Defects may involve both catalytic sites or each separately. The severity of clinical manifestations varies from that of a very severe disorder that resembles Zellweger s syndrome clinically and pathologically, to somewhat milder forms. Table 41-6 shows that biochemical abnormalities involve straight chain, branched chain fatty acids and bile acids. Bifunctional deficiency is often misdiagnosed as Zellweger s syndrome. Approximately 15% of patients initially thought to have a PBD have D-bifunctional enzyme deficiency. Differential diagnosis is achieved by the biochemical studies listed in Table 41-7 and by mutation analysis. 

Energy metabolism has been studied extensively in skeletal muscle, and several metabolic disorders have been documented [1, 4]. Comparatively less is known about metabolic defects in cerebral energy metabolism. This may be because muscle tissue is more accessible for biochemical analysis and because certain cerebral enzyme defects are lethal. 

Because the enzyme defect is expressed in all tissues except sperm, diagnosis can be made by biochemical... 

An additional cause of weakness may be involvement of the anterior horn cells of the spinal cord, which is very conspicuous in infantile acid maltase deficiency. All three glycogenoses causing weakness are in fact due to generalized enzyme defects, but histological signs of denervation are not evident. 

Defects of the Krebs cycle. Fumarase deficiency was reported in children with mitochondrial encephalomyop-athy. Usually, there is developmental delay since early infancy, microcephaly, hypotonia and cerebral atrophy, with death in infancy or early childhood. The laboratory hallmark of the disease is the excretion of large amounts of fumaric acid and, to a lesser extent, succinic acid in the urine. The enzyme defect has been found in muscle, liver and cultured skin fibroblasts [16]. 

The vast majority of hypothyroid patients have thyroid gland failure (primary hypothyroidism). The causes include chronic autoimmune thyroiditis (Hashimoto s disease), iatrogenic hypothyroidism, iodine deficiency, enzyme defects, thyroid hypoplasia, and goitrogens. 

Haem synthesis is a good example of a pathway that is partly compartmentalized. The pathway (Figure 5.16) occurs in all cell types for the production of respiratory cytochromes and begins within mitochondria but the majority of the reactions occur in the cytosol cell. Because mature red cells have no subcellular organelles, haem synthesis occurs only in early RBC progenitor cells. Although this is a relatively simple pathway, there are a number of well-known enzyme defects that cause a group of diseases called the porphyrias. 

Genetically-determined deficiency of G6PD is the most common cause of haemolysis arising from enzyme defects. Mutated glycolytic enzymes such as hexokinase, phosphofructokinase, aldolase and pyruvate kinase can also bring about haemolysis but the occurrence of these defects are much rarer than for G6PD deficiency (see Case N otes at the end of this chapter). 

Type Name Genetics Enzyme defect Urinary excretion... 

Enzyme defects are also known to exist in the minor pathways of fatty acid degradation. In Refsum disease, the methyl-branched phytanic acid (obtained from vegetable foods) cannot be degraded by a-oxidation. In Zellweger syndrome, a peroxisomal defect means that long-chain fatty acids cannot be degraded. 

Jesse Gelsinger, a participant in a gene therapy trial for an inherited enzyme defect, dies as a result of the treatment... 

Succinyl coenzyme A 3-oxo acid transferase catalyses the transformation of ACAC into acetoacetyl coenzyme A in the mitochondria of extra-hepatic tissues. This enzyme defect may be suggested in cases of severe ketoacidosis often associated with neurologic dysfunction [16]. 

Carnitine and its esters are present in all biological fluids, and depending on the enzyme defect, a particular acylcarnitine pattern becomes apparent where those acyl-carnitine species serving as direct substrates for the defective enzyme accumulate disproportionately to the down- and upstream metabolites (Table 3.2.1). 

In the past decade, eight inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients (Table 5.1.1) [7, 9, 10]. Two of these disorders are due to a defect of the enzyme mevalonate kinase, and in principle affect the synthesis of all isoprenoids (Fig. 5.1.1) [5]. The hallmark of these two disorders is the accumulation of mevalonic acid in body fluids and tissues, which can be detected by organic acid analysis, or preferably, by stable-isotope dilution gas chromatography (GC)-mass spectrometry (GC-MS) [2]. Confirmative diagnostic possibilities include direct measurement of mevalonate kinase activities in white blood cells or primary skin fibroblasts [3] from patients, and/or molecular analysis of the MVK gene [8]. 

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