Enzymopathies

The urea cycle is essential for the detoxification of ammonia. The urea cycle (Fig. 40-5) converts ammonia to urea (10-20g/day in the healthy adult). A urea cycle enzymopathy, whether associated with cirrhosis or an inherited metabolic defect, often causes a hyperammone-mic encephalopathy and irreversible brain injury (see also Ch. 34). 

Celotto, A. M., Frank, A. C., Seigle, J. L., and Palladino, M. J. (2006). Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy. Genetics 174,1237-1246. 

Erythrocyte enzymopathies have rarely been observed during pregnancy and oral contraceptive treatment (197) and in these cases a cause and effect relation seems likely. 

Triosephosphate Isomerase Deficiency, a Unique Glycolytic Enzymopathy... 

As a congenital disorder, an enzyme deficiency in the urea cycle relates to carbamoylphosphate synthetase or N-ace-tyl-glutamate synthetase (= hyperammonaemia type I) and ornithine carbamoyltransferase (= hyperammonaemia type II) (D.B. Flannery et al., 1982). (27) (s. p. 594) This condition mainly affects the channelling of ammonium into the mitochondria and the conversion of ornithine into citrulline. (s. fig. 3.12) Similar acquired enzymopathies can be expected in Reye s syndrome and in cases of zinc deficiency. Such a hyperammonaemia syndrome can also produce the clinical picture of HE. 

The abnormality of this enzyme associated with hereditary nonspherocytic hemolytic anemia is an increase in activity in the erythrocyte. This results in the depletion of red cell ATP and hemolysis. Few cases with a thirtyfoid to seventyfold increase have been described. It is the only RBC enzymopathy that is inherited as an autosomal dominant disorder. The molecular mechanism of this disorder has not been identified. High levels of normal ADA mRNA were present, suggesting a mutation in an in cis transcriptional regulating element, which could not be identified. 

Deficiency of glucose phosphate isomerase (GPI) has been associated with chronic hemolytic disease in a few dozen reported cases and may also cause hemolytic disease of the newborn. Although the third most frequently reported enzymopathy causing hemolytic disease, it has been quite rare in our experience. 

Matthay KK, Mentzer WC. Erythrocyte enzymopathies in the newborn. Cfin Haematol 1981 10 31-55. 

Nagata N, Matsuda I, Oyanagi K. Estimated frequency of urea cycle enzymopathies in Japan. Am J Med Genet 1991 39 228-9. 

Some enzymopathies of erythrocytes may be associated with multisystem disease (e.g., aldolase deficiency with mental and growth retardation). Individuals with 6-phosphofructokinase deficiency exhibit hemolysis and myopathy and have increased deposition of muscle glycogen (a glycogen storage disease see Chapter 15). The myopathy is usually characterized by muscle weakness and exercise intolerance. (See also Chapters 10, 15, and 28.)... 

Finally, alterations in cell metabohsm (enzymopathies) lead to hemolytic disease by changing cell dimensions and Hgb solnbflity. 

Sodium benzoate sodium phenylacetate (25 mg/kg p.o. daily) is used as an adjunctive therapy for the prevention of hyperammonemia in patients with urea cycle enzymopathy. 

Beutler, E., 2001b, DNA-based diagnosis of red cell enzymopathies how we threw out the baby with the bathwater. Blood 97 3325. 

Inborn errors of metabolism the title of a book by Archibold Garrod published in 1902, in which the author recognized the relationship between genes and enzymes. Many metabolic disorders caused by the absence of a protein or the synthesis of a biologically inefficient form of a protein are genetic in origin. I. e. m. is therefore a biochemical and genetic concept synonymous with inherited metabolic block, inherited metabolic disorder, heritable disorder of metabolism, enzymopathy, and other similar terms. 

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