Glycolytic enzymes, deficiency

Other pitfalls in correct diagnosis of glycolytic enzyme deficiencies include the red cell age dependency of enzymes such as PK, HK, and G6PD. The measurement of these enzymes simultaneously can give an idea about red cell age and relative deficiencies. Many patients suffering from severe hemolysis have already received blood transfusions. When this occurs, interpreting results from red cell enzyme aissays must be done with great care, since the. presence of donor erythrocytes wdl obscme any deficiencies. In addition, some mutant enzymes display a normal activity in vitro, while in vivo severe hemolysis can occur. More sophisticated assays to measure, for example, heat instability and kinetics have to be used in those cases. 

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). 

Patients with this deficiency present with myopathy, recurrent aching muscles and myoglobinuria after prolonged exercise or starvation. It is interesting to note that there are more cases of a deficiency of this enzyme in muscle than there are cases of a deficiency of any of the glycolytic enzymes (including phosphorylase, see Chapter 6). 

Effect of pyruvate kinase deficiency Pyruvate kinase deficiency accounts for 95 percent of all inherited defects in glycolytic enzymes. It is restricted to erythrocytes, and causes mild to severe chronic hemolytic anemia. Altered kinetics (for example, increased Km, decreased Vmax, etc.) most often account for the enzyme deficiency. 

Martinov, M. V., Plotnikov, A. G., Vitvitsky, V. M., Ataullakhanov, F. I. Deficiencies of glycolytic enzymes as a possible cause of hemolytic anemia. Biochim. Biophys. Acta 2000,1474 75-87. 

HK deficiency (OMIM 235700) is a rare, recessively inherited disease with chronic nonspherocytic hemolytic anemia as the predominant clinical feature. The phenotypic expression of the disease is heterogeneous, as with most glycolytic red cell enzyme deficiencies. The spectrum ranges between severe neonatal hemolysis and death to a fully compensated chronic hemolytic anemia. Patients benefit in general from a splenectomy. Red cell morphology is normal. Since HK activity is dependent on red cell age, reticulocytosis, always present in HK-deficient patients, may obscure enzyme deficiency. Other age-dependent red cell enzymes (e.g., pyruvate kinase and/or G6PD) should be measured simultaneously as an internal control to assess the influence of reticulocyte enzyme activity. 

In contrast with the fall in the activity of muscle glycolytic enzymes in human muscular dystrophy, Dreyfus and his colleagues (DIO) found little or no decrease in the concentrations of certain enzymes involved in oxidative breakdown of fuel, notably succinate dehydrogenase, cytochrome oxidase, fumarase, and aconitase. In the mouse myopathy, the concentration of cytochrome oxidase is increased (W12) elevated levels of respiratory enzymes have been reported also in myopathy resulting from vitamin E deficiency (D6) and in genetically dystrophic chickens... 

The only pathway that provides ATP in mature erythrocytes is glycolysis. Because these cells lack mitochondria, a nucleus, and other organelles required for protein synthesis, deficiency of glycolytic enzymes may... 

Pancytopenia-thrombocytopenia-leukopenia in organic acidurias hemolytic anemia in galactosemia, congenital erythropoietic porphyria, glycolytic and pentose-phosphate enzymes deficiencies macrocytic anemia in inborn errors of cobalamin and folate metaboUsm Metabolic acidosis in organic acidurias (anion gap) respiratory alkalosis in hyperammonemias... 

Inherited diseases due to deficiency of red cell glycolytic enzymes are rare causes of hereditary, non-spherocytic haemolytic anaemia. This... 

An inborn error of metabolism in which there is a deficiency of pyruvate kinase the glycolytic enzyme which converts phos-phoenolpyruvate to ATP and pyruvate. This deficiency results in a reduced synthesis of ATP and a diminished capacity to cycle NAD in erythrocytes. This results in a haemolytic anaemia. The condition can be diagnosed by measuring the level of the enzyme in erythrocytes. It is inherited as an autosomal recessive. 

In 1965 Japanese workers [128] identified a deficiency in muscle of phosphofructokinase, another glycolytic enzyme the symptoms were quite similar to those of muscle phosphorylase deficiency. The enzyme was also low in erythrocytes. Inheritance is probably autosomal recessive and a small number of other cases have since been reported. A late-onset muscle disorder in two brothers associated with a low activity of phosphohexoseisomerase in the muscle has been reported in another Japanese family [129]. 

Glycogenosis type VIII (phosphorylase b kinase deficiency) gives rise to myopathy and liver disease, either singly or in combination. Phosphorylase b kinase (PBK) converts the inactive b form of both muscle and liver phosphorylases to the active a forms of the enzymes. The ischemic lactate test sometimes shows a flat result as in McArdle s disease, but is more likely to be normal. Histochemical demonstration of myophosphorylase activity in tissue sections shows a near-normal reaction due to the presence of phosphorylase a. Accumulation of glycogen is modest and found mainly in type 2 (fast-twitch glycolytic) muscle fibers. 

The classic function of TPI is to adjust the rapid equilibrium between the two triosephosphates, glycerinealdehyde-3-phosphate and DH AP. Patients with TPI deficiency have unimpressive alterations in glucose utilization, ATP and lactate production. Modeling studies and experimental data suggested that the physiological ATP level was maintained due to the activation of enzymes involved in the pen-tosephosphate and glycolytic pathways (Fig. 8.2) [80, 81]. The interconnection of the two pathways with increased activities can compensate for the reduced TPI activity of deficient cells in TPI-deficient erythrocytes [80, 81]. 

Phosphoglycerate kinase deficiency, the seventh enzyme step of the glycolytic pathway, is an inherited X-linked recessive disorder, meaning it mostly affects males, although females are carriers. Onset is infancy to early adulthood. Symptoms may include anaemia, enlargement of the spleen, mental retardation and epilepsy (seizures) more rarely, weakness, exercise intolerance, muscle cramps and episodes of myoglobinuria occur. 

In the liver, kidney, and intestine, fructose can be converted to glycolytic/ gluconeogenic intermediates by the actions of three enzymes—fructokinase, aldolase B, and triokinase (also called triose kinase)—as shovra in Figure 24-1. In these tissues, fructose is rapidly phosphorylated to fructose 1-phosphate (FIP) by fructokinase at the expense of a molecule of adenosine triphosphate (ATP). This has the effect of trapping fructose inside the cell. A deficiency in this enzyme leads to the rare but benign condition known as essential fmcto-suria. In other tissues such as muscle, adipose, and red blood cells, hexokinase can phosphorylate fructose to the glycolytic intermediate fmctose 6-phosphate (F6P). 

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