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New Treatments for Disorders of Red Blood Cell Enzymes

The first enzyme deficiency in the Embden-Meyerhof pathway, or the first enzyme in this pathway is the hexokinase. It is the least active of the glycolytic enzymes but it is still number one in the cascade there. Its activity decreases as the red blood cell matures. So the older the red blood cells there are, the less the activity of this enzyme. The activity of HK can be decreased due to a quantitative or qualitative problem. So it could be lack of enough quantity of HK or the HK activity can be qualitatively abnormal.

Number two; another enzymopathy affecting the E-M pathway is the phosphoglycerate kinase deficiency, PGK deficiency. Itís the only X-linked enzymopathy in the E-M pathway. Most of the other enzymopathyís of the E-M pathway are autosomal recessive. So this one is X-linked. PGK deficient males usually develop normally.

Phosphofructokinase deficiency is another deficiency that can be seen affecting the E-M pathway. PFK is a tetramatic enzyme. Itís usually composed of three basic units; an M-unit, refers to muscle, L-refers to granulocyte and F to fibroblasts and platelets. If you look at the PFK of the red blood cells it consists of the L-4 tetramer. PFK deficiency can present, in addition to hemolytic anemia, as a myopathy or a combination of the two. So those patients can have either a myopathy, hemolytic.

Pyruvate kinase deficiency is another problem seen with the E-M pathway. Itís the most common enzymopathy in this pathway. So if you want to remember a common one that may come up frequently, it is the pyruvate kinase deficiency. Itís worldwide. It is multiracial so it is present all over the world and no race is spared.

Glucose phosphate isomerase, GPI, deficiency is the third most common enzymopathy after G6PD and PK deficiency. Thatís in general, not in the E-M pathway but in general. If you want to rank them in terms of occurrence, G6PD is number one, PK deficiency is number two and GPI deficiency is number three. GPI is encoded by a single gene in all body cells. Hemolytic anemia can be the only clinical manifestation in some of these patients because only the mature RBC seems to be unable to synthesize enough enzyme in an accelerated fashion. So most of the cells of the body.

The other enzyme deficiency in the E-M pathway is the triosephosphate isomerase, a TPI deficiency. TPI is present in all tissues in the body and TPI deficiency is inherited as autosomal recessive. Those patients present with a progressive, multi-syndrome disorder. This includes a hemolytic anemia, hyperbilirubinemia, neurologic problems that can manifest as spasticity, paresthesia, weakness and mental retardation. So now there is a common theme, if you want, with these enzymopathies.

Now weíll move from the E-M pathway to the nucleotide metabolism and defects in that, and what I am going to go over is only one deficiency there. The rest of them are listed in your handout. This is because it tends to be a little bit more common and more important than the other ones. The other ones are very rare, and itís the pyrimidine 5 prime nucleotide deficiency. As I mentioned earlier, you will have basophilic stippling.

Hyperactivity of adenosine deaminase. The adenosine deaminase in an enzyme, deficiency of that enzyme will lead to immune deficiency. This is where some of the drugs work. For example, 10-2 statin and 2-chloro-2í-deoxyadenosine. What they do is, you use them to treat hairy cell leukemia and those drugs usually inhibit the adenosine deaminase and cause a breakdown in the lymphocytes there and a degradation.

Next is the monophosphate shunt. The hexose monophosphate shunt. And this shunt is the major source of NADH in red blood cells. So it allows the production of NADH in the erythrocytes; 10% of red blood cell glucose is metabolized via this pathway also. So this pathway is needed but probably to a little bit lesser extent in terms of glucose metabolism, compared to the E-M pathway. Normal blood cells usually can increase the amount of glucose metabolized through this pathway upon exposure.

The most important enzyme, probably, in the whole enzymopathy that we are discussing is probably the G6PD deficiency. Itís an enzyme of the HNP shunt but also it is by far the most common of all of these enzymopathyís and I think you need to be very aware of all of its problems, complications and all of that. So what do we have here? Itís the most prevalent inborn error of red blood cell metabolism. It affects more than 150 million people worldwide, so it is widely spread. It affects practically all races also. The gene is located on the long arm of the X chromosome, band XQ28.