Nadp

Pyruvate Kinase Deficiency

Pyruvate kinase (PK) is an enzyme active in the penultimate conversion in the

Embden-Meyerhof pathway. Although deficiency is rare, it is the most common enzyme abnormality in the Embden-Meyerhof pathway.

Genetics

1. Autosomal recessive inheritance

2. Significant hemolysis seen in homozygotes

3. Found predominantly in people of northern European origin

4. Deficiency not simply quantitative; probably often reflects the production of PK variants with abnormal characteristics.

Pathogenesis

1. Defective red cell glycolysis with reduced ATP formation

2. Red cells rigid, deformed, and metabolically and physically vulnerable (reticu-locytes less vulnerable because of ability to generate ATP by oxidative phos-phorylation).

Hematology

1. Features of nonspherocytic hemolytic anemia: macrocytes, oval forms, poly-chromatophilia, anisocytosis, occasional spherocytes, contracted red cells with multiple projecting spicules, rather like acanthocytes or pyknocytes

2. Erythrocyte PK activity decreased to 5-20% of normal; 2,3-diphosphoglycerate (2,3-DPG) and other glycolytic intermediary metabolites increased (because of two- to threefold increase in 2,3-DPG, there is a shift to the right in P50*)

3. Autohemolysis markedly increased, showing marked correction with ATP but not with glucose.

Clinical Features

1. Variable severity; can cause moderately severe anemia (not drug induced)

2. Usually presents with neonatal jaundice

3. Splenomegaly common but not invariable

4. Late: gallstones, hemosiderosis (from multiple transfusions), bone changes of chronic hemolytic anemia

5. Erythroblastopenic crisis due to parvovirus B19 infection.

Treatment

1. Folic acid supplementation

2. Transfusions as required

3. Splenectomy (if transfusion requirements increase); splenectomy does not arrest hemolysis, but decreases transfusion requirements.

Other Enzyme Deficiencies

1. Hexokinase deficiency, with many variants

2. Glucose phosphate isomerase deficiency

*Because of the right shift of P50, patients do not exhibit fatigue and exercise intolerance proportionate to the degree of anemia.

3. Phosphofructokinase deficiency, with variants

4. Aldolase

5. Triosephosphate isomerase deficiency

6. Phosphoglycerate kinase deficiency

7. 2,3-DPG deficiency due to deficiency of diphosphoglycerate mutase

8. Adenosine triphosphatase deficiency

9. Enolase deficiency.

These enzyme deficiencies have the following features:

1. General hematologic features:

a. Autosomal recessive disorders except phosphoglycerate kinase deficiency, which is sex linked b. Chronic nonspherocytic hemolytic anemias (CNSHAs) of variable severity c. Osmotic fragility and autohemolysis normal or increased d. Improvement in anemia after splenectomy e. Diagnosed by specific red cell assays

2. Specific nonhematologic features:

a. Phosphofructokinase deficiency associated with type VII glycogen storage disease and myopathy b. Triosephosphate isomerase deficiency associated with progressive debilitating neuromuscular disease with generalized spasticity and recurrent infections (some patients have died of sudden cardiac arrest)

c. Phosphoglycerate kinase deficiency associated with mental retardation and a behavioral disorder.

Note the three exceptions to the general hematologic features listed above: (1) Adenosine deaminase excess (i.e., not an enzyme deficiency) is an autosomal dominant disorder. (2) Pyrimidine 5'-nucleotidase deficiency is characterized by marked basophilic stippling, although the other chronic nonspherocytic hemolytic anemias lack any specific morphologic abnormalities. (3) Deficiency of diphospho-glycerate mutase results in polycythemia.

Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) is the first enzyme in the pentose phosphate pathway of glucose metabolism. Deficiency diminishes the reductive energy of the red cell and may result in hemolysis, the severity of which depends on the quantity and type of G6PD and the nature of the hemolytic agent (usually an oxidation mediator that can oxidize NADPH, generated in the pentose phosphate pathway in red cells).

Genetics

1. Sex-linked recessive mode of inheritance by a gene located on the X chromosome (similar to hemophilia).

2. Disease is fully expressed in hemizygous males and homozygous females.

3. Variable intermediate expression is shown by heterozygous females (due to random deletion of X chromosome, according to Lyon hypothesis).

4. As many as 3% of the world's population is affected; most frequent among African Americans and those of Mediterranean origin.

The molecular basis of G6PD deficiency and its clinical implications follow:

1. Deletions of G6PD genes are incompatible with life because it is a housekeeping gene and complete absence of G6PD activity, called hydeletions, will result in death of the embryo.

2. Point mutations are responsible for G6PD deficiencies. They result in:

a. Sporadic mutations: They are not specific to any geographic areas. The same mutation may be encountered in different parts of the world that have no causal (e.g., encountering G6PD Guadalajara in Belfast) relationship with malarial selection. These patients manifest with chronic nonspherocytic hemolytic anemia (CNSHA WHO Class I).

b. Polymorphic mutations: These mutations have resulted from malaria selection; hence, they correlate with specific geographic areas. They are usually WHO Class II or III and not Class I.

The World Health Organization (WHO) classification of G6PD variants on the basis of magnitude of the enzyme deficiency and the severity of hemolysis are shown here:

WHO Class

Variant

Magnitude of enzyme deficiency

Severity of hemolysis

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