Abstract
Nonspherocytic hemolytic anemia due to hexokinase deficiency is a hereditary disorder marked by the annihilation of red blood cells. The disease occurs as a consequence of a deficiency in hexokinase that is specific to the erythrocytes. An inadequate amount of hexokinase in the red blood cells occurs because of an alteration in the HK1 gene. Consequently, the glycolytic pathway is affected leading to the inability of erythrocytes to withstand oxidative stress. The condition is transmitted through the genes in an autosomal recessive manner implying that faulty genes from both parents are prerequisites for the development of the disease. Grave anemia is the hallmark of the condition among other indicators such as pallor, fatigue and jaundice. Diagnosis of nonspherocytic hemolytic anemia due to hexokinase deficiency is done by performing a peripheral blood count and screening for the enzyme glucose-6-phosphate dehydrogenase. During the management of nonspherocytic hemolytic anemia due to hexokinase deficiency, supplementation of folic acid is done to promote the regeneration of erythrocytes. In extreme cases of anemia, the transfusion of red blood cells may be performed. Studies involving gene therapy as a permanent cure for the condition are currently being investigated.
Introduction
Nonspherocytic hemolytic anemia due to hexokinase deficiency is an uncommon disorder typified by serious, longstanding lysis of red blood cells (hemolysis). According to the National Institutes of Health (2013), about twenty incidents of this disorder have been documented so far. This condition normally begins during infancy and is often referred to as congenital nonspherocytic hemolytic anemia. It is a consequence of the deficiency of the enzyme hexokinase (ATP: D-hexose 6-phosphotransferase) (Bianchi & Magnani, 1995). Tissues such as the kidney, brain and erythrocytes depend heavily on glucose to perform their normal physiological functions (Karen, Wouter, Annet, Kersting, & Richard, 2009). Therefore, they require adequate amounts of hexokinase to function properly. For this reason, a deficiency of this vital enzyme affects the integrity and function of erythrocytes.
The indicators of nonspherocytic hemolytic anemia due to hexokinase deficiency (NSHA) closely resemble the signs of another condition referred to as pyruvate kinase deficiency. Both diseases are related to defects in carbohydrate metabolism. The indicators of NSHA due to HK1 deficiency include anemia, numerous deformities, dormant diabetes as well as panmyelopathy (Mallouh, 2012). Infants often have elevated levels of bilirubin, which is known as hyperbilirubinemia (Becker, 2003). In addition, the skin becomes pale and may have an unrelenting yellow coloration (jaundice). The spleen and liver may also enlarge in an unusual manner (splenomegaly and hepatomegaly) (National Organization for Rare Diseases, 2014). It has also been established that the activity of hexokinase in the red blood cells declines to approximately 0.25 of the normal values. There is also the possibility of the formation of gallbladder stones during the early stages of development.
Causes of Nonspherocytic Hemolytic Anemia due to Hexokinase Deficiency
A mutation in the HK1 (hexokinase 1) gene that codes for the enzyme hexokinase-R are responsible for the development of NSHA. Hexokinase-R is the hexokinase isoenzyme that is found exclusively in the erythrocytes. The HK1 gene is situated on the 10th chromosome at the 22nd position (HK1, 2014). Therefore, its cytogenetic position is described as 10q22. The mutation occurs in the form of deletion or switch of a single nucleotide (Hexokinase 1, 2014). The transformation can be homozygous or heterozygous. Consequently, the amino acid at position 529 changes from leucine to serine. This change is transmitted genetically in an autosomal recessive manner. Therefore, an individual can only suffer from the condition if he or she possesses a pair of defective genes. For this reason, men and women have equal chances of developing the disorder. The probability of two carrier parents siring offspring with the condition is about 0.25 with each pregnancy (National Organization for Rare Diseases, 2014). Inheriting one copy of the defective gene makes one a carrier of the disease without the manifestation of disease symptoms. It is thought that a large number of people have defective genes. However, only intimately related people possess similar defective genes, which raises the odds of producing children with the recessive genetic condition.
In the absence (or insufficient quantities) of hexokinase, the structure of the red blood cells becomes distorted from the normal biconcave-shaped discs to asymmetrical non-spherical shapes that are easily damaged. Anemia comes about when the rate of destruction of red blood cells surpasses the rate of the renewal of novel cells.
The Metabolic Pathway Affected by Nonspherocytic Hemolytic Anemia due to Hexokinase Deficiency
Glycolysis is a vital process in the breakdown of glucose to yield energy. During this process, glucose is broken down via a series of ten chemical reactions to yield two molecules of pyruvic acid. The pyruvic acid spawned from this reaction then enters the tricarboxylic acid cycle to produce reducing power that is converted into energy in the form of ATP by means of the electron transport chain. However, in the red blood cells, the absence of mitochondria means that the tricarboxylic acid cycle and electron transport chain cannot take place. Therefore, two different pathways are used in energy production in the erythrocytes. These pathways are the Embden-Meyerhof (glycolysis) pathway and the hexose monophosphate shunt (Nayak, Rai, & Gupta, 2012). The majority of the energy used in erythrocytes is generated via the Embden-Meyerhof pathway, which leads to the preservation of lipids as well as sodium and potassium. The hexose monophosphate shunt, on the other hand, produces only a tenth of erythrocyte energy requirements. However, this pathway is vital in the prevention of oxidative damage to erythrocytes. During glycolysis, glucose reacts with a phosphate molecule to form glucose-6-phosphate in a reaction that is catalyzed by the enzyme hexokinase (Bianchi, & Magnani, 1995). This reaction is the rate-limiting step in glucose metabolism as additional steps cannot proceed without this vital step.
Glucose-6-phosphate, which is the second intermediate in glycolysis, is the first reactant in the hexose monophosphate shunt. Glucose-6-phosphate dehydrogenase, a key enzyme in this pathway, also serves as a forager of free radicals (Nayak, Rai, & Gupta, 2012). Therefore, deficient hexokinase means that energy is not produced via glycolysis and that the hexose monophosphate shunt cannot take place. Therefore, nicotinamide adenine dinucleotide phosphate (NADPH) is not produced leading to reduced amounts of glutathione, an important antioxidant. Consequently, the red blood cells are unable to respond to oxidative stress leading to the destruction of vital proteins of the red blood cells. The damaged proteins cannot maintain the integrity of the erythrocytes leading to hemolysis.
Detection and Treatment of the Disease
Laboratory tests are used in the identification of NSHA. Such tests include a total “blood count, peripheral blood smear, reticulocyte count, serum total and direct bilirubin, and Lactate dehydrogenase” (Becker, 2003, p. 369). It is often realized that the hematocrit and hemoglobin values are lower than normal. In addition, abnormal hemoglobin with irregular shapes referred to as Heinz bodies are often visualized (National Organization for Rare Diseases, 2014).
The conventional method of treating nonspherocytic hemolytic anemia due to hexokinase deficiency is supplementation of folic acid to encourage the regeneration of new red blood cells. An infusion of fluids is often necessary to safeguard against shock as well as to sustain urinary output. In instances of severe anemia, red cell transfusion may be performed. It is also imperative for patients to steer clear of substances that promote the damage of erythrocytes. Iron chelation treatment through the administration of drugs such as deferoxamine or deferasirox is helpful when frequent transfusions are required. This procedure prevents iron overload from the frequent transfusions of red blood cells.
Approaches being Investigated
There is no permanent cure for nonspherocytic hemolytic anemia due to hexokinase deficiency since the condition is a consequence of a gene mutation. However, it is hypothesized that replacing the mutant gene with a normal one may reverse the situation. Gene therapy using the human isoenzyme has yielded success in the treatment of pyruvate kinase deficiency in animal models (Meza et al., 2009). As a result, studies are underway to determine the possibility of gene transfer in treating NSHA (HK1, 2014).
Conclusion
The mechanism of genetic transmission of nonspherocytic anemia due to hexokinase deficiency makes it an extremely rare occurrence. However, the few cases that have been reported are characterized by extreme anemia. Currently, there is no lasting cure for this condition. Nevertheless, maintaining the levels of red blood cells has proved useful in managing the situation. Therefore, it is essential that patients with this condition receive regular medical attention to safeguard their health.
References
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