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Download Download Journal of Pediatric Academy Year: 2021 Volume: 2 Issue: 1 Invited Review Doi: 10.51271/jpea-2021-0120 Hereditary Red Blood Cell Enzymopathies Author(s) Tekin Aksu Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Hematology, Ankara, Affiliation(s) Turkey Article Type: Invited Review Received: 15.03.2021 Article Article Group: Pediatric Hematology Accepted: 21.04.2021 Information Available Online: 30.04.2021 Cite this article as: Aksu T. Hereditary Red Blood Cell Enzymopathies. J Pediatr Acad 2021; 2: 9-13. Abstract Red cell metabolic disturbances result in hemolysis, which leads to a significant shortening of the erythrocyte life span. The most common enzyme deficiencies are glucose 6-phosphate dehydrogenase (G6PD) in the antioxidant pathway, pyruvate kinase in the anaerobic glycolysis pathway, and pyrimidine 5’ nucleotidase (P5’N) in the nucleotide metabolism. While the X chromosome inherits G6PD and phosphoglycerate kinase deficiencies, other enzymopathies show autosomal recessive inheritance. Although the causes of hereditary hemolytic disorders are diverse, clinical, laboratory findings and complications overlap. A history of neonatal jaundice requiring phototherapy and exchange transfusion is quite usual. Mild to severe anemia may be accompanied with episodic or constant hemolysis associated with icterus, hyperbilirubinemia, growth retardation, gallstones, splenomegaly, and a variable degree of iron overload. Erythrocyte enzyme disorders should be suspected in patients with severe hemolytic episodes, or chronic hemolysis, after excluding hemoglobinopathies, membranopathies, and immune-mediated hemolysis. Keywords: Glucose 6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, glucose phosphate isomerase deficiency, triosephosphate isomerase deficiency, pyrimidine 5’-nucleotidase deficiency Introduction Erythrocytes use two main biochemical pathways to maintain The most common enzyme deficiencies are glucose their physiological state. The Embden-Meyerhof anaerobic 6-phosphate dehydrogenase (G6PD) in the antioxidant pathway is used for energy, and the hexose monophosphate pathway, pyruvate kinase (PK) in the anaerobic glycolysis (HMP) shunt pathway for reducing potential toxicities. With pathway, and pyrimidine 5 ‘nucleotidase (P5’N) in the the energy gained, cell shape, elasticity, intracellular cation, nucleotide metabolism. While the X chromosome inherits and water content are preserved. Purine and pyrimidine G6PD and phosphoglycerate kinase deficiency, other nucleotides are obtained through nucleotide metabolism. enzymopathies show autosomal recessive inheritance.1 Correspondence: Tekin Aksu, Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Hematology, Ankara, Turkey E-mail: [email protected] This Work Is Licensed Under A Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License Journal of Pediatric Academy 10 Red cell metabolic disturbances result in hemolysis, activity. Whereas in the variants of the Class II, including which leads to a significant shortening of the erythrocyte the Mediterranean variant, erythrocytes of all ages life span. Although the causes of hereditary hemolytic are deficient in the enzyme. Class II variants are more disorders are diverse, clinical, laboratory findings and susceptible to oxidant damage and may experience complications overlap. A history of neonatal jaundice severe hemolysis. requiring phototherapy and Clinical findings exchange transfusion is Highlights quite usual. Mild to severe The patients with most anemia may be associated • Glucose 6-phosphate dehydrogenase G6PD variants are usually with episodic or constant deficiency is often associated with asymptomatic, and there are no hemolysis associated with episodic hemolysis triggered by associated laboratory findings icterus, hyperbilirubinemia, infections, certain drugs, and fava beans. related to hemolysis. The growth retardation, gallstones, • Pyruvate kinase deficiency should acute hemolytic episode may splenomegaly, and a variable be suspected in patients with chronic pursue oxidant injury within 24- degree of iron overload. hemolysis with subtle peripheral 48 hours, triggered by certain Reticulocytosis due to smear findings after excluding drugs, toxins, infections, and compensatory erythropoiesis hemoglobinopathies, membranopathies, fava beans. It seems infections usually accompanies with and immune-mediated hemolysis. are the most common cause of the disease, except in some hemolytic episodes, especially forms of PK deficiency cases in children.1 Jaundice, pallor, with ineffective erythropoiesis. Erythrocyte enzyme dark urine develop, and mild to severe hemoglobin disorders should be suspected in patients with severe decrease may be seen after exposure. Drugs and episodic or chronic hemolytic anemia, after excluding chemicals that cause hemolysis and should be avoided hemoglobinopathies, membranopathies, and immune- are listed elsewhere.1,2,7 While some drugs do not cause mediated hemolysis. These patients may experience clinically significant hemolysis in therapeutic doses, such accelerated hemolysis with infections or aplastic crises as low-dose aspirin and trimethoprim-sulfamethoxazole, due to parvovirus infection. high doses are associated with hemolysis. An acute hemolytic process is seen due to fava beans consumption, Glucose-6-phosphate dehydrogenase deficiency which is called favism, particularly in Mediterranean and Glucose-6-phosphate dehydrogenase deficiency is the Asian G6PD variants. Fava contains divicine, isouramil, most common enzyme deficiency in the HMP pathway and convicine, which increase reactive oxygen products that causes hemolytic anemia. G6PD is involved in and induce hemolysis. the production of nicotinamide adenine dinucleotide In the neonatal period, it may cause spontaneous phosphate (NADPH), which protects the cell from oxidant hemolysis and hyperbilirubinemia, even kernicterus.8 injury triggered by certain drugs or infections by ensuring a In most cases, jaundice is much more common than reduced state of glutathione (GSH).2 Its deficiency mostly anemia. If the patient has Gilbert’s syndrome [uridine- affects erythrocytes. Erythrocytes do not have alternative diphosphate-glucuronyl transferase 1 family, polypeptide pathways for NADPH production. In NADPH deficiency, A1 (UGT1A1) mutation], the severity of hemolysis hemolysis occurs by precipitation of hemoglobin (Heinz increases. Neonates with severe jaundice should be body) in erythrocytes by oxidative stress and damaging tested for G6PD deficiency. Exposure of the neonate and the erythrocyte membrane.2 G6PD deficiency leads to mother to drugs that cause oxidant stress, acidosis, and episodic or chronic non-spherocytic hemolytic anemia. It hypoxia may trigger hemolysis. affects more than 400 million people around the world.3 Its prevalence in the world is 4.9%.3 While it is common in males due to its X-linked inheritance (hemizygous), in Table 1 The World Health Organization classification of G6PD deficiency populations where mutations are common, the disease due to homozygous mutations is reported in females. Class I: Severe deficiency Besides, in carrier womens, moderate-to-mild findings Chronic non-spherocytic hemolytic anemia due to X chromosome inactivation (Lyon hypothesis) can Sporadic and rare be seen.2 G6PD deficiency is common in Africa, Asia, Residual enzyme activity: <10% of normal the Mediterranean, and the Middle East regions. The Class II: Severe deficiency disease is more common in areas where malaria was Episodic severe hemolysis with oxidant injury once endemic due to the protection of G6PD deficiency Mediterranean or Asian variants Residual enzyme activity: <10% of normal against Plasmodium falciparum malaria.4 The frequency Class III: Mild to moderate deficiency of the G6PD deficiency was reported to vary from 0.5- 5 Intermittent acute hemolysis with oxidant injury 2.9% in Turkey. It has been reported with a rate of 8.2% Common A- variant in the Çukurova region.5 The World Health Organization African American classified G6PD deficiency according to enzyme activity Residual enzyme activity: 10-60% of normal and the degree of hemolysis (Table 1).6 Of note, the Class IV: Normal activity normal enzyme is referred to as G6PD B (wild-type). Enzyme activity: 60-150% of normal No clinical findings Normally, the G6PD activity declines with red blood cell Class V: Increased enzyme activity aging. In mild G6PD variants (Class III), especially older Enzyme activity: >150% of normal erythrocytes are affected due to declining enzymatic No clinical findings 11 Aksu T. Red cell enzymopathies In rare instances, G6PD Class I deficient patients Disorders of the glycolytic enzymes have chronic nonspherocytic hemolytic anemia that G6PD deficiency is far more common than glycolytic indistinguishable from other glycolytic enzyme disorders. enzyme abnormalities. While the most common cause of They have mild to moderate anemia with a high glycolytic pathway disorders is PK deficiency, diseases reticulocyte count between 10-15%. related to deficiencies of all other enzymes have also been described. Glycolytic pathway enzymopathies Laboratory findings usually show an autosomal recessive inheritance. With acute hemolytic episodes, patients with G6PD deficiency present with sudden drops in hemoglobin Pyruvate Kinase Deficiency and hematocrit. Anemia is normochromic, normocytic, Hemolytic anemias resulting from the red cell metabolism’s accompanied
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