Red cell pyruvate kinase deficiency in neonatal jaundice cases in India
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《美国医学杂志》
Institute of Immunohaematology, Indian Council of Medical Research, K.E.M. Hospital Campus, Parel, Mumbai, India
Abstract
Objective. Pyruvate Kinase (PK) deficiency is the most common enzymopathy of the glycolytic pathway in erythrocytes. It constitutes one of the common causes of hereditary non-spherocytic hemolytic anemia. The aim of this study was to screen newborns in India for pyruvate kinase (PK) deficiency in relation to unconjugated hyperbilirubinemia. Methods. Laboratory investigations done included complete blood counts, reticulocyte counts, direct and indirect bilirubin, assay of G6PD and PK activity, ATP and 2,3 DPG levels. All variables were studied in 50-cord blood samples from normal deliveries and 218 neonates with hyperbilirubinemia. Results. 7 of the 218 cases of neonatal jaundice were PK deficient with 30-40 % reduction in PK activity. These cases also had a 3-4-fold increase in 2,3 DPG:ATP ratios, which is one of the additional indicators for PK deficiency. Six of the 7 infants had a severe clinical course. Conclusion. This study shows that the prevalence of PK deficiency in Indian neonatal jaundice cases is 3.21%, which is relatively high. This emphasizes the need for screening neonatal hyperbilirubinemia cases in India for PK deficiency.
Keywords: Pyruvate Kinase deficiency; Hereditary non-spherocytic hemolytic anemia; Neonatal jaundice; Hyperbilirubinemia
Red cell pyruvate kinase (PK.EC.2.7.1.40) deficiency is the most common enzyme abnormality in the Embden Meyerhoff pathway of glycolysis in humans. PK deficiency is associated with hereditary non-spherocytic hemolytic anemia (HNSHA) and is transmitted as an autosomal recessive disorder, with both the sexes being equally affected. The clinical severity of this disorder varies widely, ranging from a mildly compensated anemia to severe anemia of childhood, though in some cases it does not manifest itself until adulthood. Affected newborns usually present with unconjugated hyperbilirubinemia and may require exchange transfusion. PK deficiency was first described by Valentine et al in 1961 and since then, approximately 450 cases have been described in the literature[1],[2]. Most of these are of North European origin while occasional cases have been reported from the Middle East, Japan, China, Spain and Saudi Arabia.[3],[4],[5],[6]
The common causes for inherited hemolytic anemia in the Indian Subcontinent include thalassemia, sickle cell anemia, other hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency (G6PD). The distribution of these hereditary defects in this population have been described earlier.[7] There is no data on the prevalence of PK deficiency in the Indian population. This study was thus undertaken to determine the incidence of PK deficiency in Indian newborns presenting with neonatal jaundice and to evaluate the severity of the disease in these cases.
Materials and Methods
50-cord blood samples from clinically and hematologically normal deliveries were collected in EDTA and analyzed within 24 hr (Normal controls). 218 neonates (103 males and 115 females) presenting with unconjugated hyperbilirubinemia were included in this study. Hematological indices were measured on an automated cell counter. (Sysmex- K-1000, Japan) Peripheral smear examination and reticulocyte counts were done using standard techniques. Direct and indirect antiglobulin test was done to exclude immune causes of hemolysis. Total and indirect bilirubin levels were determined by standard methods. Depletion of reticulocytes was done by differential centrifugation and confirmation was done by reticulocyte staining with new methylene blue.[8] The red cells were prepared for enzyme assay by passing the whole blood through a column containing a mixture of a-cellulose and microcrystalline cellulose (Sigma, USA) to remove leucocytes.[9] Glucose-6-phosphate dehydrogenase and pyruvate kinase activities were assayed by the method described by Beutler.[10] 2,3 Diphospho glycerate (2-3 DPG) level was determined by a modification of the chromotropic acid method of Bartlett as described by Eaton.[11] ATP was estimated on perchloric acid extracts using the G6PD: Hexokinase double enzyme method.[12]
Results
The normal PK activity in newborns was established using 50-cord blood samples from clinically and hematologically normal deliveries and it ranged from 7.4 - 12.5 IU/g Hb. This is lower than the adult levels studied by us earlier (12.5- 17.5 IU/g Hb). 7 of the 218 cases of neonatal jaundice were PK deficient with a 30-40 % reduction in PK activity. The prevalence of PK deficiency in newborns with hyperbilirubinemia was thus 3.21 %. The hematological and biochemical data of the PK deficient cases with neonatal jaundice at presentation and follow-up are presented in table1table2. All these cases presented with unconjugated hyperbilirubinemia with reticulocytosis in the first 2 weeks of postnatal life. All of them needed phototherapy and three of them required exchange blood transfusions. table1. All the cases were followed up between one and nine-months of age to reconfirm PK deficiency. Their hemoglobin levels on follow-up ranged from 4.3 to 11.0 g/dl and they had marked reticulocytosis (6 to 30%) table2. Other causes of intracorpuscular hemolysis like presence of unstable hemoglobins, thalassemia, hereditary spherocytosis and G6PD deficiency were ruled out. The presence of auto antibodies and cold antibodies were also excluded. These cases also had a 3-4-fold increase in 2-3 DPG:ATP ratios, which is one of the additional indicators for PK deficiency. On follow up, it was seen that except for one case the remaining six cases had required variable numbers of blood transfusions table2.
Discussion
There are innumerable causes of hyperbilirubinemia in newborns, most of which are hereditary in nature such as hemoglobinopathies, enzymopathies and membrane disorders.[13],[14] Metabolic activity is very limited in mature red blood cell (RBCs) because of lack of ribosomes and mitochondria. Mature RBCs need ATP to maintain their metabolic activities and discoid shape. The only metabolic pathway for ATP generation is anaerobic glycolysis in these cells. Lack of PK activity in this pathway will stop energy production and cause destruction of erythrocytes, because PK catalyses one of the major glycolytic reactions responsible for ATP production. A deficiency of this enzyme leads to hemolytic anemia and neonatal jaundice.[15]
It is well known that neonatal RBCs differ from adult red cells in their metabolic features and have a shorter lifespan. The activity of enzymes in the glycolytic pathway also differ according to cell age.[16] We have established the normal range for PK activity in our newborns using 50 cord blood samples from normal deliveries. It was 9.85±2.65 IU/g Hb, which is lower than the PK activity in adults (13.86±2.36 IU/g Hb). In the study by Travis et al (1980)[17], the activities of hexokinase and PK were found to be diminished in the first 8-9 weeks of life in term infants and then slightly increased until the end of the first year.
PK deficiency causes accumulation of few glycolytic intermediates like phosphoenol pyruvate (PEP), 2-Phoshoglycerate (2-PG), 3-Phosphoglycerate (3-PG) and 2-3 DPG in the red cell.[18] Several previous investigators have also reported a good correlation of increased levels of 2,3 DPG with PK deficiency. ATP formation is reduced but in the presence of marked reticulocytosis absolute levels may be normal. An increase in the ratio of 2,3 DPG:ATP has been found to be a more reliable predictor of PK deficiency.[19] We also found a 3 to 4 fold increase in 2,3 DPG : ATP ratios in our cases. The prevalence of several inherited red cell disorders, likes thalassemias, sickle cell anemia and G6PD deficiency have been determined in the Indian populations.[20] G6PD is the most common enzyme deficiency studied extensively in the Indian population.[21] The prevalence of G6PD deficiency in the general population in India is 1.5% whereas in icteric newborns with hyperbilirubinemia it is reported to be 12.2 %.[22] There are no earlier reports on the prevalence of pyruvate kinase deficiency in neonatal jaundice in India. In the present study 3.21% of neonates with hyperbilirubinemia were PK deficient with a 30-40% reduction in PK activity. Out of 302 cases of non-spherocytic hemolytic anemia screened by us for PK deficiency in the last 5-yrs, 9 cases (2.98%) were found to be PK deficient. Majority of these cases originated from Maharashtra, Gujrat or Utter Pradesh (Unpublished observation). Hence, PK deficiency is not uncommon in these regions. Mohrenweiser (1981) [23] have shown that PK deficiency is the second most common cause of HNSHA and neonatal jaundice after G6PD deficiency. The true prevalence of PK deficiency in different parts of the world is unknown because it occurs relatively rarely and diagnosis is generally done only in symptomatic cases in specialized centers and some commercial and hospital based laboratories. Nevertheless, few efforts have been made to obtain some information regarding the prevalence of this disorder. Assay of red cell PK in 214 newborns by Furnkranz (1985) showed that 1.4% of the German subjects were heterozygous for this deficiency.[24] Fung et al (1969) had found PK deficiency in 3.4% of 700 consecutive newborn Chinese infants in Hong Kong.[6] In a later study, an incidence of 2.2% of PK deficiency was reported among 1159 Chinese infants.[25] Low prevalence rates have been reported in Northern Europeans (1.0 - 1.4%)[3] and Americans (1.4%),[26] however, a relatively high incidence of 2.92% was reported in 513 newborns from Saudi Arabia.[27] The prevalence was found to be higher in eastern Quebec (Canada) (1/81,838) than in western Quebec (1/139,086).[28] On the basis of gene frequency, Beutler and Gelbart (2000).[29] estimated that the prevalence of homozygous PK deficiency would be 51 cases per million in the white population. Their experience showed that under diagnosis was also likely and misdiagnosis was common, even when a quantitative assay of PK was performed.
To the best of our knowledge, only one case of PK deficiency has been reported from India so far. This was a 5 1/ 2 -year-old child with anemia and splenomegaly and repeated episodes of jaundice.[30] This child had a reduction in PK activity by 60% and had been transfused twice for his anemia. Besides this, only one study on screening for PK deficiency in a tribal population group from Baster district in Madhya Pradesh in Central India has been reported.[31]
Conclusion
We diagnosed 7 cases of PK deficiency by a systematic screening of neonatal jaundice cases over a period of 4- years. 6 of these infants had a severe clinical course. Hence, PK deficiency is not uncommon in India and needs to be investigated in greater details including the molecular basis of this enzyme deficiency in the Indian population.
References
1. Valentine WN, Tanaka KK, Miwa S. A specific erythrocyte glycolytic enzyme defect (Pyruvate Kinase) in three subjects with congenital non-spherocytic hemolytic anemia. Trans Assoc Am Phys 1961; 74 : 100-110.
2. Lilleyman J, Hann I, Blanchette V eds. Pediatric Hematology , 2nd edn. New York, Churchill Livingstone, 1999; pp. 191-192.
3. Carey PJ, Chandler J, Hendrick A, Reid MM, Saunders PWG, Tinegate H, Taylor PR, West N. Prevalence of pyruvate kinase deficiency in a northern European population in the north of England. (Letter) Blood 2000 ; 96: 4005.
4. Lenzner, C, Nurnberg P, Jacobasch G, Gerth, C, Thiele, BJ. Molecular analysis of 29 pyruvate kinase-deficient patients from Central Europe with hereditary hemolytic anemia. Blood 1997; 89 : 1793-1799.
5. Miwa S, Nishina T. Studies on pyruvate kinase (PK) deficiency Clinical, hematological and erythrocyte enzyme studies. Acta Hematologica Japonica 1974; 37 : 1-16.
6. Fung RHP, Keung YK, Chung GSH. Screening of PK and G6PD deficiency in Chinese newborns in Hong Kong. Arch Dis Child 1969; 44 : 373-376.
7. Sukumaran PK, Master HR. The distribution of the abnormal hemoglobinopathies in Indian population. In Sanghavi LD, Balkrishnan V, Bhatia HM, Sukumaran PK, Undevia JV, ed. New Delhi, India; Human Population Genetics in India, Indian Society of Human Genetics, 1974; 1-9.
8. Dacie JV, Lewis SM. Practical Hematology: London; Churchill Livingstone, 1999.
9. Beutler E, West C, Blume KG. The removal of leucocytes and platelets from whole blood . J Lab Clin Med 1976; 88 : 328-333.
10. Beutler E. Red cell metabolism" A manual of biochemical methods" 2nd edition, New York; Grune & Straton, 1975.
11. Eaton JW, Brewer GJ, Grover RF. Role of red cell 2-3 DPG in adaptation of man to altitude. J Lab Clin Med 1969; 73 : 603-608.
12. Brewer G J, Powell RD. The ATP content of G6PD deficient and normal erythrocytes including studies of G6PD deficient man with elevated erythrocyte ATP. J Lab Clin Med 1966; 67: 726-730.
13. Meitzer WC (Jr). Pyruvate kinase deficiency and disorders of glycolysis. In Nathan DG, Oski FA eds. Hematology of infancy and childhood W.B. Saunders, Philadelphia 1993; 634-674.
14. Oski FA, Naiman JL. Hematological problems in the newborn, Philadelphia, W.B. Saunders, 1982; pp 108-111.
15. El Hazmi MA, Warsy AS. Correlation between red cell pyruvate kinase activity and hematological parameters. Med Lab Sci 1990; 47 : 80-84.
16. Berti D, Buonocore L, Hayek Y, Cito G, Ciccoli L. Variation in erythrocyte enzymatic activity in the first days of life . Bull Soc Ital Biol Sper 1981; 57 : 1340-1345.
17. Travis SF, Kumar SP, Paes PC, Delicoria Papadopoulos M. Red cell metabolic alteration in post life in term infants: Glycolytic enzymes and G6PD . Pediatr Res 1980; 14 : 1349-1352.
18. Lestas AN, Kai LA, Bellingham AJ. Red cell phosphoglycerate level as a diagnostic aid in pyruvate kinase deficiency. Br J Hematol 1987; 67 : 485-488.
19. Valentine WN, Tanaka KR. Pyruvate kinase and other enzyme deficiency hereditary hemolytic anemia. In Stanbury JB, Wyngarden JB, Fredrickson DS, eds. The metabolic basis of inherited disease . New York; McGraw- Hill, 1981:1608-1628.
20. Mohanty D, Colah R, Gorakshakar AC et al. Genetic disorders in hematological practice in India. Community Genet 2002; 5 : 197-200.
21. Mohanty D, Mukherjee MB, Colah RB: Glucose-6-Phosphate Dehydrogenase deficiency in India. Ind J Pediatr. 2004; 17 : 525-529.
22. Madan N, Sundaram KR, Bhargava SK, Sood SK. Glucose-6-Phosphate dehydrogenase deficiency and Neonatal jaundice. Ind J Med Res 1989; 90 : 306-313.
23. Mohrenweiser HW: Frequency of enzyme deficiency variants in erythrocytes of newborn infants. Proc Natl Acad Sci USA 1981; 78: 5046-5050.
24. Furnkranz H. Pyruvate Kinase deficiency in the newborn infants. Pediatr Padol 1985; 20: 267-273.
25. Wu ZL, Yu WD, Chen SC: Frequency of erythrocyte pyruvate Kinase deficiency in Chinese infants. Am J Hematol 1985; 20: 139-144.
26. Tanaka KR, Paglia DE. Pyruvate kinase deficiency. Sem Hematol 1971; 8 : 367-396.
27. Abu-Melha A.M, Ahmed MAM, Knox-Macaulay H, Al-Sowayan SA, El-Yahia A. Erythrocyte pyruvate kinase deficiency in newborns of eastern Saudi Arabia. Acta Haematol . 1991; 85 : 192-194.
28. de Medicis E, Ross P, Friedman R, Hume H, Marceau D, Milot M. Lyonnais J, De Braekeleer M. Hereditary nonspherocytic hemolytic anemia due to pyruvate kinase deficiency: a prevalence study in Quebec (Canada). Hum Hered 1992; 42: 179-183.
29. Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from gene frequency in the general white population . Blood 2000; 95 : 3585-3588.
30. Bhargava A B, Pavri R S, Veer S, Bhatia H M. Congenital non- spherocytic hemolytic anemia due to Pyruvate kinase deficiency in an Indian Muslim . Ind J Hematol. 1985; 3: 20-21.
31. Basu S, Jindal A. Red cell enzyme deficiencies in the tribal population groups of Bastar District (Madhya Pradesh) India, Anthropologischer Anzeiger 1995; 53: 331-335.(Kedar Prabhakar S, Warang)
Abstract
Objective. Pyruvate Kinase (PK) deficiency is the most common enzymopathy of the glycolytic pathway in erythrocytes. It constitutes one of the common causes of hereditary non-spherocytic hemolytic anemia. The aim of this study was to screen newborns in India for pyruvate kinase (PK) deficiency in relation to unconjugated hyperbilirubinemia. Methods. Laboratory investigations done included complete blood counts, reticulocyte counts, direct and indirect bilirubin, assay of G6PD and PK activity, ATP and 2,3 DPG levels. All variables were studied in 50-cord blood samples from normal deliveries and 218 neonates with hyperbilirubinemia. Results. 7 of the 218 cases of neonatal jaundice were PK deficient with 30-40 % reduction in PK activity. These cases also had a 3-4-fold increase in 2,3 DPG:ATP ratios, which is one of the additional indicators for PK deficiency. Six of the 7 infants had a severe clinical course. Conclusion. This study shows that the prevalence of PK deficiency in Indian neonatal jaundice cases is 3.21%, which is relatively high. This emphasizes the need for screening neonatal hyperbilirubinemia cases in India for PK deficiency.
Keywords: Pyruvate Kinase deficiency; Hereditary non-spherocytic hemolytic anemia; Neonatal jaundice; Hyperbilirubinemia
Red cell pyruvate kinase (PK.EC.2.7.1.40) deficiency is the most common enzyme abnormality in the Embden Meyerhoff pathway of glycolysis in humans. PK deficiency is associated with hereditary non-spherocytic hemolytic anemia (HNSHA) and is transmitted as an autosomal recessive disorder, with both the sexes being equally affected. The clinical severity of this disorder varies widely, ranging from a mildly compensated anemia to severe anemia of childhood, though in some cases it does not manifest itself until adulthood. Affected newborns usually present with unconjugated hyperbilirubinemia and may require exchange transfusion. PK deficiency was first described by Valentine et al in 1961 and since then, approximately 450 cases have been described in the literature[1],[2]. Most of these are of North European origin while occasional cases have been reported from the Middle East, Japan, China, Spain and Saudi Arabia.[3],[4],[5],[6]
The common causes for inherited hemolytic anemia in the Indian Subcontinent include thalassemia, sickle cell anemia, other hemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency (G6PD). The distribution of these hereditary defects in this population have been described earlier.[7] There is no data on the prevalence of PK deficiency in the Indian population. This study was thus undertaken to determine the incidence of PK deficiency in Indian newborns presenting with neonatal jaundice and to evaluate the severity of the disease in these cases.
Materials and Methods
50-cord blood samples from clinically and hematologically normal deliveries were collected in EDTA and analyzed within 24 hr (Normal controls). 218 neonates (103 males and 115 females) presenting with unconjugated hyperbilirubinemia were included in this study. Hematological indices were measured on an automated cell counter. (Sysmex- K-1000, Japan) Peripheral smear examination and reticulocyte counts were done using standard techniques. Direct and indirect antiglobulin test was done to exclude immune causes of hemolysis. Total and indirect bilirubin levels were determined by standard methods. Depletion of reticulocytes was done by differential centrifugation and confirmation was done by reticulocyte staining with new methylene blue.[8] The red cells were prepared for enzyme assay by passing the whole blood through a column containing a mixture of a-cellulose and microcrystalline cellulose (Sigma, USA) to remove leucocytes.[9] Glucose-6-phosphate dehydrogenase and pyruvate kinase activities were assayed by the method described by Beutler.[10] 2,3 Diphospho glycerate (2-3 DPG) level was determined by a modification of the chromotropic acid method of Bartlett as described by Eaton.[11] ATP was estimated on perchloric acid extracts using the G6PD: Hexokinase double enzyme method.[12]
Results
The normal PK activity in newborns was established using 50-cord blood samples from clinically and hematologically normal deliveries and it ranged from 7.4 - 12.5 IU/g Hb. This is lower than the adult levels studied by us earlier (12.5- 17.5 IU/g Hb). 7 of the 218 cases of neonatal jaundice were PK deficient with a 30-40 % reduction in PK activity. The prevalence of PK deficiency in newborns with hyperbilirubinemia was thus 3.21 %. The hematological and biochemical data of the PK deficient cases with neonatal jaundice at presentation and follow-up are presented in table1table2. All these cases presented with unconjugated hyperbilirubinemia with reticulocytosis in the first 2 weeks of postnatal life. All of them needed phototherapy and three of them required exchange blood transfusions. table1. All the cases were followed up between one and nine-months of age to reconfirm PK deficiency. Their hemoglobin levels on follow-up ranged from 4.3 to 11.0 g/dl and they had marked reticulocytosis (6 to 30%) table2. Other causes of intracorpuscular hemolysis like presence of unstable hemoglobins, thalassemia, hereditary spherocytosis and G6PD deficiency were ruled out. The presence of auto antibodies and cold antibodies were also excluded. These cases also had a 3-4-fold increase in 2-3 DPG:ATP ratios, which is one of the additional indicators for PK deficiency. On follow up, it was seen that except for one case the remaining six cases had required variable numbers of blood transfusions table2.
Discussion
There are innumerable causes of hyperbilirubinemia in newborns, most of which are hereditary in nature such as hemoglobinopathies, enzymopathies and membrane disorders.[13],[14] Metabolic activity is very limited in mature red blood cell (RBCs) because of lack of ribosomes and mitochondria. Mature RBCs need ATP to maintain their metabolic activities and discoid shape. The only metabolic pathway for ATP generation is anaerobic glycolysis in these cells. Lack of PK activity in this pathway will stop energy production and cause destruction of erythrocytes, because PK catalyses one of the major glycolytic reactions responsible for ATP production. A deficiency of this enzyme leads to hemolytic anemia and neonatal jaundice.[15]
It is well known that neonatal RBCs differ from adult red cells in their metabolic features and have a shorter lifespan. The activity of enzymes in the glycolytic pathway also differ according to cell age.[16] We have established the normal range for PK activity in our newborns using 50 cord blood samples from normal deliveries. It was 9.85±2.65 IU/g Hb, which is lower than the PK activity in adults (13.86±2.36 IU/g Hb). In the study by Travis et al (1980)[17], the activities of hexokinase and PK were found to be diminished in the first 8-9 weeks of life in term infants and then slightly increased until the end of the first year.
PK deficiency causes accumulation of few glycolytic intermediates like phosphoenol pyruvate (PEP), 2-Phoshoglycerate (2-PG), 3-Phosphoglycerate (3-PG) and 2-3 DPG in the red cell.[18] Several previous investigators have also reported a good correlation of increased levels of 2,3 DPG with PK deficiency. ATP formation is reduced but in the presence of marked reticulocytosis absolute levels may be normal. An increase in the ratio of 2,3 DPG:ATP has been found to be a more reliable predictor of PK deficiency.[19] We also found a 3 to 4 fold increase in 2,3 DPG : ATP ratios in our cases. The prevalence of several inherited red cell disorders, likes thalassemias, sickle cell anemia and G6PD deficiency have been determined in the Indian populations.[20] G6PD is the most common enzyme deficiency studied extensively in the Indian population.[21] The prevalence of G6PD deficiency in the general population in India is 1.5% whereas in icteric newborns with hyperbilirubinemia it is reported to be 12.2 %.[22] There are no earlier reports on the prevalence of pyruvate kinase deficiency in neonatal jaundice in India. In the present study 3.21% of neonates with hyperbilirubinemia were PK deficient with a 30-40% reduction in PK activity. Out of 302 cases of non-spherocytic hemolytic anemia screened by us for PK deficiency in the last 5-yrs, 9 cases (2.98%) were found to be PK deficient. Majority of these cases originated from Maharashtra, Gujrat or Utter Pradesh (Unpublished observation). Hence, PK deficiency is not uncommon in these regions. Mohrenweiser (1981) [23] have shown that PK deficiency is the second most common cause of HNSHA and neonatal jaundice after G6PD deficiency. The true prevalence of PK deficiency in different parts of the world is unknown because it occurs relatively rarely and diagnosis is generally done only in symptomatic cases in specialized centers and some commercial and hospital based laboratories. Nevertheless, few efforts have been made to obtain some information regarding the prevalence of this disorder. Assay of red cell PK in 214 newborns by Furnkranz (1985) showed that 1.4% of the German subjects were heterozygous for this deficiency.[24] Fung et al (1969) had found PK deficiency in 3.4% of 700 consecutive newborn Chinese infants in Hong Kong.[6] In a later study, an incidence of 2.2% of PK deficiency was reported among 1159 Chinese infants.[25] Low prevalence rates have been reported in Northern Europeans (1.0 - 1.4%)[3] and Americans (1.4%),[26] however, a relatively high incidence of 2.92% was reported in 513 newborns from Saudi Arabia.[27] The prevalence was found to be higher in eastern Quebec (Canada) (1/81,838) than in western Quebec (1/139,086).[28] On the basis of gene frequency, Beutler and Gelbart (2000).[29] estimated that the prevalence of homozygous PK deficiency would be 51 cases per million in the white population. Their experience showed that under diagnosis was also likely and misdiagnosis was common, even when a quantitative assay of PK was performed.
To the best of our knowledge, only one case of PK deficiency has been reported from India so far. This was a 5 1/ 2 -year-old child with anemia and splenomegaly and repeated episodes of jaundice.[30] This child had a reduction in PK activity by 60% and had been transfused twice for his anemia. Besides this, only one study on screening for PK deficiency in a tribal population group from Baster district in Madhya Pradesh in Central India has been reported.[31]
Conclusion
We diagnosed 7 cases of PK deficiency by a systematic screening of neonatal jaundice cases over a period of 4- years. 6 of these infants had a severe clinical course. Hence, PK deficiency is not uncommon in India and needs to be investigated in greater details including the molecular basis of this enzyme deficiency in the Indian population.
References
1. Valentine WN, Tanaka KK, Miwa S. A specific erythrocyte glycolytic enzyme defect (Pyruvate Kinase) in three subjects with congenital non-spherocytic hemolytic anemia. Trans Assoc Am Phys 1961; 74 : 100-110.
2. Lilleyman J, Hann I, Blanchette V eds. Pediatric Hematology , 2nd edn. New York, Churchill Livingstone, 1999; pp. 191-192.
3. Carey PJ, Chandler J, Hendrick A, Reid MM, Saunders PWG, Tinegate H, Taylor PR, West N. Prevalence of pyruvate kinase deficiency in a northern European population in the north of England. (Letter) Blood 2000 ; 96: 4005.
4. Lenzner, C, Nurnberg P, Jacobasch G, Gerth, C, Thiele, BJ. Molecular analysis of 29 pyruvate kinase-deficient patients from Central Europe with hereditary hemolytic anemia. Blood 1997; 89 : 1793-1799.
5. Miwa S, Nishina T. Studies on pyruvate kinase (PK) deficiency Clinical, hematological and erythrocyte enzyme studies. Acta Hematologica Japonica 1974; 37 : 1-16.
6. Fung RHP, Keung YK, Chung GSH. Screening of PK and G6PD deficiency in Chinese newborns in Hong Kong. Arch Dis Child 1969; 44 : 373-376.
7. Sukumaran PK, Master HR. The distribution of the abnormal hemoglobinopathies in Indian population. In Sanghavi LD, Balkrishnan V, Bhatia HM, Sukumaran PK, Undevia JV, ed. New Delhi, India; Human Population Genetics in India, Indian Society of Human Genetics, 1974; 1-9.
8. Dacie JV, Lewis SM. Practical Hematology: London; Churchill Livingstone, 1999.
9. Beutler E, West C, Blume KG. The removal of leucocytes and platelets from whole blood . J Lab Clin Med 1976; 88 : 328-333.
10. Beutler E. Red cell metabolism" A manual of biochemical methods" 2nd edition, New York; Grune & Straton, 1975.
11. Eaton JW, Brewer GJ, Grover RF. Role of red cell 2-3 DPG in adaptation of man to altitude. J Lab Clin Med 1969; 73 : 603-608.
12. Brewer G J, Powell RD. The ATP content of G6PD deficient and normal erythrocytes including studies of G6PD deficient man with elevated erythrocyte ATP. J Lab Clin Med 1966; 67: 726-730.
13. Meitzer WC (Jr). Pyruvate kinase deficiency and disorders of glycolysis. In Nathan DG, Oski FA eds. Hematology of infancy and childhood W.B. Saunders, Philadelphia 1993; 634-674.
14. Oski FA, Naiman JL. Hematological problems in the newborn, Philadelphia, W.B. Saunders, 1982; pp 108-111.
15. El Hazmi MA, Warsy AS. Correlation between red cell pyruvate kinase activity and hematological parameters. Med Lab Sci 1990; 47 : 80-84.
16. Berti D, Buonocore L, Hayek Y, Cito G, Ciccoli L. Variation in erythrocyte enzymatic activity in the first days of life . Bull Soc Ital Biol Sper 1981; 57 : 1340-1345.
17. Travis SF, Kumar SP, Paes PC, Delicoria Papadopoulos M. Red cell metabolic alteration in post life in term infants: Glycolytic enzymes and G6PD . Pediatr Res 1980; 14 : 1349-1352.
18. Lestas AN, Kai LA, Bellingham AJ. Red cell phosphoglycerate level as a diagnostic aid in pyruvate kinase deficiency. Br J Hematol 1987; 67 : 485-488.
19. Valentine WN, Tanaka KR. Pyruvate kinase and other enzyme deficiency hereditary hemolytic anemia. In Stanbury JB, Wyngarden JB, Fredrickson DS, eds. The metabolic basis of inherited disease . New York; McGraw- Hill, 1981:1608-1628.
20. Mohanty D, Colah R, Gorakshakar AC et al. Genetic disorders in hematological practice in India. Community Genet 2002; 5 : 197-200.
21. Mohanty D, Mukherjee MB, Colah RB: Glucose-6-Phosphate Dehydrogenase deficiency in India. Ind J Pediatr. 2004; 17 : 525-529.
22. Madan N, Sundaram KR, Bhargava SK, Sood SK. Glucose-6-Phosphate dehydrogenase deficiency and Neonatal jaundice. Ind J Med Res 1989; 90 : 306-313.
23. Mohrenweiser HW: Frequency of enzyme deficiency variants in erythrocytes of newborn infants. Proc Natl Acad Sci USA 1981; 78: 5046-5050.
24. Furnkranz H. Pyruvate Kinase deficiency in the newborn infants. Pediatr Padol 1985; 20: 267-273.
25. Wu ZL, Yu WD, Chen SC: Frequency of erythrocyte pyruvate Kinase deficiency in Chinese infants. Am J Hematol 1985; 20: 139-144.
26. Tanaka KR, Paglia DE. Pyruvate kinase deficiency. Sem Hematol 1971; 8 : 367-396.
27. Abu-Melha A.M, Ahmed MAM, Knox-Macaulay H, Al-Sowayan SA, El-Yahia A. Erythrocyte pyruvate kinase deficiency in newborns of eastern Saudi Arabia. Acta Haematol . 1991; 85 : 192-194.
28. de Medicis E, Ross P, Friedman R, Hume H, Marceau D, Milot M. Lyonnais J, De Braekeleer M. Hereditary nonspherocytic hemolytic anemia due to pyruvate kinase deficiency: a prevalence study in Quebec (Canada). Hum Hered 1992; 42: 179-183.
29. Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from gene frequency in the general white population . Blood 2000; 95 : 3585-3588.
30. Bhargava A B, Pavri R S, Veer S, Bhatia H M. Congenital non- spherocytic hemolytic anemia due to Pyruvate kinase deficiency in an Indian Muslim . Ind J Hematol. 1985; 3: 20-21.
31. Basu S, Jindal A. Red cell enzyme deficiencies in the tribal population groups of Bastar District (Madhya Pradesh) India, Anthropologischer Anzeiger 1995; 53: 331-335.(Kedar Prabhakar S, Warang)