Alternative titles; symbols
SNOMEDCT: 124331002; ORPHA: 766; DO: 0111077;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Pyruvate kinase deficiency | 266200 | Autosomal recessive | 3 | PKLR | 609712 |
A number sign (#) is used with this entry because red cell pyruvate kinase (PK) deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding pyruvate kinase (PKLR; 609712) on chromosome 1q22.
Red cell pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. PK deficiency is also the most frequent enzyme abnormality of the glycolytic pathway (Zanella et al., 2005).
Valentine et al. (1961) first reported pyruvate kinase deficiency in 3 patients with congenital nonspherocytic hemolytic anemia. Tanaka et al. (1962) observed a compensated hemolytic anemia in young adults who had been relatively little incapacitated. At that time, separate alleles or even genes at different loci were thought to be the possible bases for clinical variability.
Bowman and Procopio (1963) observed a severe form of hemolytic anemia in the Old Order Amish of Mifflin Co., Pennsylvania. The disorder was much more severe than that reported by Tanaka et al. (1962), leading to death in the first years of life if not treated by transfusions and splenectomy. One of the Amish patients with PK deficiency hemolytic anemia and splenectomy at age 30 months had persistent thrombocytosis and carotid artery thromboses (Ginter, 1974).
Necheles et al. (1966) illustrated the clinical variability of PK deficiency in 2 unrelated patients. One had cholecystitis and cholelithiasis for which surgery was performed at age 23. He was well thereafter until age 28 when anemia developed, for which splenectomy was performed with good results. The second case was an infant who required exchange transfusion in the neonatal period because of jaundice and anemia. Results of splenectomy, performed at 14 months, were excellent. Zuelzer et al. (1968) noted marked intrafamilial clinical variability, which studies suggested was due to heterozygosity for 2 distinct interacting mutants in mildly affected relatives of severely affected probands. Persons possibly heterozygous for an anomalous pyruvate kinase had anemia in the family reported by Sachs et al. (1968).
Etiemble et al. (1984) reported a family in which hemolytic anemia due to red cell PK deficiency behaved as a seemingly autosomal dominant trait. In affected members, residual PK activity was about 20% of normal, an unusually low level for heterozygotes. The anemia was mild except in the proband, a 2-year-old boy with severe anemia. Etiemble et al. (1984) suggested that the presence of one or more mutated subunits in the tetrameric form of L-type PK may lead to inactivation of these tetramers. The greater severity in the proband was considered merely part of a spectrum of expression of the same defect.
Gilsanz et al. (1993) reported PK deficiency as a cause of fetal anemia and nonimmune hydrops fetalis. They described a woman in whom 3 previous pregnancies had resulted in stillbirth or early neonatal death due to anemic hydrops fetalis; PK deficiency was diagnosed in a later pregnancy by umbilical vessel sampling at 30 weeks' gestation. The infant survived with transfusion-dependent hemolytic anemia.
Koler et al. (1964) found that patients with PK deficiency in red blood cells had normal PK activity in white blood cells, suggesting that the 2 enzymes were encoded by different loci.
Paglia et al. (1968) and Sachs et al. (1968) both reported families with familial hemolytic anemia and postulated an inherited molecular lesion of red cell PK. Both groups identified kinetically abnormal PK isozymes that were associated with premature hemolysis. Bigley and Koler (1968) found decreased liver PK activity in a patient with hemolytic anemia due to red cell PK deficiency. The findings further suggested that the 2 enzymes are identical and likely derived from a common gene.
Boivin and Galand (1974) reported a mutant human red cell PK that showed high affinity for the substrate phosphoenolpyruvate (PEP). Shinohara et al. (1976) described a new pyruvate kinase variant, PK Osaka, and discussed the various PK isozymes and their nomenclature. The variant was ascertained through a patient with PK deficiency hemolytic anemia. A genetic compound for 2 different PK mutations was studied by Zanella et al. (1978).
The International Committee for Standardization in Haematology (1979) provided recommended methods for the characterization and nomenclature of red cell pyruvate kinase variants.
Variant pyruvate kinase enzymes isolated from patients with PK deficiency were reported by many groups, including Vives-Corrons et al. (1980), Kahn et al. (1981), Lakomek et al. (1983), Dente et al. (1982), Paglia et al. (1983, 1983), and Schroter et al. (1982). The enzymes were characterized by variable changes, including low activity, low substrate affinity, high sensitivity to allosteric activation, thermolability, aberrant kinetic properties, abnormal electrophoretic patterns, and decreased antigenic concentrations.
Etiemble et al. (1982) described a new variant of erythrocyte PK associated with severe hemolytic anemia. In contrast to previously reported cases, the molecular abnormalities could not be detected in a liver specimen.
In 2 of 651 unrelated patients with nonspherocytic hemolytic anemia, Beutler et al. (1987) observed elevated red cell PK activities commensurate with the decreased mean red cell age, but the residual PK had marked kinetic abnormalities. Accumulation of metabolic intermediates before pyruvate kinase and reduced levels of enzyme activity of the red blood cells in the parents of both patients supported the diagnosis of inherited PK abnormality as the cause of the hemolytic anemia.
In 2 unrelated patients, the offspring of consanguineous parents, Tani et al. (1988) identified PK variants associated with enzyme deficiency and nonspherocytic hemolytic anemia. The variants were called PK Sendai and PK Shinshu. Valentine et al. (1988) characterized the PK Greensboro variant. Findings suggested that although heterozygotes may have abnormal PK function, they may not have clinical manifestations or hemolysis.
In 2 Japanese patients, born of consanguineous parents, with hereditary hemolytic anemia due to pyruvate kinase deficiency, Kanno et al. (1991) identified a homozygous mutation in the PKLR gene (609712.0004). Larochelle et al. (1991) identified a mutation in the PKLR gene (609712.0001) in French Canadian patients with pyruvate kinase deficiency.
Baronciani and Beutler (1995) found 19 different mutations among 58 of 60 PKLR alleles in 30 unrelated patients with hereditary nonspherocytic hemolytic anemia due to PK deficiency. Miwa and Fujii (1996) tabulated 47 mutations in the PK gene known to result in hereditary hemolytic anemia. Rouger et al. (1996) identified 7 different PK mutations in 26 unrelated families in France; 5 of these had not previously been described. Beutler and Baronciani (1996) found that in all 55 different mutations that had been described in patients with PK-deficient hemolytic anemia, the mutations were widely distributed, occurring throughout exons 4 to 12 in this 12-exon gene. Baronciani et al. (1996) tabulated 59 different mutations in red cell pyruvate kinase of hematologic importance.
In 23 patients from 21 unrelated families with PK deficiency, Fermo et al. (2005) identified a total of 27 different mutations in the PKLR gene, including 17 novel mutations. In a detailed review of PK deficiency, Zanella et al. (2005) stated that more than 150 different PKLR mutations had been identified.
Pissard et al. (2006) identified 41 different mutations in the PKLR gene, including 27 novel mutations, among 56 French families with PK deficiency. Most cases were ascertained because of neonatal or chronic anemia; 2 cases were lethal in the neonatal period.
Prenatal Diagnosis
Baronciani and Beutler (1994) reported successful prenatal diagnosis of PK deficiency using 2 different techniques. In the first case, they used PCR amplification and restriction endonuclease analysis and identified a mutation in fetus genomic DNA from amniotic fluid cells. In the second case, they used cord blood to analyze 2 polymorphic sites linked to the PKRL gene and were able to identify which chromosome had been inherited from which parent.
In a scheme to detect mutational events, Satoh et al. (1983) screened for activity in erythrocytes of 11 enzymes chosen because of relatively small coefficients of variation for mean activity. The object was to determine the frequency of heterozygotes as identified by activities at or below 66% of the mean value. The frequency of heterozygotes per 1,000 persons varied, with PK being 13.8 per 1,000. For these same enzymes the frequency of 'rare' electrophoretic variants is 2.3/1,000 in the Japanese, almost precisely the same.
Muir et al. (1984) extended the observations on PK deficiency in the Amish with identification of 8 affected persons in Geauga County, Ohio. Earlier reported cases came from Mifflin County, Pennsylvania (Bowman et al., 1965). All 8 Ohio cases were traced to a common ancestor in Mifflin County; his sister was a common ancestor of all cases identified in the original studies (Bowman et al., 1965). The common ancestor was Christopher Beiler, son of Jacob Beiler (born 1772) and Ferona Beiler and brother of Anna, wife of 'Strong' Jacob Yoder, who was the progenitor identified by Bowman et al. (1965).
From laboratories performing tests for PK deficiency and from attending physicians in the province of Quebec, de Medicis et al. (1992) collected 58 cases of hereditary nonspherocytic hemolytic anemia due to deficiency of the enzyme. Using the postal addresses of the probands, a prevalence map was constructed for the various regions of the province. The prevalence was found to be higher in eastern Quebec (1 in 81,838) than in western Quebec (1 in 139,086). Fifty probands were French Canadian, whereas the remaining 6 were recent immigrants.
On the basis of gene frequency, Beutler and Gelbart (2000) estimated that the prevalence of homozygous PK deficiency at 51 cases per million in the white population. Carey et al. (2000) had been centrally registering all patients with PK deficiency within the Northern Health Region of the United Kingdom since 1974. In this mainly white population, they found a prevalence of 3.3 per million, which is more than an order of magnitude lower than the prevalence predicted by Beutler and Gelbart (2000). In their registry there were very few older patients. They postulated that a possible explanation for this was that the advent of routine blood transfusion and neonatal exchange transfusion did not occur until the post-World War II period. Both Carey et al. (2000) and Beutler and Gelbart (2000) pointed out that prenatal or neonatal mortality lowers the frequency with which the disease is found in the population at large. Underdiagnosis is also likely. Beutler and Gelbart (2000) noted that in their experience misdiagnosis is common, even when PK assays are performed.
Blume et al. (1970) reported that intravenous administration of inosine and adenine was effective therapy, leading to decreased hemolysis, in some patients with PK deficiency.
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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. 42: 179-183, 1992. [PubMed: 1511997] [Full Text: https://doi.org/10.1159/000154063]
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Etiemble, J., Picat, C., Dhermy, D., Buc, H. A., Morin, M., Boivin, P. Erythrocytic pyruvate kinase deficiency and hemolytic anemia inherited as a dominant trait. Am. J. Hemat. 17: 251-260, 1984. [PubMed: 6475936] [Full Text: https://doi.org/10.1002/ajh.2830170305]
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Kanno, H., Fujii, H., Hirono, A., Miwa, S. cDNA cloning of human R-type pyruvate kinase and identification of a single amino acid substitution (thr384-to-met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic anemia. Proc. Nat. Acad. Sci. 88: 8218-8221, 1991. [PubMed: 1896471] [Full Text: https://doi.org/10.1073/pnas.88.18.8218]
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Larochelle, A., De Braekeleer, M., Marceau, D., de Medicis, E. Hereditary non-spherocytic hemolytic anemia: a pyruvate kinase mutation in Quebec patients. (Abstract) Advances in Gene Technology: The Molecular Biology of Human Genetic Disease. Proceedings of the 1991 Miami Bio/Technology Winter Symposium, January 1991. P. 33.
Miwa, S., Fujii, H. Molecular basis of erythroenzymopathies associated with hereditary hemolytic anemia: tabulation of mutant enzymes. Am. J. Hemat. 51: 122-132, 1996. [PubMed: 8579052] [Full Text: https://doi.org/10.1002/(SICI)1096-8652(199602)51:2<122::AID-AJH5>3.0.CO;2-#]
Muir, W. A., Beutler, E., Wasson, C. Erythrocyte pyruvate kinase deficiency in the Ohio Amish: origin and characterization of the mutant enzyme. Am. J. Hum. Genet. 36: 634-639, 1984. [PubMed: 6731438]
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Paglia, D. E., Valentine, W. N., Holbrook, C. T., Brockway, R. Pyruvate kinase isozyme (PK-Greenville) with defective allosteric activation by fructose-1,6-diphosphate: the role of F-1,6-P modulation in normal erythrocyte metabolism. Blood 62: 972-979, 1983. [PubMed: 6626748]
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