Alternative titles; symbols
SNOMEDCT: 124678007; ORPHA: 714; DO: 0111630;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q33 | Erythrocytosis, familial, 8 | 222800 | Autosomal recessive | 3 | BPGM | 613896 |
A number sign (#) is used with this entry because familial erythrocytosis-8 (ECYT8) is caused by homozygous or compound heterozygous mutation in the BPGM gene (613896), which encodes a multifunctional enzyme, on chromosome 7q33.
Schroter (1965) described severe hemolytic anemia in an infant. Although the proband's blood could not be studied because of multiple transfusions, the erythrocytes of the consanguineous parents, the sister and the father's mother showed activity of 2,3-diphosphoglycerate mutase about half of normal. The family of Bowdler and Prankerd (1964) is puzzling in that father and son had hemolytic anemia for which splenectomy was performed. In father and son, Labie et al. (1970) found a decrease in DPGM by about 50%. An increase in oxygen affinity of hemoglobin was observed. Schroter (1965) observed heterozygotes in 3 generations including both parents of a homozygous child with hemolytic anemia.
Rosa et al. (1978) described a French family in which a man and his 3 sisters had erythrocytosis and complete deficiency of bisphosphoglycerate mutase. As a consequence, the affinity of his red cells for oxygen was increased. Hemoglobin concentration was 19.0 g per dl. The morphology of his red cells was normal and there was no evidence of hemolysis. Low levels of red cell 2,3-DPG prompted assay of the enzyme.
Scott and Wright (1982) found DPGM to be polymorphic in 4 Alaskan ethnic groups. Hemoglobin and hematocrit were elevated in all deficient persons. Thus, both hemolytic anemia and polycythemia have been observed with deficiency of DPGM.
Galacteros et al. (1984) reported 2 families; in one, 3 sisters and a brother were homozygotes and all 3 offspring of 2 of them were heterozygotes with male-to-male transmission. Diphosphoglycerate phosphatase activity paralleled DPGM activity in all subjects.
Hoyer et al. (2004) reported a 28-year-old asymptomatic man, born to first-cousin parents of Iranian Jewish (Meshadi) heritage, who was found to have erythrocytosis with a hemoglobin of 19.2 g/dl and a Hct of 58.9%. The patient's 2,3-bisphosphoglycerate (BPG) level was markedly decreased at 0.3 micromol/g Hb (normal, 11.4-19.4) as was his bisphosphoglycerate mutase enzyme activity at 0.16 IU/g Hb (normal range, 4.13-5.43). Both parents had normal 2,3-BPG levels, but their BPGM activity was approximately 50% of normal. The parents did not have erythrocytosis and were asymptomatic.
Petousi et al. (2014) reported a 27-year-old Caucasian man and his mother who were heterozygous for a mutation in the BPGM gene. The patient presented with fatigue and was found to have a high Hb concentration of 193 g/dl (normal range for males, 130-180), hematocrit of 58.6%, elevated red cell mass (146% predicted), and a mild leftward shift in the Hb-oxygen dissociation curve. His serum erythropoietin (Epo) level was 15.9 mIU/mL (normal range, 2.5-10.5). His BPGM level was low at 3.62 IU/g Hb (compared to 4.21 in a control sample with comparable Hb), and his BPG was 14.5 low at micromol/g Hb (compared to 18.7 micromol/g Hb in a control sample with comparable Hb). He was treated with low-dose aspirin and phlebotomy, aiming to keep his hematocrit under 50%. His mother had a normal hemoglobin of 150 g/L (normal range for females, 115-155) and a normal serum Epo level of 7.5 miU/mL. Her BPGM level was low at 3.27 IU/g Hb as was her BPG level at 11.3 micromol/g Hb.
Camps et al. (2016) developed a targeted next-generation sequencing panel encompassing the exonic regions of 21 genes from relevant pathways, and sequenced 125 patients with idiopathic erythrocytosis with the panel. Among these patients, 1 patient with an elevated hemoglobin and hematocrit, but a normal Epo level, had a heterozygous missense mutation (Q102K) in the BPGM gene.
Familial erythrocytosis is an autosomal recessive disorder (Lemarchandel et al., 1992).
In a patient with complete deficiency of erythrocyte BPGM reported by Rosa et al. (1978), Rosa et al. (1989) identified a heterozygous missense mutation in the BPGM gene (R90C; 613896.0001). Lemarchandel et al. (1992) studied the family originally reported by Rosa et al. (1978). They found that the affected individuals were, in fact, compound heterozygous for the R90C mutation and a deletion of nucleotide 205C or 206C (amino acid 19) (613896.0002).
By sequencing the BPGM gene in a 28-year-old Iranian Jewish man with familial erythrocytosis, who was born of first-cousin parents, Hoyer et al. (2004) identified homozygosity for a missense mutation (R62Q; 613896.0003).
Using whole-genome sequencing, Petousi et al. (2014) identified a novel heterozygous missense mutation in the BPGM gene (R90H; 613896.0004) in a 27-year-old Caucasian man with erythrocytosis and a low level of BPGM and BPG. His mother, who had normal levels of hemoglobin and Epo, but low BPGM and BPG, had the same variant.
Camps et al. (2016) developed a targeted next-generation sequencing panel encompassing the exonic regions of 21 genes from relevant pathways for idiopathic erythrocytosis and sequenced 125 patients with idiopathic erythrocytosis. Among these patients, 10 had known erythrocytosis-causing variants and 22 had novel variants in erythrocytosis-associated genes, including 1 patient with a novel heterozygous missense mutation in the BPGM gene (Q102K).
Bowdler, A. J., Prankerd, T. A. J. Studies in congenital non-spherocytic haemolytic anaemias with specific enzyme defects. Acta Haemat. 31: 65-78, 1964. [PubMed: 14131784] [Full Text: https://doi.org/10.1159/000209615]
Camps, C., Petousi, N., Bento, C., Cario, H., Copley, R. R., McMullin, M. F., van Wijk, R., WGS500 Consortium, Ratcliffe, P. J., Robbins, P. A., Taylor, J. C. Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. Haematologica 101: 1306-1318, 2016. [PubMed: 27651169] [Full Text: https://doi.org/10.3324/haematol.2016.144063]
Galacteros, F., Rosa, R., Prehu, M. O., Najean, Y., Calvin, M. C. Deficit en diphosphoglycerate mutase: nouveaux cas associes a une polyglobulie. Nouv. Rev. Franc. Hemat. 26: 69-74, 1984. [PubMed: 6326048]
Hoyer, J. D., Allen, S. L., Beutler, E., Kubik, K., West, C., Fairbanks, V. F. Erythrocytosis due to bisphosphoglycerate mutase deficiency with concurrent glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Am. J. Hemat. 75: 205-208, 2004. [PubMed: 15054810] [Full Text: https://doi.org/10.1002/ajh.20014]
Labie, D., Leroux, J.-P., Najman, A., Reyrolle, C. Familial diphosphoglycerate mutase deficiency: influence on the oxygen affinity curves of hemoglobin. FEBS Lett. 9: 37-40, 1970. [PubMed: 11947623] [Full Text: https://doi.org/10.1016/0014-5793(70)80305-2]
Lemarchandel, V., Joulin, V., Valentin, C., Rosa, R., Galacteros, F., Rosa, J., Cohen-Solal, M. Compound heterozygosity in a complete erythrocyte bisphosphoglycerate mutase deficiency. Blood 80: 2643-2649, 1992. [PubMed: 1421379]
Lohr, G. W., Waller, H. D. Zur Biochemie einiger angeborener haemolytischer Anaemien. Folia Haemat. 8: 377-397, 1963.
Petousi, N., Copley, R. R., Lappin, T. R. J., Haggan S. E., Bento, C. M., Cario, H., Percy, M. J., the WGS Consortium, Ratcliffe, P. J., Robbins, P. A., McMullin, M. F. Erythrocytosis associated with a novel missense mutation in the BPGM gene. Haematologica 99: e201, 2014. Note: Electronic Article. [PubMed: 25015942] [Full Text: https://doi.org/10.3324/haematol.2014.109306]
Rosa, R., Blouquit, Y., Calvin, M.-C., Prome, D., Prome, J.-C., Rosa, J. Isolation, characterization, and structure of a mutant 89 arg-to-cys bisphosphoglycerate mutase: implication of the active site in the mutation. J. Biol. Chem. 264: 7837-7843, 1989. [PubMed: 2542247]
Rosa, R., Gaillardon, J., Rosa, J. Diphosphoglycerate mutase and 2,3-diphosphoglycerate phosphatase activities of red cells: comparative electrophoretic study. Biochem. Biophys. Res. Commun. 51: 536-542, 1973. [PubMed: 4350060] [Full Text: https://doi.org/10.1016/0006-291x(73)91347-8]
Rosa, R., Prehu, M.-O., Beuzard, Y., Rosa, J. The first case of a complete deficiency of diphosphoglycerate mutase in human erythrocytes. J. Clin. Invest. 62: 907-915, 1978. [PubMed: 152321] [Full Text: https://doi.org/10.1172/JCI109218]
Schroter, W. Kongenitale nichtsphaerocytaere haemolytische Anaemie bei 2,3-Diphosphoglyceratmutasemangel der Erythrocyten im fruehen Saeuglingsalter. Klin. Wschr. 43: 1147-1153, 1965. [PubMed: 5885535] [Full Text: https://doi.org/10.1007/BF01733168]
Scott, E. M., Wright, R. C. An alternate method for demonstration of bisphosphoglyceromutase (DPGM) on starch gels. Am. J. Hum. Genet. 34: 1013-1015, 1982. [PubMed: 6295140]