Abstract
Phosphoglycerate kinase (PGK) deficiency, a rare X-linked inherited disorder, manifests as various combinations of hemolytic anemia, neurological dysfunction, and myopathy. We report a Japanese boy with PGK deficiency presenting as chronic hemolytic anemia. The diagnosis of PGK1 deficiency was made at 11 months of age on the basis of low PGK enzyme activity (36.7 IU/g Hb; normal, 264–326 IU/g Hb) and the identification through PGK1 gene sequencing of a novel missense mutation: c. 1180A>G at exon 10. The mutation, which has been designated PGK-Aoto, results in a Thr394Ala amino-acid substitution at β-strand L. Because β-strand L plays an important role in the function of the hinge connecting the two domains of PGK, the Thr394Ala substitution may perturb this motion. At 3 years of age the patient has transfusion-dependent hemolytic anemia but no evidence of neuromuscular disease or developmental delay. Long-term follow-up will be needed to identify possible future clinical manifestations.
This is a preview of subscription content, log in via an institution to check access.
References
Beutler E. PGK deficiency. Br J Haematol. 2007;136:3–11.
Chiarelli LR, Morera SM, Bianchi P, Bianchi P, Fermo E, Zanella A, Galizzi A, et al. Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency. PLoS ONE. 2012;7:e32065.
Fujii H, Kanno H, Hirono A, Shiomura T, Miwa S. A single amino acid substitution (157 Gly → Val) in a phosphoglycerate kinase variant (PGK Shizuoka) associated with chronic hemolysis and myoglobinuria. Blood. 1992;79:1582–5.
Morimoto A, Ueda I, Hirashima Y, Sawai Y, Usuku T, Kano G, et al. A novel missense mutation (1060G → C) in the phosphoglycerate kinase gene in a Japanese boy with chronic haemolytic anaemia, developmental delay and rhabdomyolysis. Br J Haematol. 2003;122:1009–13.
Fermo E, Bianchi P, Chiarelli LR, Maggi M, Mandara GML, Vercellati C, et al. A new variant of phosphoglycerate kinase deficiency (p.I371 K) with multiple tissue involvement: molecular and functional characterization. Mole Genet Metab. 2012;106:455–61.
Maeda M, Bawle EV, Kulkarni R, Beutler E, Yoshida A. Molecular abnormalities of a phsphoglycerate kinase variant generated by spontaneous mutation. Blood. 1992;79:2759–62.
Spiegel R, Gomez EA, Akman HO, Krishna S, Horovitz Y, DiMauro S. Myopathic form of phosphoglycerate kinase (PGK) deficiency: a new case and pathogenic considerations. Neuromuscul Disord. 2009;19:207–11.
Valentin C, Birgens H, Craescu CT, Brodum-Nielsen K, Cohen-Solal M. A phosphoglycerate kinase mutant (PGK Herlev; D285V) in a Danish patient with isolated chronic hemolytic anemia: mechanism of mutation and structure-function relationships. Hum Mutat. 1998;12:280–7.
Szilagyi AN, Ghosh M, Garman E, Vas M. A 1.8 Å resolution structure of pig muscle 3-phosphoglycerate kinase with bound MgADP and 3-phosphoglycerate in open conformation: new insight into the role of the nucleotide in domain closure. J Mol Biol. 2001;306:499–511.
Rhodes M, Ashford L, Manes B, Calder C, Domm J, Frangoul H. Bone marrow transplantation in phosphoglycerate kinase (PGK) deficiency. Br J Haematol. 2011;152:500–2.
Noel N, Flanagan J, Kalko SG, Bajo MJR, del Mar Manu M, Fuster JLG, et al. Two new phosphoglycerate kinase mutations associated with chronic haemolytic anaemia and neurological dysfunction in two patients from Spain. Brit J Haematol. 2006;132:523–9.
Ramirez-Bajo MJ, Repiso A, de la Ossa P, Banon-Maneus E, de Atauri P, Climent F, et al. Enzymatic and metabolic characterization of the phosphoglycerate kinase deficiency associated with chronic hemolytic anemia caused by the PGK-Barcelona mutation. Blood Cell Mol Dis. 2011;46:206–11.
Maeda M, Yoshida A. Molecular defect of a phosphoglucerate kinase variant (PGK-Matsue) associated with hemolytic anemia: Leu → Pro substitution caused by T/A → C/G transition in exon 3. Blood. 1991;77:1348–52.
Flanagan JM, Rhodes M, Wilson M, Beutler E. The identification of a recurrent phosphoglycerate kinase mutation associated with chronic haemolytic anaemia and neurological dysfunction in a family from USA. Br J Haematol. 2006;134:233–7.
Fujii H, Chen S, Akatsuka J, Miwa S, Yoshida A. Use of cultured lymphoblastoid cells for the study of abnormal enzymes: molecular abnormality of a phosphoglycerate kinase variant associated with hemolytic anemia. Proc Natl Acad Sci USA. 1981;78:2587–90.
Fujii H, Yoshida A. Molecular abnormality of phosphoglycerate kinase-Uppsala associated with chronic nonspherocytic hemolytic anemia. Proc Natl Acad Sci USA. 1980;77:5461–5.
Yoshida A, Twele TW, Dave V, Beutler E. Molecular abnormality of a phosphoglycerate kinase variant (PGK-Alabama). Blood Cells Mol Dis. 1995;21:179–81.
Hamano T, Mutoh T, Sugie H, Koga H, Kuriyama M. Phosphoglycerate kinase deficiency: an adult myopathic form with a novel mutation. Neurology. 2000;54:1188–90.
Svaasand EK, Aasly J, Landsem VM, Klungland H. Altered expression of PGK1 in a family with phosphoglycerate kinase deficiency. Muscle Nerve. 2007;36:679–84.
Ookawara T, Dave V, Willems P, Martin JJ, de Barsy T, Matthys E, et al. Retarded and aberrant splicings caused by single exon mutation in a phosphoglycerate kinase variant. Arch Biochem Biophys. 1996;327:35–40.
Sugie H, Sugie Y, Nishida M, Ito M, Tsurui S, Suzuki M, et al. Recurrent myoglobinuria in a child with mental retardation: phosphoglycerate kinase deficiency. J Child Neurol. 1989;4:95–9.
Fujii H, Krietsch WKG, Yoshida A. A single amino acid substitution (Asp → Asn) in a phosphoglycerate kinase variant (PGK Munchen) associated with enzyme deficiency. J Biol Chem. 1980;255:6421–3.
Rosa R, George C, Fardeau M, Calvin MC, Rapin M, Rosa J. A new case of phosphoglycerate kinase deficiency: PGK Creteil associated with rhabdomyolysis and lacking hemolytic anemia. Blood. 1982;60:84–91.
Tsujino S, Tonin P, Shanske S, Nohria V, Boustany RM, Lewis D, et al. A splice junction mutation in a new myopathic variant of phosphoglycerate kinase deficiency (PGK North Carolina). Ann Neurol. 1994;35:349–53.
Shirakawa K, Takahashi Y, Miyajima H. Intronic mutation in the PGK1 gene may cause recurrent myoglobinuria by aberrant splicing. Neurology. 2006;66:925–7.
Acknowledgments
The authors thank Prof. Hisaichi Fujii, Department of Cell Processing and Transfusion Medicine, Tokyo Women’s Medical University, for evaluating RBC enzyme activities and Dr. Hideaki Suzuki, Department of anatomy, The Jikei University School of Medicine, for helpful discussion and comment on the manuscript.
Conflict of interest
We declare that we have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Tamai, M., Kawano, T., Saito, R. et al. Phosphoglycerate kinase deficiency due to a novel mutation (c. 1180A>G) manifesting as chronic hemolytic anemia in a Japanese boy. Int J Hematol 100, 393–397 (2014). https://doi.org/10.1007/s12185-014-1615-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-014-1615-x