Phosphoglycerate kinase deficiency and phosphoglycerate mutase deficiency
- Basil T Darras, MD
Basil T Darras, MD
- Professor of Neurology
- Harvard Medical School
- William J Craigen, MD, PhD
William J Craigen, MD, PhD
- Professor of Molecular and Human Genetics
- Baylor College of Medicine
Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).
There are a number of inborn errors of glycogen metabolism that result from mutations in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs) (table 1).
Glycogen is most abundant in liver and muscle. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly, and the primary features of those defects that affect muscle are muscle cramps, exercise intolerance, easy fatigability, and progressive weakness.
This topic will review phosphoglycerate kinase (PGK) deficiency and phosphoglycerate mutase (PGAM) deficiency (GSD X). An overview of disorders of glycogen metabolism is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
PHOSPHOGLYCERATE KINASE DEFICIENCY
PGK catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate. One molecule of adenosine triphosphate (ATP) is generated in the process. Deficiency of PGK (MIM #311800) results in three different clinical presentations. (See 'Clinical features' below.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Meera Khan P, Westerveld A, Grzeschik KH, et al. X-linkage of human phosphoglycerate kinase confirmed in man-mouse and man-Chinese hamster somatic cell hybrids. Am J Hum Genet 1971; 23:614.
- Miwa S, Fujii H. Molecular basis of erythroenzymopathies associated with hereditary hemolytic anemia: tabulation of mutant enzymes. Am J Hematol 1996; 51:122.
- Spiegel R, Gomez EA, Akman HO, et al. Myopathic form of phosphoglycerate kinase (PGK) deficiency: a new case and pathogenic considerations. Neuromuscul Disord 2009; 19:207.
- Chiarelli LR, Morera SM, Bianchi P, et al. Molecular insights on pathogenic effects of mutations causing phosphoglycerate kinase deficiency. PLoS One 2012; 7:e32065.
- DiMauro S, Miranda AF, Khan S, et al. Human muscle phosphoglycerate mutase deficiency: newly discovered metabolic myopathy. Science 1981; 212:1277.
- Sugie H, Sugie Y, Nishida M, et al. Recurrent myoglobinuria in a child with mental retardation: phosphoglycerate kinase deficiency. J Child Neurol 1989; 4:95.
- Beutler E. PGK deficiency. Br J Haematol 2007; 136:3.
- 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 2014; 100:393.
- Ramírez-Bajo MJ, Repiso A, la Ossa PP, et al. Enzymatic and metabolic characterization of the phosphoglycerate kinase deficiency associated with chronic hemolytic anemia caused by the PGK-Barcelona mutation. Blood Cells Mol Dis 2011; 46:206.
- Noel N, Flanagan JM, Ramirez Bajo MJ, et al. Two new phosphoglycerate kinase mutations associated with chronic haemolytic anaemia and neurological dysfunction in two patients from Spain. Br J Haematol 2006; 132:523.
- 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.
- Valentine WN, Hsieh HS, Paglia DE, et al. Hereditary hemolytic anemia associated with phosphoglycerate kinase deficiency in erythrocytes and leukocytes. A probable X-chromosome-linked syndrome. N Engl J Med 1969; 280:528.
- DiMauro S, Dalakas M, Miranda AF. Phosphoglycerate kinase deficiency: another cause of recurrent myoglobinuria. Ann Neurol 1983; 13:11.
- Shirakawa K, Takahashi Y, Miyajima H. Intronic mutation in the PGK1 gene may cause recurrent myoglobinuria by aberrant splicing. Neurology 2006; 66:925.
- Rosa R, George C, Fardeau M, et al. A new case of phosphoglycerate kinase deficiency: PGK Creteil associated with rhabdomyolysis and lacking hemolytic anemia. Blood 1982; 60:84.
- Morimoto A, Ueda I, Hirashima Y, 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.
- Sotiriou E, Greene P, Krishna S, et al. Myopathy and parkinsonism in phosphoglycerate kinase deficiency. Muscle Nerve 2010; 41:707.
- DiMauro S, Spiegel R. Progress and problems in muscle glycogenoses. Acta Myol 2011; 30:96.
- Akman HO, Oldfors A, DiMauro S. Glycogen storage diseases of muscle. In: Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician's Approach, Darras BT, Jones HRJ, Ryan MM, et al. (Eds), Academic Press, San Diego 2015. p.735.
- PGK1 full gene sequencing through Emory Genetics Laboratory: http://genetics.emory.edu/egl/tests/?testid=1481 (Accessed on December 13, 2011).
- Morava E, Wortmann SB, van Essen HZ, et al. Biochemical characteristics and increased tetraglucoside excretion in patients with phosphorylase kinase deficiency. J Inherit Metab Dis 2005; 28:703.
- Aasly J, van Diggelen OP, Boer AM, Brønstad G. Phosphoglycerate kinase deficiency in two brothers with McArdle-like clinical symptoms. Eur J Neurol 2000; 7:111.
- Rhodes M, Ashford L, Manes B, et al. Bone marrow transplantation in phosphoglycerate kinase (PGK) deficiency. Br J Haematol 2011; 152:500.
- Edwards YH, Sakoda S, Schon E, Povey S. The gene for human muscle-specific phosphoglycerate mutase, PGAM2, mapped to chromosome 7 by polymerase chain reaction. Genomics 1989; 5:948.
- Tsujino S, Sakoda S, Mizuno R, et al. Structure of the gene encoding the muscle-specific subunit of human phosphoglycerate mutase. J Biol Chem 1989; 264:15334.
- Junien C, Despoisse S, Turleau C, et al. Assignment of phosphoglycerate mutase (PGAMA) to human chromosome 10. Regional mapping of GOT1 and PGAMA to subbands 10q26.1 (or q25.3). Ann Genet 1982; 25:25.
- Naini A, Toscano A, Musumeci O, et al. Muscle phosphoglycerate mutase deficiency revisited. Arch Neurol 2009; 66:394.
- Tsujino S, Shanske S, Sakoda S, et al. The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency. Am J Hum Genet 1993; 52:472.
- Tsujino S, Shanske S, Sakoda S, et al. Molecular genetic studies in muscle phosphoglycerate mutase (PGAM-M) deficiency. Muscle Nerve Suppl 1995; 3:S50.
- Toscano A, Tsujino S, Vita G, et al. Molecular basis of muscle phosphoglycerate mutase (PGAM-M) deficiency in the Italian kindred. Muscle Nerve 1996; 19:1134.
- Tonin P, Bruno C, Cassandrini D, et al. Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M gene. Neuromuscul Disord 2009; 19:776.
- Hadjigeorgiou GM, Kawashima N, Bruno C, et al. Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene. Neuromuscul Disord 1999; 9:399.
- Joshi PR, Knape M, Zierz S, Deschauer M. Phosphoglycerate mutase deficiency: case report of a manifesting heterozygote with a novel E154K mutation and very late onset. Acta Neuropathol 2009; 117:723.
- Salameh J, Goyal N, Choudry R, et al. Phosphoglycerate mutase deficiency with tubular aggregates in a patient from Panama. Muscle Nerve 2013; 47:138.
- Servidei S, DiMauro S. Disorders of glycogen metabolism of muscle. Neurol Clin 1989; 7:159.
- Vissing J, Quistorff B, Haller RG. Effect of fuels on exercise capacity in muscle phosphoglycerate mutase deficiency. Arch Neurol 2005; 62:1440.
- Oh SJ, Park KS, Ryan HF Jr, et al. Exercise-induced cramp, myoglobinuria, and tubular aggregates in phosphoglycerate mutase deficiency. Muscle Nerve 2006; 34:572.
- Vissing J, Schmalbruch H, Haller RG, Clausen T. Muscle phosphoglycerate mutase deficiency with tubular aggregates: effect of dantrolene. Ann Neurol 1999; 46:274.