Phosphorylase b kinase 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). They have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.
Glycogen is most abundant in liver and muscle, which are most affected by these disorders. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease.
●The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus".)
●Glycogen serves as the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance and easy fatigability, and progressive weakness.
- DiMauro S, Tsujino S. Nonlysosomal glycogenoses. In: Myology, Engel A, Banker B (Eds), McGraw-Hill, New York 1994. p.1554.
- Jones TA, da Cruz e Silva EF, Spurr NK, et al. Localisation of the gene encoding the catalytic gamma subunit of phosphorylase kinase to human chromosome bands 7p12-q21. Biochim Biophys Acta 1990; 1048:24.
- Achouitar S, Goldstein JL, Mohamed M, et al. Common mutation in the PHKA2 gene with variable phenotype in patients with liver phosphorylase b kinase deficiency. Mol Genet Metab 2011; 104:691.
- Burwinkel B, Shin YS, Bakker HD, et al. Mutation hotspots in the PHKA2 gene in X-linked liver glycogenosis due to phosphorylase kinase deficiency with atypical activity in blood cells (XLG2). Hum Mol Genet 1996; 5:653.
- Burwinkel B, Maichele AJ, Aagenaes O, et al. Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB). Hum Mol Genet 1997; 6:1109.
- Francke U, Darras BT, Zander NF, Kilimann MW. Assignment of human genes for phosphorylase kinase subunits alpha (PHKA) to Xq12-q13 and beta (PHKB) to 16q12-q13. Am J Hum Genet 1989; 45:276.
- Maichele AJ, Burwinkel B, Maire I, et al. Mutations in the testis/liver isoform of the phosphorylase kinase gamma subunit (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans. Nat Genet 1996; 14:337.
- Burwinkel B, Rootwelt T, Kvittingen EA, et al. Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatr Res 2003; 54:834.
- Wehner M, Clemens PR, Engel AG, Kilimann MW. Human muscle glycogenosis due to phosphorylase kinase deficiency associated with a nonsense mutation in the muscle isoform of the alpha subunit. Hum Mol Genet 1994; 3:1983.
- Bak H, Cordato D, Carey WF, Milder D. Adult-onset exercise intolerance due to phosphorylase b kinase deficiency. J Clin Neurosci 2001; 8:286.
- Echaniz-Laguna A, Akman HO, Mohr M, et al. Muscle phosphorylase b kinase deficiency revisited. Neuromuscul Disord 2010; 20:125.
- Nyegaard M, Overgaard MT, Søndergaard MT, et al. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. Am J Hum Genet 2012; 91:703.
- Crotti L, Johnson CN, Graf E, et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation 2013; 127:1009.
- Willems PJ, Gerver WJ, Berger R, Fernandes J. The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. Eur J Pediatr 1990; 149:268.
- Schippers HM, Smit GP, Rake JP, Visser G. Characteristic growth pattern in male X-linked phosphorylase-b kinase deficiency (GSD IX). J Inherit Metab Dis 2003; 26:43.
- 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.
- Wuyts W, Reyniers E, Ceuterick C, et al. Myopathy and phosphorylase kinase deficiency caused by a mutation in the PHKA1 gene. Am J Med Genet A 2005; 133A:82.
- Abarbanel JM, Bashan N, Potashnik R, et al. Adult muscle phosphorylase "b" kinase deficiency. Neurology 1986; 36:560.
- Van den Berg IE, Berger R. Phosphorylase b kinase deficiency in man: a review. J Inherit Metab Dis 1990; 13:442.
- Clemens PR, Yamamoto M, Engel AG. Adult phosphorylase b kinase deficiency. Ann Neurol 1990; 28:529.
- Servidei S, Metlay LA, Chodosh J, DiMauro S. Fatal infantile cardiopathy caused by phosphorylase b kinase deficiency. J Pediatr 1988; 113:82.
- Regalado JJ, Rodriguez MM, Ferrer PL. Infantile hypertrophic cardiomyopathy of glycogenosis type IX: isolated cardiac phosphorylase kinase deficiency. Pediatr Cardiol 1999; 20:304.
- Burwinkel B, Scott JW, Bührer C, et al. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am J Hum Genet 2005; 76:1034.
- Akman HO, Sampayo JN, Ross FA, et al. Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the gamma2-subunit of AMP-activated protein kinase. Pediatr Res 2007; 62:499.
- Laforêt P, Richard P, Said MA, et al. A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy with conduction system disease and muscular glycogenosis. Neuromuscul Disord 2006; 16:178.
- Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005; 352:362.
- Bali DS, Goldstein JL, Fredrickson K, et al. Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene. Mol Genet Metab 2014; 111:309.
- Burwinkel B, Shiomi S, Al Zaben A, Kilimann MW. Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. Hum Mol Genet 1998; 7:149.
- Bührer C, van Landeghem F, Brück W, et al. Fetal-onset severe skeletal muscle glycogenosis associated with phosphorylase-b kinase deficiency. Neuropediatrics 2000; 31:104.
- Beauchamp NJ, Dalton A, Ramaswami U, et al. Glycogen storage disease type IX: High variability in clinical phenotype. Mol Genet Metab 2007; 92:88.
- Ørngreen MC, Schelhaas HJ, Jeppesen TD, et al. Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology 2008; 70:1876.
- Preisler N, Orngreen MC, Echaniz-Laguna A, et al. Muscle phosphorylase kinase deficiency: a neutral metabolic variant or a disease? Neurology 2012; 78:265.