27 Diseases Associated with Glycogen Degradation

Dr. Chirantan Rawal

epgp books

   

 

 

 

Diseases Associated With Glycogen Degradation

 

Objectives

  1. To understand the concept of glycogen storage diseases (GSD).
  2. To study Glycogen storage diseases associated with the glycogen degradation
  3. To understand the molecular basis of diseases.

 

  Introduction

  • Glycogen storage disease (GSD) relates to a set of metabolic disorder occurs due to the defective glycogenesis or glycogenolysis.
  • Classification of glycogen storage diseases are according to the type of enzymatic deficiency. It is also classified on the basis of kind of primary organs involved. GSDs are usually diagnosed in infants or early childhood.
  • Enzymes associated with GSDs are involved in the regulation of glycogen metabolism. It is observed that there is phenotypic variation is observed when specific enzyme is altered by mutation.
  • Such diseases concern primarily the liver, skeletal muscle, heart and sometimes the central nervous system and the kidneys.
  • These distinctive diseases are relatively diverse in age of onset of symptoms, morbidity and mortality.
  • A person with a GSD has a deficiency of one of the enzymes responsible for synthesis or degradation of glycogen in the body. It results in to abnormal concentration of glycogen in the tissue or imperfectly formed glycogen.
  • In Glycogen storage diseases, human body is not able to make enough glucose, or not able to use glucose as a source of energy. Diagnosis of GSDs depends on an individual’s symptoms.
  • Glycogen storage diseases are genetic disorders. They are caused due to mutation in the genes related to glycogen metabolism.
  • General diagnosis: It is detected in infancy or early childhood. In severe case it is immediately identified while milder types may not be identified or unnoticed for several years. General characteristic symptoms include hypoglycaemia, hepatomegaly (enlarged liver), growth retardation, and irregular blood biochemistry. A more specific diagnosis can be done by analysing concentration of glycogen in a biopsy sample or by assaying the sample for enzyme activity. Genetic diagnostic techniques are also available.
  • In this chapter, we will learn GSDs associated with Glycogen Degradation.

 

Overview of Glycogen degradation

  • Glycogen phosphorylase catalyzes phosphorolytic cleavage. It occurs at the non reducing terminal of glycogen chains.
  • Debranching enzyme separates the branch and transfers it to the main chain. It also releases the residue at α 1-6 branch as free glucose.
  • Phosphoglucomutase converts glucose 1-phosphate into glucose 6-phosphate. Glucose -6-phosphate can enter in to glycolysis. In endoplasmic reticulum of liver, Glucose 6 phosphate can be changed in to free glucose by glucose 6-phosphatase. Free glucose is release in to blood.

Fig: 28.2 OVERVIEW OF GLYCOGENOLYSIS

 

Diseases Associated with Glycogen Degradation

  • Glycogen Storage Disease Type I (von Gierke’s Disease, Hepatorenal Glycogenosis)
  • Glycogen Storage Disease Type II (Pompe Disease)
  • Glycogen Storage Disease Type III (Cori Disease, Forbes Disease, Limit Dextrinosis,Debranching Enzyme Disease)
  • Glycogen Storage Disease V (McArdle Disease)
  • Glycogen Storage Disease Type VI (Hers disease)
  • Glycogen Storage Disease Type X

     

 

Glycogen Storage Disease Type I (von Gierke’s Disease, Hepatorenal Glycogenosis)

  • It is also known as von Gierke’s disease; Hepatorenal Glycogenosis; Type I Glycogenosis; Glucose-6-Phosphatase Deficiency Glycogen Storage Disease.
  • General symptoms: enlarged liver (hepatomegaly) and hypoglycemia (low blood glucose)
  • Subtypes: It is observed as an autosomal recessive disease. It is of three subtypes.

 

 

Glycogen Storage Disease Type II (Pompe Disease)

  • It is also known as Pompe diseases; Type 2 Glycogenosis.
  • It occurs due to deficiency in lysosomal-1, 4-glucosidase. It is also known as acid maltase. Lysosome carryout digestion of cellular components along with the digestion of glycogen,

   

Glycogen Storage Disease Type II (Pompe Disease)

  • It is also known as Pompe diseases; Type 2 Glycogenosis.
  • It occurs due to deficiency in lysosomal-1, 4-glucosidase. It is also known as acid maltase. Lysosome carryout digestion of cellular components along with the digestion of glycogen,

 

Glycogen Storage Disease Type III (Cori Disease)

  • It is also known as Debrancher Deficiency; Cori Disease; Forbes Disease; Limit Dextrinosis
  • It occurs due to deficiency of glycogen debranching enzyme (GDE) activity
  • Glycogen debranching enzyme helps in the removal of branches in the chain of glycogen. Deficiency of Glycogen debranching enzyme results in to the partial breakdown of the glycogen. It produces glycogen with short outer chains. Such partially digested glycogen accumulated in organ tissues. It causes damage to tissues of liver and muscles.
  • General symptoms: enlarged liver (hepatomegaly) and hypoglycemia (low blood glucose), hypotonia, small stature
  • It is observed as an autosomal recessive disease. Debranching enzyme is synthesized by the gene amylo-1,6-glucosidase, 4-alpha-glucoanotransferase gene (AGL) gene.

 

  • Subtypes: It is of two subtypes.
    •  Glycogen Storage Disease type IIIa and
  • Glycogen Storage Disease type IIIb

 

Glycogen Storage Disease V (McArdle Disease)

  • It is also known as McArdle diseases; Type 5 Glycogenosis; Myophosphorylase deficiency,
  • It occurs due to deficiency in muscle glycogen phosphorylase.
  • It is also known as myopathic glycogen storage disease since it affects mainly muscle tissue . Glycogen phosphorylase is also found in the hepatic tissue.
  • Glycogen is broken-down in to Glucose-1-Phosphate (G1P) by Glycogen Phosphorylase. It is carried out by phosphorolysis reaction. Glycogen phosphorylase will act repeatedly on non-reducing ends of a glycogen chain. Glycogen phosphorylase can act continuously until it reaches 4 glucose away from α 1-6 branch point.
  • General symptom: muscle pain, muscle cramps, tenderness in masticatory muscles and exercise intolerance
  • Forms of disease:

    Rapidly fatal neonatal form

Mild form with congenital myopathy

Benign classic form with myalgia and dark colored urine.

 

 

 

 

Glycogen Storage Disease Type VI (Hers disease)

  • It is also known as Hers disease; Type 6 Glycogenosis.
  • It occurs due to deficiency in liver glycogen phosphorylase.
  • Glycogen is broken-down in to Glucose-1-Phosphate (G1P) by Glycogen Phosphorylase. It is carried out by phosphorolysis reaction.
  • General symptom: enlarged liver (hepatomegaly) and hypoglycemia (low blood glucose)

 

 

Glycogen Storage Disease Type X

  • It is observed due to deficiency of cyclic 3’,5’ AMP-dependent kinase (PKA)
  • It is an autosomal recessive disorder.
  • This disease directly does not relate to the glycogen degradation. Infect It affects the regulation of glycogenolysis.
  • Gene of the cyclic 3’,5’ AMP-dependent kinase is located on chromosome 17q23-24.
  • During regulation of glycogenolysis, Cyclic AMP acts as a second messenger. The cAMP binds to cAMP-dependent protein kinase (PKA). The active protein kinase A phosphorylates phosphorylase kinase. Phosphorylated phosphorylase kinase is active form of phosphorylase kinase. It phosphorylates serine residue in phosphorylase b, which converts it into phosphorylase a, that is a more active form. Glycogen is broken-down in to Glucose-1-Phosphate (G1P) by Glycogen Phosphorylase.
  • Symptom: asymptomatic hepatomegaly
  • Glucagon or adrenalin does not stimulate the glycogenolysis.
  • Diagnosis: Microscopic studies of liver biopsy, enzyme analysis and DNA based genetic testing.
you can view video on Diseases Associated with Glycogen Degradation

 

 

References

  • John Hicks, Eric Wartchow, James Barrish , Shen-Hua, Zhu Gary Mierau. Glycogen Storage Diseases: A Brief Review and Update on Clinical Features, Genetic Abnormalities, Pathologic Features and Treatment. ULTRASTRUCTURAL PATHOLOGY. (2011) DOI: 10.3109/01913123.2011.601404.
  • Bayraktar Y. Glycogen storage diseases: new perspectives. World J Gastroenterol 207;13(18):2541-53
  • Wolfsdorf JI, Weinstein DA. Glycogen storage diseases. Reviews Endocrinol Metab Disorders 2003;4:95-102.

Web site

  • http://www.medchrome.com/basic-science/biochemistry/glycogen-metabolism-and-glycogenstorage
  • https://www.uic.edu/classes/phar/phar332/Clinical_Cases/carbometabcases/glycogenmeta/
  • http://themedicalbiochemistrypage.org/glycogen.php
  • https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Gluconeogenesis_and_Glycogenesi s

Books

  • Nyhan, William L., Pinar, T. Ozand, Atlas of Metabolic Diseases, Chapman & Hall Medical, 1998.
  • Harper’sIllustrated Biochemistry by Robert K.. Murray, Daryl K. Granner, Peter A. Mayes, 26th Edition (2003)
  • Lehninger’S Principle of Biochemistry David L. Nelson and Michael M. Cox,5th Edition (2008)
  • Textbook of Biochemistry, 4th Edition Donald Voet, Judith G. Voet (2011)
  • Fernandes J, Smit GPA (2000) The glycogen storage diseases. In: Fernandes J, Saudubray J-M, Berghe G van den (eds) Inborn errors of metabolism, 3rd edn. Springer,Berlin Heidelberg New York, pp 86–101