Glycogen Storage Diseases:

1. Glycogen Storage Diseases:

2. Overview of Glycogen Metabolism • Excess glucose stored as glycogen • Glucose units joined by α-1,4 and α -1,6 glycosidic bonds • Glucosyl chains are branched • Fasted state (catabolic)—glycogen breakdown • Fed state (anabolic)—glycogen synthesis

3. Anabolism – Glycogenesis • Glycogen synthaseextends chains (α-1,4) from non-reducing ends; uses UDP-glucose as substrate • Branching enzyme (transferase function) required to form branched chains; forms α-1,6 glycosidic bonds; moves 7 residues

4. Anabolism – Glycogenesis • Glycogen synthase needs to be activated for glycogenesis to occur • Enzymes involved in breakdown need to be deactivated • Fed state dominated by insulin • Protein phosphatase I activated (also inactivates phosphorylase kinase, not shown below)

5. Catabolism - Glycogenolysis • Glycogen phosphorylase removes glucosyl unit from non-reducing end by phosphorylysis (releases glucose-1-phosphate) • Debranching enzyme (transferase activity) moves 3 glucose units to another branch; hydrolyzes α-1,6 linkage with glucosidase function (same polypeptide chain for eukaryotes)

6. Catabolism - Glycogenolysis

7. GSD Type 0 • An inherited genetic disease • Enzyme affected: glycogen synthase • The body is unable to store glycogen • LIVER: Chromosome 12 -hypoglycemia when fasting -hyperglycemia right after meals • MUSCLE: Chromosome 19 -frequent fatigue and muscle cramps

8. GSD Type 1 • Edgar von Gierke’s Disease • Most common disease type (approximately 1 in 20,000 infants) • Characterized by: • -an abnormally large abdomen due to an accumulation of glycogen in the liver • -prominent hypoglycemia in between meals (may cause convulsions in infants)

9. Deficiency of the Enzyme glucose-6-phosphatase Glucagon Cascade • An inherited defect in chromosome 17 • The body is not able to break down glycogen into glucose

10. Prolonged hypoglycemia can cause

11. GSD Type IIPompe’s disease, acid maltase deficiency • Alpha-1,4-glucosidase (lysosomalglucosidase; acid maltase) • Catalyzes α-1,4- and α-1,6-glucosidic linkages (hydrolysis) • Lysosomes dispose/recycle waste products • acid alpha-glucosidase gene, mapped in chromosome 17 • Autosomal recessive disorder • Diagnosis: Determining activity of acid alpha-glucosidaseenzyme • Muscle weakness and heart problems are the most common features even though defected enzyme is present in all tissues

12. GSD Type III / Cori Disease • Caused by mutation in gene responsible for making the glycogen debranching enzyme • It is inherited and leads to abnormal glycogen in the body • Divided into types IIIa, IIIb, IIIc, IIId • Affects 1 in 100,000 individuals, whereas it affects 1 in 5,400 individuals of North African Jewish

13. GSD Type IV / Anderson Disease • Caused by mutation in gene responsible for making the glycogen branching enzyme • It is inherited and leads to abnormal glycogen in the body • Divided into 5 subtypes, which vary in severity, signs and symptoms • Affects 1 in 600,000 to 800,000 individuals world wide

14. GSD Type V / McArdle disease • Caused by mutation in gene which is responsible for myophosphorylase • It is inherited and leads to inability to break down glycogen in muscle cells • Symptoms include exercise intolerance marked by rapid fatigue and cramps in exercising muscles • Generally rare but affects 1 in 100,000 individuals

15. GSD Type VIHers disease, liver phosphorylase deficiency • Liver glycogen phosphorylase • Early signs and symptoms frequently includes hepatomegaly and hypoglycemia; growth retardation, ketosis, and hyperlipidemia.

16. GSD Type VIITarui disease, muscle phosphofructokinase deficiency • Phosphofructokinase (muscle) • PFKM, chromosome 12 • Exercise intolerance (due to muscle pain, cramping, fatigue, and tenderness), myopathy, and hemolysis; myoglobinuria may develop (dark-red or red-brown urine)