Glycogen Storage Diseases:

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

Anabolism – Glycogenesis

• Glycogen synthase extends 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

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)

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)

Catabolism - Glycogenolysis

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

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)

Deficiency of the Enzyme glucose-6-phosphatase

• An inherited defect in chromosome 17• The body is not able to break down glycogen into glucose

Glucagon Cascade

Prolonged hypoglycemia can cause

Glucagon production

Accumulation of glucose-6-phosphate

Glycolysis

pyruvate and lactate

Fat Breakdown

Beta-oxidation

Excess acetyl CoA

Ketones

GSD Type IIPompe’s disease, acid maltase deficiency

• Alpha-1,4-glucosidase (lysosomal glucosidase; 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-glucosidase enzyme

• Muscle weakness and heart problems are the most common features even though defected enzyme is present in all tissues

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

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

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

GSD Type VIHers disease, liver phosphorylase deficiency

• Liver glycogen phosphorylase

• Early signs and symptoms frequently includes hepatomegaly and hypoglycemia; growth retardation, ketosis, and hyperlipidemia.

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)