Glycogen Storage Diseases:

Objectives Structure of Glycogen. Anabolism Vs Catabolism mechanisms. Glycogen storage disorders.

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, as 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 This is an inherited autosomal recessive disease that involves the enzyme glycogen synthase. As mentioned before, this particular enzyme catalyzes the elongation of chains of glucose molecules to form glycogen. Without it, the body cannot store glycogen and this accounts for sever hypoglycemia in during the fasting state. Other than that, people with this disease usually don’t have pronounced physical abnormalities. The enzyme deficiency can either occur in the liver or in the muscle tissues. If the mutation deals with chromosome 12, the person lacks it in the liver. They will exhibit low blood sugar levels when fasting. Right after a meal, however, the person can suffer from hyperglycemia since he or she is not able to store any excess sugar. If the gene mutation deals with chromosome 19, the person will lack the enzyme in muscle tissue instead. Since the muscles can’t store glycogen, the person suffers from frequent fatigue and cramping due to an accumulation of lactic acid in the muscle cells.

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) Also known as von Gierke’s Disease, it is an inherited autosomal recessive disease and is the most common type, occuring in approximately 1 in 20,000 infants. Some symptoms include an abnormally large abdomen due to excessive glycogen in the liver and extreme hypoglycemia in between meals. Due to low blood sugar levels, this may cause convlusions in infants. There are actually two things that cause this disease…the first being lnke

Deficiency of the Enzyme glucose-6-phosphatase Glucagon Cascade Patients with disease have been found to lack a particular enzyme: glucose-6-phosphatase. This is the enzyme responsible for performing the last step in the glucagon cascade…which is the conversion of glucose-6-phosphate to glucose. Patients with this condition do not respond to glucagon administrations since this very crucial step is blocked. An inherited defect in chromosome 17 The body is not able to break down glycogen into glucose

Prolonged hypoglycemia can cause Glucagon production Accumulation of glucose-6-phosphate  Glycolysis pyruvate and lactate Fat Breakdown Beta-oxidation Excess acetyl CoA  Ketones The body’s natural response to low blood sugar levels is to produce more of the hormone glucagon. But since we are unable to proceed further down this pathway…we get an accumulation of the sugar glucose-6-phosphate. This stays in the liver and enters glycolysis…eventually increasing lactate and pyruvate levels in the blood.

GSD Type II Pompe’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 Symptoms: enlarged liver, delayed growth in childhood, low blood sugar, elevated fat in blood, possible muscle weakness Alpha 1,6 glucosidase Types a and c affect the liver and muscles while types b and d affect only the liver Types a (85%) and b (15%) are the most common AGL gene mutations lead to the production of a nonfunctional glycogen debranching enzyme. These mutations typically cause GSD types IIIa and IIIb. The mutations that cause GSD types IIIc and IIId are thought to lead to the production of an enzyme with reduced function. A buildup of abnormal glycogen damages organs and tissues throughout the body, particularly muscles and liver

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 amylo-(1,4→1,6)-transglycosylase These molecules tend to precipitate in liver, muscles and heart, leading to enlarged liver, progressive cirrhosis of the liver and muscle and heart failure. Fatal perinatal neuromuscular subtype. Most severe, signs before birth. Decreased fetal movements, severe hypotonia, muscle atrophy at birth, early neonatal death Congenital neuromuscular subtype. Develops in infancy, severe hypotonia which leads to respiratory failure, dilated cardiomyopathy, early infantile death Classic (progressive) hepatic subtype. Failure to thrive, enlarged liver, liver dysfunction, progressive liver cirrhosis with portal hypertension, death often from liver failure Non-progressive hepatic subtype. Similar to progressive type but no cirrhosis, can survive to adulthood with possible hypotonia and myopathy and life expectancy varies Childhood neuromuscular subtype. myopathy, with dilated cardiomyopathy

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 Burgundy colored urine after exercise because of break down of muscle fibers which release myoglobin into blood stream. Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells. Other cells that contain small amounts use it locally as well. Muscle cells lack the enzyme glucose-6-phosphatase, which is required to pass glucose into the blood, so the glycogen they store is designed for internal use and is not shared with other cells.  References: Genetics Home Reference. (2013) Glycogen Storage Disease type III. Retrieved from http://ghr.nlm.nih.gov/condition/glycogen-storage-disease-typ e-iii Genetics Home Reference. (2013) Glycogen Storage Disease type IV . Retrieved from http://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-iv Genetics Home Reference. (2013) Glycogen Storage Disease type V. Retrieved from http://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-v Dagli, A., Sentner, C., Weinstein, D. (2010) Glycogen Storage Disease type III. USA: University of Washington. Magoulas, P., El-Hattab, A. (2013) Glycogen Storage Disease Type IV. USA: University of Washington. Arenas, J., Martin, M., Andreu, A. (2006) Glycogen Storage Disease Type V. USA: University of Washington.

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

GSD Type VII Tarui 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)