Glycogen Storage Diseases:
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Glycogen Storage Diseases:
1Overview of Glycogen MetabolismExcess glucose stored as glycogenGlucose units joined by -1,4 and -1,6 glycosidic bondsGlucosyl chains are branchedFasted state (catabolic)glycogen breakdownFed state (anabolic)glycogen synthesis
Glycogen synthase extends chains (-1,4) from non-reducing ends; uses UDP-glucose as substrateBranching enzyme (transferase function) required to form branched chains; forms -1,6 glycosidic bonds; moves 7 residues Anabolism Glycogenesis Glycogen synthase needs to be activated for glycogenesis to occurEnzymes involved in breakdown need to be deactivatedFed state dominated by insulinProtein 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 -1,6 linkage with glucosidase function (same polypeptide chain for eukaryotes)Catabolism - Glycogenolysis
GSD Type 0An inherited genetic diseaseEnzyme affected: glycogen synthaseThe body is unable to store glycogenLIVER: Chromosome 12-hypoglycemia when fasting-hyperglycemia right after mealsMUSCLE: Chromosome 19-frequent fatigue and muscle crampsThis 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 dont 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 cant store glycogen, the person suffers from frequent fatigue and cramping due to an accumulation of lactic acid in the muscle cells.
7GSD Type 1Edgar von Gierkes DiseaseMost 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 Gierkes 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 diseasethe first being lnke8
Deficiency of the Enzyme glucose-6-phosphatase
An inherited defect in chromosome 17The body is not able to break down glycogen into glucose
Glucagon CascadePatients 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 cascadewhich 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.9Prolonged hypoglycemia can cause
The bodys 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 pathwaywe get an accumulation of the sugar glucose-6-phosphate. This stays in the liver and enters glycolysiseventually increasing lactate and pyruvate levels in the blood.10GSD Type IIPompes disease, acid maltase deficiencyAlpha-1,4-glucosidase (lysosomal glucosidase; acid maltase)Catalyzes -1,4- and -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 enzymeIt is inherited and leads to abnormal glycogen in the bodyDivided 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 weaknessAlpha 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 AGLgene 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
12GSD 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 symptomsAffects 1 in 600,000 to 800,000 individuals world wide
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 deathCongenital neuromuscular subtype.Develops in infancy, severe hypotonia which leads to respiratory failure, dilated cardiomyopathy, early infantile deathClassic (progressive) hepatic subtype.Failure to thrive, enlarged liver, liver dysfunction, progressive liver cirrhosis with portal hypertension, death often from liver failureNon-progressive hepatic subtype.Similar to progressive type but no cirrhosis, can survive to adulthood with possible hypotonia and myopathy and life expectancy variesChildhood neuromuscular subtype.myopathy, with dilated cardiomyopathy
13GSD Type V / McArdle diseaseCaused by mutation in gene which is responsible for myophosphorylaseIt is inherited and leads to inability to break down glycogen in muscle cellsSymptoms include exercise intolerance marked by rapid fatigue and cramps in exercising musclesGenerally 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 cellglycogen 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 enzymeglucose-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.
Genetics Home Reference. (2013) Glycogen Storage Disease type III. Retrieved from http://ghr.nlm.nih.gov/condition/glycogen-storage-disease-typ e-iiiGenetics Home Reference. (2013) Glycogen Storage Disease type IV . Retrieved from http://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-ivGenetics 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.
14GSD Type VIHers disease, liver phosphorylase deficiencyLiver glycogen phosphorylase
Early signs and symptoms frequently includes hepatomegaly and hypoglycemia; growth retardation, ketosis, and hyperlipidemia.
GSD Type VIITarui disease, muscle phosphofructokinase deficiencyPhosphofructokinase (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)