Glycogen Storage Disease

Glycogen Storage Disease Type O

-Deficiency in glycogen synthase -Characterized by moderately decreased glycogen stores in the liver

Tarui Syndrome (type 7)

-Genetic defect in phosphofructokinase -Interferes breakdown of glucose for energy production -Primary organ involved is skeletal muscle -partial deficiency of PFK in RBC leads to breakdown of RBC and release of bilirubin in blood (usually no symptoms)

Fanconi-Bickel Syndrome (type 11)

-Mutation of GLUT2 (glucose/galactose transporter) -Congenital defect of facilitative glucose transport -Primary organs involved: intestine, pancreas, kidney, liver

Andersen Disease (type 4)

-absence of the branching enzyme results in cellulose-like, long-chain glycogen which cannot be broken down easily because of the scarcity of the non-reducing ends and the formation of cross links -Liver is primary organ involved -patient has difficulty metabolizing glycogen -develops hypoglycemia - cellulose-like glycogen particles inhibit liver functions and cause liver failure and cell necrosis

adenylate cyclase

-activated by epinephrine and glucagon -converts ATP to cAMP, which activates PKA

Hers Disease (type 6)

-caused by a mutation in the liver glycogen phosphorylase or phosphorylase kinase (enzymes of liver glycogen degradation) -normal blood glucose levels maintained by gluconeogenesis with lactate, alanine, and glycerol as the starting materials -Ketosis is moderate and hyperlactatemia does not occur because of the use of lactate by the liver for glucose production

McArdle Disease (type 5)

-caused by a mutation in the muscle glycogen phosphorylase and leads to an excess of muscle glycogen deposition resulting from a lack of breakdown -Primary organ involved is skeletal muscle -Expressed as adult or infantile form

glycogen phosphorylase

-cleaves glucose from glycogen to generate G1P (accounts for 90% of glycogen breakdown) -requires PLP as a cofactor

Cori's Disease (type 3)

-defect or absence of α-1,6-glucosidase (debranching enzyme) -glycogen can undergo phosphorolysis, but cannot be debranched -glycogen chains can be degraded only to within four residues of the branch point -40-50% of the glucose is not accessible -Organs involved are liver, skeletal muscle -In case of increased energy demand, during exercise or starvation, glycogen cannot supply energy fast enough, and severe hypoglycemia may occur -Glycogen deposits have shorter outer branches

Pompe Disease (type 2)

-genetic defect in lysosomal α-1,4-glucosidase (organs with lysosomes affected) -oligosaccharides that are a byproduct of glycogen breakdown accumulate in the lysosome -the integrity of the lysosomal membrane is damaged and the lysosomal hydrolytic enzymes will leak out and cause severe liver necrosis -Accumulation of glycogen in large, membrane-enclosed residual bodies disrupting function of liver and muscle cells

GSK3

-inactive when phosphorylated through insulin signaling -its phosphorylation is impaired in type 2 diabetes and is hyper active to antagonize insulin signaling and cause insulin resistance

Von Gierke's Disease (type 1)

-most common glycogen storage disorder -liver is organ involved -mutation in G6Pase gene -> G6Pase activity absent or low -> G1P levels increased triggering inhibition of glycogen phosphorylase -Net result is increased glycogen accumulation

phosphorylase kinase

-phosphorylated by PKA -phosphorylates glycogen phosphorylase b converting it to its active form, a

PKA

-phosphorylates glycogen synthase (causing inactivation) when stimulated by glucagon and epinephrine -phosphorylates phosphorylase kinase

α-1,6-glycosidase/ debranching enzyme

acts at the branch point by hydrolyzing a α-1,6-glycosidic bond to generate free glucose (accounts for 10% of breakdown of glycogen)

AMP and Pi

allosteric activators of glycogen phosphorylase

branching of glycogen

allows more glucose to be stored, and also allows for faster glycogen breakdown

glycogen synthase

enzyme is inactive when phosphorylated

UDP glucose

initiates glycogen synthesis by adding a UDP-glucose to a glycogen primer

Glycogen

polysaccharide made up of repeating α-D-glucose subunits joined by an α-1,4-O-glycosidic linkage

glucose

released into circulation when blood sugar levels drop and glycogen stores in the liver are broken down

protein phosphatases

reverse the effects of PKA

glycogenolysis

stimulated by glucagon in the liver to restore blood glucose levels and by epinephrine in the muscle to provide energy for muscle contraction

McArdle Disease (type 5) manifestations

• Exercise-induced muscle pain, cramps and progressive weakness, fatigue • May be accompanied by myoglobinuria (acute muscle breakdown resulting in rust-colored urine) and release of muscle creatine kinase in blood • Could be relieved after 30 min by epinephrine-mediated release of glucose and fatty acids

Cori's Disease (type 3) manifestations

• Fasting hypoglycemia • Hepatomegaly (enlarged liver) in infancy

Fanconi-Bickel Syndrome (type 11) manifestations

• Glycogen accumulation in liver(resulting in hepatomegaly) and kidney • Rickets, growth retardation • Glucosuria • Glucose/galactose intolerance • Fasting hypoglycemia • nephropathy

Andersen Disease (type 4) manifestations

• Hepatosplenomegaly; symptoms may be due to hepatic reaction to presence of glycogen with longer outer branches • Usually fatal

Glycogen Storage Disease Type O manifestations

• Hypoglycemia • Hyperketonemia • Early death • Feeding relieves symptoms but may lead to postprandial hyperglycemia and hyperlacticacidemia

Pompe Disease (type 2) manifestations

• Infantile form: early-onset progressive muscle hypotonia • Cardiac failure, death prior to 2yrs of age

Hers Disease (type 6) manifestations

• Mild hypoglycemia (since glucose can still be synthesized from gluconeogenesis) • Hepatomegaly • Good prognosis Can be fatal

Tarui Syndrome (type 7) manifestations

• Similar to Type V phosphorylase deficiency • Exercise intolerance with pain, muscle cramps • Occasional myoglobinuria

Von Gierke's Disease (type 1) manifestations

• hypoglycemia after short fasting or exercise (can be treated with raw starch or glucose. • hypercholesterolemia, hypertriglyceridemia and increased serum lipoproteins (VLDL). • enlarged liver and kidney • Growth failure, acidosis, thrombocyte dysfunction