Glycogen storage diseases (GSD) Flashcards
➢ Defective gene: GSY2 gene that codes for hepatic glycogen synthase • GSY1 gene codes for glycogen synthase found in muscle tissue ➢ Enzyme affected: Hepatic glycogen synthase • It’s active during the fed state • It’s inactive during the fasting state and when the body is under stress • It’s active when dephosphorylated • It’s inactive when phosphorylated • Regulators: • Insulin stimulates • Glucose stimulates • cAMP inactivates • Glucagon inactivates • Epinephrine inactivates • Increased Ca2+-calmodulin inactivates ➢ Primary organ involved: Liver ➢ Presentation • Fasting Hypoglycemia • Liver can’t make glycogen during fed state, and in fasting state there is no glycogen reserves to break down for glucose. • Fasting hypoglycemia occurs a few hours after a meal. • Hyperketonemia • Because there are no glycogen stores, in the fasting state the body directly goes to ketogenesis to provide nutrition to the brain, causing increased levels of ketone bodies in the blood. • Major ketone bodies are beta-hydroxybutyrate and acetoacetate • Conversion of acetoacetate to beta-hydroxybutyrate involves oxidation of NADH+H+ to NAD+. • Failure to thrive • Infants or children affected suffer hypoglycemia and seizures before a meal. • In infants, it presents once they have outgrown nighttime feeding. • In children, it presents during periods of GI illness. • Early death ➢ What accumulates: • PAS positive glycogen ➢ Treatment: • Avoid hypoglycemic fasting • Provision for adequate diet
GSD Type O
Gene defect Type Ia: AR mutation at 17q21 Type Ib: AR mutation at 11q23 Enzyme affected: Glucose-6 phosphatase Gluc 6-phosphatase catalyzes this rxn: D-glucopyranose 6-phosphate+ H_2 O ↔D-glucose+phosphate In type Ia there is a deficiency in glucose 6-phosphatase activity In type Ib there is a deficiency in glucose 6-phosphatase translocase activity. Primary organ involved: Liver Presentation Hepatomegaly Enlarged kidney Short stature Due to growth failure Severe fasting hypoglycemia Low levels of glucose in blood Lactic acidosis High levels of lactate in blood Lipemia Increased levels of triglycerides in the blood High levels of pyruvate in blood Thrombocyte dysfunction Children with Type Ia may experience epistaxis (nose bleeds) Infants may have doll like appearance What accumulates Lipids Lactate Glucose 6-phosphate Treatment Young infants require continuous nasogastric tube feedings to sustain their blood sugar levels Older children require switching to raw cornstarch feedings, which will maintain their blood glucose concentrations for 4-6 hours. Maintain good dental and oral health to reduce incidence of infection Any infection that reduces glucose intake requires administration of IV glucose until the infection is over
Von Gierke’s disease (GSD Type P)
➢ Defect: Autosomal recessive disorder that results from deficiency of Lysosomal α-glucosidase ➢ Enzyme affected: Lysosomal α-glucosidase • It’s a lysosomal hydrolase that is required for degradation of 1-3% of cellular glycogen • Degradation of glycogen for energy is not affected, because glycogen phosphorylase does this ➢ Primary organ involved: All organs with lysosomes ➢ Presentation • Infantile form • Presents by age 6 months • Early-onset progressive muscle hypotonia • Due to glycogen accumulation in the anterior horn cells of spinal cord, affecting motor fibers of spinal nerves leading to the progressive muscle hypotonia • Cardiac failure • Clinically significant glycogen accumulation occurs in the heart causing progressive cardiomegaly and ultimately cardiac failure • Rapidly progressive disease with fatal course • Death before age 2 years • Juvenile form • It includes infants and children older than 6 months • Later-onset myopathy • Cardiac involvement may or may not be present • Most patients have respiratory involvement due to accumulation of glycogen in the muscle • Patients usually succumb to respiratory failure by age 20 or 30 • Adult form • Limb-girdle muscular dystrophy-like features • Proximal muscle weakness usually occurs between age 20 years-60 years • No cardiac involvement • Slowly progressive disease • Pts ultimately succumb to respiratory failure • Characteristic found in all three forms • Glycogen deposits accumulate in lysosomes and cytoplasm • Excessive glycogen interrupts normal functioning of other organelles leading to cellular injury, and ultimately to enlargement and dysfunction of the organ involved • Large glycogen containing vacuoles in nearly all muscle fibers ➢ What accumulates • Glycogen accumulates in lysosomes and cytoplasm ➢ Treatment • Enzyme replacement therapy • Symptomatic treatment for cardiac and respiratory failure
Pompe disease (GSD Type II)
➢ Gene defect: AGL gene defect ➢ Enzyme affected: amylo-1,6-glucosidase (debranching enzyme) • It has 2 independently functioning catalytic activities • Transferase: Oligo-1,4-1,4-glucotransferase • It transfers the 3 glucose residues from the short branch to the end of an adjacent branch of the glycogen molecule. • Glucosidase: amylo-alpha 1,6-glucosidase • It removes the glucose moiety remaining at the alpha 1,6 branch point by cleaving the 1,6 linkage. • It releases 1 free glucose moiety from each branch point that it cleaves. ➢ Primary organs involved: Liver, skeletal muscle, and heart • Type IIIa GSD is specific to the liver and muscle specific forms of amylo-1,6-glucosidase • Type IIb GSD is specific to the liver specific form of amylo-1,6-glucosidase • Type IIIc GSD is specific to the muscle specific form of amylo-1,6-glucosidase. ➢ Presentation • Fasting hypoglycemia • Hepatomegaly in infancy in some myopathic features • Glycogen deposits have short outer branches ➢ What accumulates • Glycogen with short outer branches ➢ Treatments • Young infants require nocturnal nasogastric feeding tube • Children aged 2-3 years require raw cornstarch feedings
Forbes-Cori disease (GSD Type III)
➢ Defect: Transglucosidase deficiency ➢ Enzyme affected: Amylo-4,6 glucosidase, branching enzyme • Deficiency results in formation of abnormal glycogen with long, unbranched outer chains and decreased solubility. • Branching enzyme catalyzes formation of 1,6 branches of glycogen that allow for increased solubility. ➢ Primary organ involved: Liver ➢ Presentation • Hepatosplenomegaly • Hepatic portal hypertension • Decreased albumin synthesis • Decreased clearance of drugs, bilirubin, bile acids, and waste nitrogen • Decreased urea level • Symptoms may arise from a hepatic reaction to the presence of a foreign body, glycogen with long outer branches. • It’s usually fatal ➢ What accumulates • Glycogen precipitate • Unbranched glycogen has decreased solubility so it precipitates out of the blood ➢ Treatment • There is no treatment
Andersen disease or amylopectinosis (GSD Type IV)
➢ Defect: Muscle glycogen phosphorylase (myophosphorylase) deficiency • There is an infantile form and an adult form ➢ Enzyme affected: Muscle phosphorylase • It catalyzes glycogen degradation in muscle tissue ➢ Primary organ involved: Skeletal muscle ➢ Presentation • Exercise-induced muscular pain • Cramps • Progressive weakness • Sometimes myoglobinuria • Decreased levels of lactate in the blood ➢ What accumulates • Glycogen accumulates in muscle tissue ➢ Treatment • There is no specific treatment • High protein diet may increase exercise tolerance
McArdles disease ( GSD Type V)
➢ Defect: Liver glycogen phosphorylase deficiency ➢ Enzyme affected: Liver glycogen phosphorylase and its activating system • This includes mutations in hepatic phosphorylase kinase and hepatic PKA ➢ Primary organ involved: Liver ➢ Presentation • Most common presentation is in children aged 1-5 yrs • Children present with: • Hepatomegaly • Mild hypoglycemia • Protruding abdomen • Splenomegaly is always absent • Good prognosis • Adult patients may have mild or no hepatomegaly • Splenomegaly is always absent • Good prognosis ➢ What accumulates • Glycogen accumulates in liver ➢ Treatment • Dietary management through frequent feedings and a high carbohydrate diet
Her’s disease (GSD Type VI)
➢ Defect: Phosphofructokinase (PFK) deficiency
➢ Enzyme affected: PFK
• It’s the key regulatory enzyme for glycolysis
• PFK catalyzes irreversible transfer of phosphate from ATP to fructose-6-phosphate
➢ Primary organs involved: Muscle and red blood cells
➢ Presentation:
• Exercise-induced muscular pain
• Cramps
• Progressive muscle weakness
• Enzymopathic hemolysis
• Due to defective PFK 1 in RBCs
• Hyperuricemia following exercise
• Due to accelerated degradation of muscle purine nucleotides, which serve as the substrates for the synthesis of uric acid
• Hyperuricemia may present as arthritis
• Blindness
• Psychomotor retardation may present in the infantile-onset type
• Cardiac dysfunction, arrhythmia and anginal chest pain may be symptoms of the late-onset type.
➢ What accumulates
• Fructose 6-P
• Glucose 6-P
➢ Treatment
• Treatment is not required, but patients should avoid high carbohydrate meals because they may exacerbate exercise intolerance.
Tarui syndrome (GSD Type VII)
