Glycogen storage diseases Notes

NOTES NOTES GLYCOGEN STORAGE DISEASES (GSD) GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Metabolism disorders → pathological intracellular accumulation of glycogen/ metabolic products ▪ AKA dextrinoses/glycogenoses ▪ Impaired glycogen metabolism → cells without energy between meals → cell dysfunction, death ▪ Tissues most dependent on carbohydrates most affected ▫ Liver, heart muscle, brain, skeletal muscle CAUSES ▪ Enzyme deficiency in glycogen synthesis/ breakdown ▪ Genetic, environmental factors COMPLICATIONS ▪ Rhabdomyolysis; cardiomyopathy; atrioventricular block (AV) block; renal failure (myoglobin from dead muscle cells impairs renal function); lactic acidosis due to energy being generated from triglycerides, protein; hyperuricemia, gout (lactic, uric acid excreted via same renal transport mechanism) DIAGNOSIS LAB RESULTS ▪ Cell count, hormones, metabolites Muscle/liver biopsy ▪ With periodic acid-Schiff stain ▪ Detects glycogen OTHER DIAGNOSTICS ▪ Genetic testing Fasting test for clinical orientation ▪ Hypoglycemia TREATMENT OTHER INTERVENTIONS ▪ Corrective diet ▪ Symptomatic therapy (cell growth factors) ▪ Enzyme replacement therapy for symptom relief SIGNS & SYMPTOMS ▪ Symptomatic at birth/early adulthood ▪ Hypoglycemia, hyperlipidemia (compensatory mechanism for hypoglycemia), fatigue, hypotonia (floppy baby), hepato/splenomegaly, hypoglycemia → seizures, metabolic acidosis → hyperventilation, vomiting OSMOSIS.ORG 267

GLYCOGEN STORAGE DISEASE TYPE I (GSD I) osms.it/GSD-I PATHOLOGY & CAUSES ▪ AKA von Gierke disease ▪ Pathological intracellular accumulation of glucose-6-phosphate (G6P) due to impaired glycogenolysis, gluconeogenesis ▪ Final product of both mechanisms: G6P ▪ Most common glycogen storage disease TYPES GSD Ia ▪ Mutation of G6PC gene GSD Ib ▪ Mutation of G6PT1 gene GSD Ic ▪ Mutation of SLC17A3 gene CAUSES ▪ G6P deficiency → G6P trapped inside cell (too polar to pass through cell membrane) → severe hypoglycemia ▪ Autosomal recessive mutations COMPLICATIONS ▪ Hepatomegaly; kidney enlargement; atherosclerosis due to hyperlipidemia; growth, development disorders; gout, kidney damage due to hyperuricemia SIGNS & SYMPTOMS Fasting hypoglycemia ▪ Blood glucose level regulation impaired (esp. between meals) → low insulin → high cortisol, glucagon Metabolic acidosis ▪ Lactate cannot convert into pyruvate due to 268 OSMOSIS.ORG accumulation of G6P (lactate + pyruvate → G6P via gluconeogenesis) → compensatory hyperventilation, vomiting Hypertriglyceridemia ▪ Compensate for chronically low insulin Hyperuricemia ▪ Excess G6P in pentose phosphate pathway → high blood concentrations of uric acid → competes with other organic acids (e.g. lactic acid) for excretion in kidneys DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Enlarged liver, kidneys LAB RESULTS Liver biopsy with periodic acid-Schiff stain ▪ Glycogen detection OTHER DIAGNOSTICS ▪ Genetic testing Fasting test ▪ Hypoglycemia, doesn’t respond to glucagon injection TREATMENT OTHER INTERVENTIONS ▪ Diet consisting of frequent meals high in carbohydrates ▪ Regulation of metabolic complications

Chapter 45 Glycogen Storage Diseases GLYCOGEN STORAGE DISEASE TYPE II (GSD II) osms.it/GSD-II PATHOLOGY & CAUSES DIAGNOSIS ▪ AKA Pompe disease ▪ Pathological accumulation of glycogen in lysosome ▪ Mainly affects skeletal muscles, heart; also liver, nervous system DIAGNOSTIC IMAGING TYPES ▪ ↑ creatine kinase, lactic dehydrogenase, alanine transaminase, aspartate transaminase Early/infantile onset ▪ Few months after birth, typically 4–8; progression much faster Late onset ▪ > two years; as late as 50–60 CAUSES ▪ Autosomal recessive disease caused by mutation on chromosome 17 ▪ Acid alpha-glucosidase deficiency → glycogen cannot break down, accumulates in lysosome → lysosome bursts → glycogen, lysosomal enzymes leak into cytoplasm → cell dysfunction, death X-ray ▪ Cardiomegaly LAB RESULTS Muscle biopsy ▪ Glycogen detection OTHER DIAGNOSTICS ECG ▪ Arrhythmia, cardiomyopathy TREATMENT OTHER INTERVENTIONS ▪ Enzyme replacement therapy COMPLICATIONS ▪ Rhabdomyolysis, completely impaired motor function, respiratory/heart failure, development disorders SIGNS & SYMPTOMS ▪ Progressive muscle weakness, respiratory insufficiency due to weakened diaphragm function, arrhythmia, cardiomegaly, cardiomyopathy, hepatomegaly, hypotonia, recurrent chest infections OSMOSIS.ORG 269

GLYCOGEN STORAGE DISEASE TYPE III (GSD III) osms.it/GSD-III PATHOLOGY & CAUSES ▪ AKA Cori’s disease, Forbes disease, limit dextrinosis ▪ Intracellular pathological accumulation of incompletely broken down glycogen → buildup of dextrins (intermediate products of glycogen breakdown) → osmotic pressure of cell increases → pulls water in, damages cell ▪ Affects liver, skeletal muscles, heart TYPES GSD IIIa ▪ Liver, muscles GSD IIIb ▪ Liver GSD IIIc ▪ Liver, muscles CAUSES ▪ Autosomal recessive disease ▪ Deficiency of glycogen debranching enzyme (GDE): amylo-alpha-1,6glucosidase, 4-alpha-glucanotransferase COMPLICATIONS ▪ Hepatosplenomegaly, cardiomegaly, developmental disorders, liver failure SIGNS & SYMPTOMS ▪ Hypoglycemia, hypotonia, arrhythmia, cardiomyopathy, rhabdomyolysis, musclerelated symptoms (later in life), may resemble GSD I 270 OSMOSIS.ORG DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Hepatosplenomegaly LAB RESULTS Liver/muscle biopsy with periodic acid-Schiff stain ▪ Glycogen detection OTHER DIAGNOSTICS ▪ Genetic analysis TREATMENT OTHER INTERVENTIONS ▪ High glucose, protein diet

Chapter 45 Glycogen Storage Diseases GLYCOGEN STORAGE DISEASE TYPE IV (GSD IV) osms.it/GSD-IV PATHOLOGY & CAUSES ▪ AKA Andersen’s disease ▪ Intracellular accumulation of abnormally formed glycogen ▪ Improper glycogen synthesis → buildup of polyglucosan bodies (unbranched long chains of glucose) → precipitation of polyglucosan bodies → foreign body reactions, increased osmotic pressure → cell damage CAUSES ▪ Autosomal recessive mutation of GBE1 gene on chromosome 3 ▪ Deficiency of 1,4-alpha-glucan branching enzyme (GBE) SIGNS & SYMPTOMS ▪ Fatal perinatal neuromuscular ▫ Fetal hydrops, hydramnion; hypotonia; reduced infant mobility; cardiomyopathy present at birth; death approx. one month after birth ▪ Childhood neuromuscular ▫ Variable intensity, life expectancy; manifests in childhood; myopathy, cardiomegaly ▪ Progressive hepatic ▫ Failure to thrive (FTT); liver cirrhosis; portal hypertension; ascites; death few months after birth ▪ Non-progressive hepatic ▫ Similar to progressive hepatic type, symptoms less intense; cirrhosis not present; can live into adulthood ▪ Congenital muscular ▫ Manifests shortly after birth; cardiomegaly; life expectancy few months DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Fetal hydrops, hydramnion ECG ▪ Heart abnormalities LAB RESULTS Liver/muscle biopsy with periodic acid-Schiff stain ▪ Glycogen detection OTHER DIAGNOSTICS ▪ Genetic analysis Echocardiography ▪ Heart abnormalities TREATMENT OTHER INTERVENTIONS ▪ Only symptomatic treatment available OSMOSIS.ORG 271

GLYCOGEN STORAGE DISEASE TYPE V (GSD V) osms.it/GSD-V PATHOLOGY & CAUSES ▪ AKA McArdle’s disease ▪ Intracellular pathological accumulation of glycogen in muscle tissue ▪ Cannot release glucose-1-phosphate → ↓ glycolysis, cell energy status, Na+/K+ ATPase function → osmotic cell imbalance → cell damage ▪ Affects only muscle tissue TYPES Early onset ▪ More severe symptoms, progression Adult onset ▪ Less severe symptoms, progression CAUSES ▪ Autosomal recessive disease ▪ Deficiency of myophosphorylase (musclespecific isoform of glycogen phosphorylase) COMPLICATIONS ▪ Renal failure due to myoglobinuria from rhabdomyolysis ▪ Muscle contractures due to fibrosis caused by extensive damage SIGNS & SYMPTOMS ▪ Exercise intolerance, fatigue, rhabdomyolysis, muscle fibrosis ▪ ‘’Second wind’’ phenomenon: shift in metabolism during exercise → sudden burst of energy, despite being out of breath 272 OSMOSIS.ORG DIAGNOSIS LAB RESULTS Muscle biopsy ▪ With periodic acid-Schiff stain ▪ Glycogen detection OTHER DIAGNOSTICS ▪ Genetic analysis TREATMENT OTHER INTERVENTIONS ▪ Only symptomatic treatment available

Chapter 45 Glycogen Storage Diseases OSMOSIS.ORG 273