Updated: 8/24/2020

Glycogen Storage Disorders

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  • A 16-year-old boy presents to his primary care physician with a complaint of fatigue and muscle cramps. He recently tried out for his high school basketball team and found himself exhausted and unable to run after performing a set of high intensity sprints. He notes that after resting briefly, he is able to get a “second wind.” After practice, he noticed that his urine was a brown color. Laboratory results are significant for an elevated creatine kinase level of 1,423 U/L (normal < 200 U/L). There was no elevation of lactate levels on forearm nonischemic testing. (McArdle disease)
Introduction
  • Overview
    • glycogen storage disorders (GSD) result from errors of glycogen metabolism caused by mutations in genes for enzymes involved in glycogen synthesis and degradation
  • Epidemiology
    • incidence
      • overall incidence of all forms of glycogen storage diseases in the US, Europe, and Canada is approximately 1 in 20,000-40,000
      • von Gierke disease (GSD type 1) most common type
        • ~25% of all patients with GSD
    • demographics
      • age of onset may range from the first months of life to later decades of life
      • highest incidence of Cori disease (GSD type 3) in non-Ashkenazi Jews in northern Africa
  • Pathophysiology
    • glycogen storage disorders result from abnormal glycogen metabolism and accumulation of glycogen within cells of certain tissues (i.e., liver and skeletal muscle)
  • Genetics
    • inheritance pattern
      • autosomal recessive
  • Prognosis
    • GSD type 1
      • good when dietary and medical treatments are implemented
    • GSD type 2
      • poor prognosis without treatment
    • GSD type 3
      • good prognosis with many patients surviving into adulthood
    • GSD type 5
      • variable prognosis

Glycogen Storage Diseases
GSD Defective Enzyme
Characteristics

Von Gierke disease (type 1)

  • Hepatic glucose-6-phosphatase
  • Autosomal recessive
  • Usually presenting at 3-6 months of age
  • Hepatomegaly
  • Signs of hypoglycemia
    • seizure
  • "Doll-like" face
  • Poor growth
  • ↑ uric acid
    • due to impaired renal clearance and increased production
    • gout
  • ↑ lactic acid
  • ↑ triglycerides
    • xanthomas
    • pancreatitis

Pompe disease (type 2)

  • Lysosomal α(1,4)-glucosidase
  • Autosomal recessive
  • Infantile form 
    • cardiomegaly
    • generalized muscle hypotonia
    • respiratory distress
  • Juvenile and adult form
    • skeletal myopathy
    • delayed-gross motor development
    • limb-girdle weakness
    • respiratory issues

Cori disease (type 3)

  • Glycogen debranching enzyme
  • Autosomal recessive
  • Most cases involve the muscle and liver
  • Hepatomegaly
  • Mild hypoglycemia
    • intact gluconeogenesis

McArdle disease (type 5)

  • Muscle glycogen phosphorylase
  • Autosomal recessive
  • Affects the skeletal muscle
  • No elevation of blood lactate during forearm exercise test
  • ↑ creatine kinase
  • Muscle cramp, fatigue, myalgias, and myoglobinuria
  • "Second wind" phenomenom
    • rapid relief of fatigue and myalgia
    • secondary to increase blood flow, improved free fatty acid delivery, and liver glucose utilization
 
Studies
  • Von Gierke disease (type 1)
    • serum glucose and electrolyte levels
      • fasting hypoglycemia (serum glucose < 2.5 mmol/L)
    • serum uric acid level
      • hyperuricemia (uric acid > 5.0 mg/dL)
    • serum triglyceride level
      • hypertriglyceridemia (triglyceride level > 250 mg/dL)
    • serum cholesterol level
      • hypercholesterolemia (cholesterol level > 200 mg/dL)
  • Pompe disease (type 2)
    • acid α-glucosidase testing
      • initial test
      • gives definitive diagnosis
    • laboratory testing 
      • ↑ creatine kinase, lactic acid, and aspartate aminotransferase
  • Cori disease (type 3)
    • serum glucose and electrolyte levels
      • fasting hypoglycemia (serum glucose < 2.5 mmol/L)
    • laboratory testing 
      • ↑ creatine kinase and aspartate aminotransferase
  • McArdle disease (type 5)
    • serum creatine kinase levels
      • ↑ serum CK at rest
      • further ↑ in CK after intensive exercise
    • myophosphorylase enzyme activity assay
      • ↓↓ myophosphorylase levels
    • genetic testing
      • identification of pathogenic variants in the PYGM gene
      • gives definitive diagnosis
Treatment
  • Von Gierke disease (type 1)
    • dietary management
      • frequent oral glucose/cornstarch consumption
      • avoid fructose and galactose
        • prevent lactic acidosis
  • Pompe disease (type 2)
    • enzyme replacement therapy
      • alglucosidase alfa
  • Cori disease (type 3)
    • symptomatic treatment
  • McArdle disease (type 5)
    • sucrose consumption before exercise may improve symptoms
 

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