What is glycogen storage disease?

Glycogen Storage Disease

Glycogen storage disease (GSD) is a group of inherited metabolic disorders caused by enzymatic deficiencies affecting glycogen metabolism, leading to abnormal accumulation of glycogen in various tissues, primarily liver and muscle, resulting in clinical manifestations such as hypoglycemia, hepatomegaly, myopathy, and cardiomyopathy. 1

Classification and Epidemiology

• GSDs are rare disorders with an estimated incidence of 1 case per 20,000-43,000 live births 1, 2
• More than 20 different types have been identified, classified according to the specific enzyme deficiency and affected tissues 1, 2
• GSDs primarily affect the liver, muscle, or both, as glycogen is particularly abundant in these tissues 2

Pathophysiology

• GSDs result from deficiencies in enzymes involved in glycogen synthesis or degradation
• In GSD type III (Cori's disease), there is a deficiency of the glycogen debranching enzyme (GDE) 3
• GDE is unusual as it has two independent catalytic activities on a single polypeptide chain: transferase and amylo-1,6-glucosidase (AGD) 3
• Both debranching enzyme and phosphorylase enzyme are needed for complete glycogen degradation 3
• The human debranching enzyme gene is located on chromosome 1p21, spans 85 kb, and contains 35 exons 3

Clinical Manifestations

Hepatic Symptoms

• Hepatomegaly
• Hypoglycemia
• Hyperlipidemia
• Elevated liver enzymes (AST/ALT)
• Potential progression to cirrhosis and hepatic adenomas 3, 1

Muscular Symptoms

• Exercise intolerance
• Muscle cramps and pain
• Rhabdomyolysis
• Progressive muscle weakness
• Elevated creatine kinase (CK) levels 1, 2

Other Manifestations

• Growth retardation/short stature
• Cardiomyopathy (in some types)
• Hyperuricemia
• Lactic acidosis (in some types) 3, 1

Types of Glycogen Storage Diseases

Type I (von Gierke disease)

• Deficiency of glucose-6-phosphatase
• Severe hypoglycemia, hyperlipidemia, hyperuricemia, lactic acidosis
• No muscle involvement 3, 4

Type II (Pompe disease)

• Deficiency of lysosomal alpha-glucosidase (GAA)
• Primarily affects muscle
• Progressive muscle weakness, cardiomyopathy 5, 4

Type III (Cori disease/Forbes disease)

• Deficiency of glycogen debranching enzyme
• Type IIIa: affects both liver and muscle
• Type IIIb: affects only liver
• Hepatomegaly, hypoglycemia, muscle weakness 3, 4

Type IV (Andersen disease)

• Deficiency of glycogen branching enzyme
• Progressive liver cirrhosis
• Neuromuscular involvement in some cases 3, 4

Type V (McArdle disease)

• Muscle phosphorylase deficiency
• Exercise intolerance, muscle cramps, myoglobinuria 4, 6

Type VI and IX

• Liver phosphorylase and phosphorylase kinase deficiencies
• Hepatomegaly, growth retardation, hypoglycemia
• Generally milder than other types 3, 4

Diagnosis

The diagnosis of GSD requires a systematic approach:

1. Clinical evaluation: Assessment of symptoms including hepatomegaly, hypoglycemia, muscle weakness, and growth retardation

2. Laboratory tests:

   • Blood glucose, lactate, uric acid
   • Liver profile (AST, ALT)
   • Lipid profile
   • Creatine kinase (CK) for muscle involvement
   • Carnitine and acylcarnitine profiles 1

3. Histological studies:

   • Liver or muscle biopsies showing glycogen accumulation
   • In GSD III, abnormal glycogen with shorter outer branches and extremely high glycogen content (3-5 times normal levels) 3, 1

4. Enzymatic analysis:

   • Measurement of specific enzyme activities
   • For GSD III, confirmation by deficient debranching enzyme activity 3, 1

5. Genetic analysis:

   • Molecular testing to identify specific mutations
   • For GSD III, mutations in the AGL gene on chromosome 1p21 3

Differential Diagnosis

The differential diagnosis of GSD is extensive and includes:

• Other metabolic disorders affecting the liver (hereditary fructose intolerance)
• Primary liver diseases (alpha-1-antitrypsin deficiency, hepatitis)
• Other storage disorders (Niemann-Pick B, Gaucher disease)
• Disorders of gluconeogenesis 3

Treatment and Management

Nutritional Management

• Maintain glucose homeostasis
• Avoid prolonged fasting
• Use of uncooked cornstarch as a slow-release carbohydrate source
• High-protein diet (especially for GSD III) 3, 1, 7

Specific Therapies

• Enzyme replacement therapy for Pompe disease (alglucosidase alfa) 5
• SGLT2 inhibitors for neutropenia in GSD Ib 8

Management of Complications

• Regular surveillance for hepatic adenomas
• Control of hyperlipidemia
• Treatment of hyperuricemia
• Cardiac monitoring in types with myocardial involvement 3, 1

Emerging Therapies

• Gene therapy approaches are under investigation 2, 8
• Liver transplantation for progressive liver disease 3

Prognosis

• Prognosis varies depending on the type of GSD, severity, and age at diagnosis
• With early diagnosis and appropriate treatment, many patients can lead relatively normal lives
• In GSD III, hepatic symptoms often improve with age, but muscle involvement may progress
• Long-term complications include liver cirrhosis, hepatic adenomas, and cardiomyopathy 3, 1

Key Points for Clinical Practice

• Consider GSD in patients with hepatomegaly, hypoglycemia, and/or muscle symptoms
• Early diagnosis and aggressive treatment are associated with better outcomes
• Regular monitoring for disease-specific complications is essential
• Multidisciplinary care involving metabolic specialists, hepatologists, cardiologists, and nutritionists is recommended 3, 1, 2