Glycogen storage Disorders are biochemical disorders characterised by abnormal glycogen metabolism which can be presented by two major organs i.e, Liver and Muscle. In this particular section, we will provide a concise note on types of liver glycogen storage disorders aka Liver Glycogenosis.

Figure : Types of Glycogen Storage Disorders

LIVER GLYCOGENOSIS :

Figure : Types of Liver Glycogenosis with their respective enzyme deficiency / defects

TYPE 1 GSD : VON GIERKE’S DISEASE

INHERITANCE : Autosomal recessive

DEFICIENT ENZYME :

In subtype 1a, Glucose-6-phosphatase

In subtype 1b, Translocase (carries glucose-6-phosphate across microsomal membrane)

ORGANS AFFECTED : Liver, Kidney, Intestinal Mucosa

CLINICAL FINDINGS :

  1. Neonatal period: Hypoglycemia and Lactic Acidosis
  2. 3-4 months: Hepatomegaly
  3. Physical features: Doll-like facies, fat cheeks, thin extremities, short stature, protuberant abdomen
  4. Growth retardation
  5. Easy bruising and epistaxis
  6. Diarrhoea and malnutrition (long-standing cases of subtype 1b)

LABORATORY FINDINGS :

  1. Prolonged bleeding time
  2. Hyperuricemia
  3. Elevation of TGs, LDL, Total cholesterol
  4. In type 1b, neutropenia (leading to recurrent bacterial infections and mucosal ulcerations) 

LONG TERM COMPLICATIONS :

  1. Gout (presented at puberty)
  2. Polycystic ovaries and menorrhagia in women
  3. Pancreatitis
  4. Systemic hypertension
  5. Osteopenia/osteoporosis (seen in adults)
  6. Hepatic adenomas (2nd-3rd decade of life)
  7. End stage renal disease in patients who developed proteinuria, nephrocalcinosis and alteration in creatinine clearance

DIAGNOSIS :

  1. Clinical presentation
  2. Lab findings (mentioned above)
  3. Genetic testing
  4. Liver biopsy (historic value)- Distended by glycogen and fat, with large lipid vacuoles

TREATMENT :

  1. First line: Avoid fasting and frequent feedings
  2. Diet preferred:  Complex carbohydrates with uncooked corn-starch
  3. For nephrocalcinosis: Citrate supplementation
  4. For hyperuricemia: Allopurinol
  5. For lipid abnormalities: HMG-CoA reductase inhibitors and fibrates
  6. For microalbuminuria: ACE inhibitors
  7. For liver adenoma: Surgical resection, radiofrequency ablation, percutaneous ethanol injection
  8. Liver and Kidney transplantation may be indicated
  9. For subtype 1b: G-CSF and Empagliflozin 

TYPE 3 GSD : CORI’S DISEASE

INHERITANCE : Autosomal recessive

ENZYME INVOLVED : Glycogen debranching enzyme

CLASSIFICATION :

3a: Liver, skeletal muscle and cardiac involvement

3b: Primarily liver involvement

CLINICAL FINDINGS :

  1. Infancy: Hypoglycemia(ketotic or non-ketotic in only 50% of patients) , hepatomegaly (reduces with age), hyperlipidemia, short stature
  2. 3a: Skeletal myopathy and cardiomyopathy may be present with the above findings
  3. Liver: Hepatomegaly reduces with age but many patients in late adulthood have fibrosis, cirrhosis, liver failure, hepatocellular carcinoma, hepatic adenomas( less common than in Von Gierke’s disease)
  4. Heart: Left ventricular hypertrophy, arrhythmia
  5. Skeletomuscular: Muscle weakness (severe by 4th decade), exercise intolerance, osteoporosis
  6. Nervous system: Peripheral Neuropathy
  7. Polycystic ovaries in females

LABORATORY FINDINGS :

  1. Elevated ALT and AST
  2. Normal blood lactate and uric acid
  3. Elevation of TGs, LDL, Total cholesterol
  4. Serum creatine kinase may be elevated

DIAGNOSIS :

  1. Clinical presentation
  2. Lab findings (mentioned above)
  3. Genetic testing- DNA based analyses
  4. Liver biopsy (historic value)- distended hepatocytes, periportal fibrosis along with few fat infiltration 

TREATMENT :

  1. Diet preferred:  As gluconeogenesis is intact, high-protein diet and complex carbohydrates with uncooked corn-starch
  2. Dietary lipid modifications: High fat diet/ketogenic diet/supplementation of medium-chain TGs
  3. For lipid abnormalities: HMG-CoA reductase inhibitors and fibrates
  4. For liver adenoma: Surgical resection, radiofrequency ablation, percutaneous ethanol injection
  5. Liver and heart transplantation may be indicated

TYPE 4 GSD : ANDERSON’S DISEASE

ENZYME DEFICIENT : Branching Enzymes

CLASSIFICATION WITH FEATURES :

  1. Hepatic form- Failure to thrive, hypotonia, hepatomegaly, cirrhosis, failure (Death by 5 years), hypoglycemia (late finding secondary to liver lesions); small subset has extrahepatic involvement
  1. Neuromuscular forms-

It has 4 subtypes: 

  1. Perinatal– Death in neonatal period
  2. Congenital– Death in neonatal period
  3. Childhood– Myopathy, cardiomyopathy, systemic findings
  4. Adult Polyglucosan Body Disease (APBD)– B/L Lower limb weakness, spasticity; neurogenic bladder; peripheral neuropathy; cognitive impairment

DEFINITIVE DIAGNOSIS :

  1. Demonstrate pathogenic variants in the GBE1 gene; or
  2. Enzyme deficiency in liver, muscle, cultured skin fibroblasts, leukocytes

TREATMENT :

  1. Liver transplantation
  2. Symptomatic for gait abnormalities and bladder dysfunction in APBD 

TYPE 9 GSD

ENZYME INVOLVED : Liver Phosphorylase Kinase (PhK)

CLASSIFICATION :

  1. 9 alpha 2 (PHKA2 pathogenic variants): 
  • X-linked 
  • commonly seen
  • high phenotypic variability
  • Enzymes in liver, erythrocyte, leukocyte affected, not muscles
  1. 9 beta (PHKB pathogenic variants)
  2. 9 gamma 2 (PHKG2 pathogenic variants): Severe with early cirrhosis and fibrosis
  3. 9 alpha 1 (PRKAG2 pathogenic variants): Affect only muscles
  4. 9 gamma 1 (PRKAG2 pathogenic variants): Affect only muscles

TYPE 10 GSD : FANCONI-BICKEL SYNDROME

ENZYMES DEFICIENT : GLUT2 deficiency

FEATURES : Proximal renal tubular dysfunction leading to increased renal clearance of glucose, amino acids, phosphate and uric acid

Medicine is a science of uncertainty and an art of probability.

William osler

REFERENCE :

Harrison’s Principles of Internal Medicine, 21e Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. Loscalzo J, & Fauci A, & Kasper D, & Hauser S, & Longo D, & Jameson J(Eds.),Eds. Joseph Loscalzo, et al.