Glycogen Storage Disorders

I. INTRODUCTION

• Definition: Inherited errors of metabolism resulting from defects in the enzymes or transport proteins involved in glycogen synthesis or degradation.
• Pathophysiology:
  • Accumulation: Abnormal quantity or quality of glycogen accumulates in tissues (liver, muscle, heart).
  • Energy Failure: Inability to liberate glucose from glycogen leads to hypoglycemia (liver types) or muscle energy failure (muscle types).
• Classification:
  • Hepatic GSDs (Ketotic vs. Non-ketotic Hypoglycemia): Types I, III, IV, VI, IX, 0, XI.
  • Muscle GSDs (Weakness/Cardiomyopathy vs. Exercise Intolerance): Types II, IIIa, IV, V, VII.

II. HEPATIC GLYCOGENOSES (Hypoglycemia + Hepatomegaly)

A. GSD Type I (Von Gierke Disease)

• Defect: Glucose-6-Phosphatase complex (Final common pathway of glycogenolysis and gluconeogenesis).
  • Type Ia: Glucose-6-phosphatase catalytic subunit (G6PC).
  • Type Ib: Glucose-6-phosphate translocase (SLC37A4).
• Pathophysiology:
  • Inability to convert G6P $\to$ Glucose.
  • Metabolic Shunting: Excess G6P shunted to:
    • Glycolysis $\to$ Lactic Acidosis.
    • Lipogenesis $\to$ Hypertriglyceridemia (VLDL).
    • Pentose Phosphate Pathway $\to$ Uric acid $\to$ Hyperuricemia.
• Clinical Features:
  • Presentation: 3–6 months (night fasting/weaning). Seizures, failure to thrive.
  • Facies: "Doll-like" face, fat cheeks, protuberant abdomen.
  • Organomegaly: Massive hepatomegaly (glycogen + fat), renomegaly. Spleen is normal (differentiates from GSD III/IV/Lipidosis).
  • GSD Ib Specifics: Neutropenia, neutrophil dysfunction $\to$ Recurrent infections, Inflammatory Bowel Disease (Crohn-like).
• Biochemistry:
  • Severe fasting Hypoglycemia + Lactic Acidosis.
  • Hypertriglyceridemia (plasma looks milky), Hyperuricemia.
  • Glucagon stimulation test: No rise in glucose, significant rise in lactate.
• Complications:
  • Hepatic Adenomas (risk of HCC).
  • Renal failure (FSGS), Nephrocalcinosis.
  • Gout, Pancreatitis (from triglycerides), Osteoporosis.

B. GSD Type III (Cori/Forbes Disease)

• Defect: Debranching Enzyme (Amylo-1,6-glucosidase).
• Subtypes:
  • IIIa: Liver and Muscle involvement (most common).
  • IIIb: Liver only.
• Pathophysiology: Accumulation of "Limit Dextrin" (abnormal structure). Gluconeogenesis is intact.
• Clinical Features:
  • Hepatomegaly (often resolves by puberty), growth retardation.
  • Myopathy: Progressive muscle weakness, distal atrophy.
  • Cardiomyopathy: Left ventricular hypertrophy (distinct from GSD I).
• Biochemistry:
  • Ketotic Hypoglycemia: Fasting tolerance better than GSD I (gluconeogenesis intact).
  • Lactate: Normal. Uric acid: Normal.
  • CK: Elevated (in type IIIa). Transaminases: Elevated.

C. GSD Type IV (Andersen Disease)

• Defect: Branching Enzyme.
• Pathology: Accumulation of unbranched, insoluble glycogen ("Polyglucosan bodies") $\to$ acts as foreign body $\to$ intense fibrosis.
• Clinical:
  • Classic: Failure to thrive, hepatosplenomegaly, Cirrhosis progressing to liver failure/death by age 5.
  • Neuromuscular forms exist (Cardiomyopathy, hypotonia).

D. GSD Type VI (Hers) & IX (Phosphorylase Kinase)

• Defect: Liver Phosphorylase (VI) or Phosphorylase Kinase (IX - X-linked most common).
• Clinical: Mildest hepatic GSDs. Hepatomegaly, growth retardation, mild ketotic hypoglycemia. Often improve with age.

E. GSD Type 0 (Glycogen Synthase Deficiency)

• Defect: Hepatic Glycogen Synthase.
• Pathophysiology: Inability to synthesize glycogen $\to$ No hepatic stores.
• Clinical:
  • Fasting Ketotic Hypoglycemia (rapid onset).
  • Post-prandial Hyperglycemia/Lactate (unable to store glucose).
  • No Hepatomegaly (Key distinguishing feature).

III. MUSCLE GLYCOGENOSES

A. GSD Type II (Pompe Disease)

• Defect: Lysosomal Acid $\alpha$-Glucosidase (GAA).
• Pathophysiology: Lysosomal accumulation of glycogen in muscle, heart, liver.
• Clinical Subtypes:
  1. Infantile (Classic):
     • Onset <6 months.
     • Cardiomyopathy: Massive hypertrophic cardiomyopathy, EKG (High voltage, short PR).
     • Hypotonia: Profound, "Floppy infant", macroglossia.
     • Death by 1 year (cardiorespiratory) if untreated.
  2. Late-Onset (Juvenile/Adult):
     • Proximal muscle weakness (Limb-girdle mimic).
     • Respiratory failure: Diaphragmatic weakness is disproportionate/early.
     • No cardiomyopathy.
• Diagnosis: Enzyme assay (DBS/Leukocytes), GAA sequencing. Urine Hex4 (glucose tetrasaccharide) elevated.

B. GSD Type V (McArdle Disease)

• Defect: Muscle Phosphorylase.
• Clinical:
  • Exercise intolerance, muscle cramps, myalgia.
  • "Second Wind" Phenomenon: Improved tolerance after ~10 mins (switch to fatty acid oxidation).
  • Myoglobinuria: Risk of Acute Kidney Injury (AKI) after intense exercise.
• Diagnosis:
  • Forearm Exercise Test: Flat Lactate curve (no rise) with normal Ammonia rise.
  • CK: Elevated at rest.

IV. DIAGNOSTIC APPROACH

1. Initial Screen: Glucose, Lactate, Ketones, Uric Acid, Lipids, CK, LFTs.
   • Hypoglycemia + High Lactate = GSD I.
   • Hypoglycemia + Ketones + Normal Lactate = GSD III, VI, IX, 0.
   • Hepatomegaly + Hypotonia + Cardiomegaly = GSD II.
2. Functional Tests: Glucagon stimulation test (rarely needed now; dangerous in GSD I).
3. Confirmatory:
   • Molecular Genetics: NGS (Gene panels) is the gold standard.
   • Enzyme Assay: Liver/Muscle biopsy (invasive, largely replaced by genetics).
   • Histology: PAS-positive vacuoles (Glycogen).

V. MANAGEMENT PRINCIPLES

A. Hepatic GSDs (Type I)

• Goal: Maintain normoglycemia (Glucose >70 mg/dL) to prevent metabolic shunting.
• Dietary:
  • Frequent feeds (every 3–4 hours).
  • Uncooked Cornstarch (UCCS): 1.6–2.5 g/kg/dose every 4–6 hours (slow release glucose).
  • Glycosade: Modified starch for overnight coverage (older children/adults).
  • Restriction: Limit Fructose and Galactose (sucrose/lactose) in GSD I (cannot be converted to glucose, worsen lactate).
  • Continuous nocturnal gastric drip feeding (infants).
• Pharmacotherapy:
  • Allopurinol (for uric acid).
  • Lipid-lowering agents (fibrates/statins).
  • ACE inhibitors (for microalbuminuria).
  • G-CSF (Filgrastim): For neutropenia in GSD Ib.
• Transplantation: Liver transplant corrects metabolic defect (indicated for poor control/adenomas). Kidney transplant for renal failure.

B. Muscle GSDs

• Pompe (Type II):
  • Enzyme Replacement Therapy (ERT): Alglucosidase alfa (Myozyme/Lumizyme). Lifesaving in infantile form; stabilizes late-onset.
  • Immunomodulation (methotrexate/rituximab) for CRIM-negative patients (to prevent antibody formation against enzyme).
• McArdle (Type V):
  • Exercise avoidance (anaerobic).
  • Oral sucrose before exercise (“Second wind” induction).

VI. PROGNOSIS

• Type I: Survival to adulthood is expected with tight control. Risk of hepatic adenoma/HCC (20–30s) and renal failure.
• Type II: Infantile mortality high without ERT. ERT has transformed prognosis (now seeing new phenotype of treated survivors).
• Type III: Cirrhosis/fibrosis in liver. Progressive myopathy/cardiomyopathy in adults.
• Type IV: Poor (transplant required).