GSDs Overview - Glycogen's Glitches
- Inherited metabolic disorders caused by enzyme deficiencies in glycogen synthesis or breakdown.
- Leads to abnormal glycogen accumulation (either quantity or quality) in various tissues.
- Primarily affects liver (e.g., hepatomegaly, hypoglycemia) and/or muscle (e.g., weakness, exercise intolerance).
- Inheritance pattern: Predominantly Autosomal Recessive (AR).
⭐ Most GSDs manifest with either hypoglycemia (liver involvement) or muscle cramping and weakness (muscle involvement).
Hepatic GSDs - Liver's Lament
| Disease (Type) | Enzyme Defect | Glycogen Structure | Key Features |
|---|---|---|---|
| Von Gierke (I) | Glucose-6-phosphatase (📌 'V'ery low glucose) | Normal structure, ↑ amount | Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia. Doll-like face. |
| Cori (III) | Debranching enzyme (amylo-1,6-glucosidase) | Abnormal (short outer branches), ↑ amount | Milder hypoglycemia, hepatomegaly, muscle weakness (IIIa), normal lactate/uric acid. |
| Andersen (IV) | Branching enzyme | Abnormal (long unbranched chains) | Infantile cirrhosis, progressive liver failure, hepatosplenomegaly, early death. |
| Hers (VI) | Liver phosphorylase | Normal structure, ↑ amount | Mild hypoglycemia, hepatomegaly, good prognosis. Ketosis. |
Myopathic GSDs - Muscle's Misery
Primarily affect skeletal muscle, leading to exercise intolerance and muscle damage.
| Disease (Type) | Enzyme Deficient | Key Features |
|---|---|---|
| McArdle (V) | Muscle Glycogen Phosphorylase | 📌 "M"cArdle - "M"uscle. Exercise intolerance, cramps, "second wind" phenomenon, myoglobinuria. No lactate rise. |
| Tarui (VII) | Muscle Phosphofructokinase-1 (PFK-1) | Similar to McArdle; rhabdomyolysis, myoglobinuria. Compensated hemolysis (PFK also in RBCs). |
⭐ In McArdle disease, venous lactate fails to rise after ischemic exercise, a key diagnostic feature.
Pompe & Others - Systemic Spoilers
- Pompe Disease (GSD II): Lysosomal $\alpha$-1,4-glucosidase (acid maltase) deficiency.
- 📌 Pompe affects the 'P'ump (heart).
- Infantile: Severe hypotonia, massive cardiomegaly, death by 2 yrs.
- Late-onset: Milder; skeletal muscle weakness, respiratory failure.
- Key: Only GSD that is a lysosomal storage disease.
⭐ Enzyme replacement therapy (ERT) with alglucosidase alfa is a treatment modality for Pompe disease.
GSD Dx & Rx - Unravel & Undo
- Dx:
- Blood: ↓Glucose, ↑Lactate, ↑Uric acid, ↑Lipids. Glucagon challenge test.
- Enzyme assay (liver/muscle/fibroblasts) - definitive diagnosis.
- Biopsy: Liver/muscle shows PAS+ve, diastase-sensitive glycogen.
- Genetic tests for confirmation.
- Rx:
- Diet: Frequent feeds, nocturnal uncooked cornstarch (GSD I, III, VI, IX). Avoid fructose/galactose (GSD I). High protein (GSD III, V).
- ERT: Alglucosidase alfa for Pompe disease (GSD II).
- Supportive: Allopurinol (hyperuricemia), G-CSF (GSD Ib neutropenia). Liver transplant for severe GSD I, IV.
⭐ Uncooked cornstarch is a cornerstone of GSD I management, providing slow-release glucose.
High‑Yield Points - ⚡ Biggest Takeaways
- Von Gierke (Type I): Glucose-6-phosphatase def.; severe fasting hypoglycemia, lactic acidosis, hepatomegaly, hyperuricemia, doll-like facies.
- Pompe (Type II): Lysosomal acid α-1,4-glucosidase def.; cardiomegaly, hypotonia, macroglossia, normal glucose. Affects "PUMP".
- Cori (Type III): Debranching enzyme def.; milder Type I features, muscle weakness, ketotic hypoglycemia, normal lactate.
- Andersen (Type IV): Branching enzyme def.; progressive infantile cirrhosis, splenomegaly, abnormal glycogen structure.
- McArdle (Type V): Muscle glycogen phosphorylase def.; exercise intolerance, painful cramps, myoglobinuria, second wind phenomenon.
- Hers (Type VI): Liver glycogen phosphorylase def.; mild hypoglycemia, hepatomegaly, generally good prognosis.
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