A 7-year-old girl from Delhi presents with a 2-year history of progressive muscle weakness and calf pain on exertion. Her parents report that she tires easily during play and has difficulty climbing stairs. On examination, she has mild proximal muscle weakness and calf hypertrophy. Serum creatine kinase is elevated at 800 U/L. A muscle biopsy shows glycogen accumulation in muscle fibres with normal glycogen branching pattern. Electromyography shows myopathic changes. Which enzyme deficiency is responsible for this glycogen storage disorder?

Explanation

## Diagnosis: Glycogen Storage Disease Type V (McArdle Disease) ### Clinical Presentation Analysis The vignette describes: - **Progressive muscle weakness** and **exercise intolerance** - **Calf pain and hypertrophy** (pseudohypertrophy from glycogen accumulation) - **Elevated serum creatine kinase** (myopathy marker) - **Glycogen accumulation in muscle** with **normal branching pattern** - **Myopathic EMG changes** These findings are characteristic of **GSD Type V (McArdle disease)**, caused by **muscle phosphorylase deficiency**. ### Pathophysiology of Muscle Phosphorylase Deficiency **Key Point:** Muscle phosphorylase catalyzes the first step of glycogenolysis in skeletal muscle — the release of glucose-1-phosphate from the outer chains of glycogen. Without this enzyme, muscle cannot mobilize its glycogen stores during contraction. #### Metabolic Consequences: 1. **During muscle contraction:** Glycogen cannot be broken down → no glucose-1-phosphate → no ATP production from glycolysis 2. **Energy crisis:** Muscle relies on fatty acid oxidation and blood glucose (limited), leading to rapid fatigue 3. **Glycogen accumulation:** Unused glycogen accumulates in muscle fibres 4. **Muscle damage:** Severe contractions → myoglobinuria, rhabdomyolysis, acute kidney injury 5. **"Second wind" phenomenon:** After 10 minutes of rest, increased blood glucose and fatty acid uptake allow continued exercise ### Distinguishing GSD Type V from Other Muscle Glycogenoses | Feature | GSD V (McArdle) | GSD II (Pompe) | GSD III (Cori) | GSD VII | |---------|-----------------|----------------|----------------|--------| | **Enzyme defect** | Muscle phosphorylase | Acid maltase | Debranching enzyme | Phosphofructokinase | | **Age of onset** | Childhood–adolescence | Infancy (severe) or adulthood | Childhood | Childhood | | **Muscle weakness** | Exercise-induced | Progressive, severe | Mild | Exercise-induced | | **Calf hypertrophy** | Yes (pseudohypertrophy) | No | Possible | Possible | | **Myoglobinuria** | Yes (with exertion) | No | No | Yes | | **Glycogen structure** | Normal | Normal | Normal | Normal | | **Cardiomegaly** | No | Yes (infantile form) | No | No | | **Second wind** | Yes | No | No | No | ### High-Yield Clinical Features **High-Yield:** The **"second wind" phenomenon** is pathognomonic for GSD Type V. After 10 minutes of rest during exercise, patients can resume activity because: - Blood glucose rises (from hepatic glycogenolysis) - Fatty acid oxidation increases - Muscle energy demand is partially met **Clinical Pearl:** Myoglobinuria (dark urine) after intense exercise is a red flag for GSD Type V and indicates risk of acute kidney injury. Patients should avoid strenuous exercise and maintain hydration. **Mnemonic:** **CAMP** — **C**alf hypertrophy, **A**cute myoglobinuria, **M**uscle phosphorylase deficiency, **P**rogressively worsens with exertion (McArdle disease). ### Diagnostic Confirmation 1. **Ischemic forearm exercise test:** Normal rise in venous lactate and ammonia is ABSENT in GSD Type V (pathognomonic) 2. **Muscle biopsy:** Glycogen accumulation with normal structure; absent or reduced phosphorylase on histochemistry 3. **Genetic testing:** Mutations in PYGM gene (muscle phosphorylase) 4. **Serum CK:** Elevated at baseline, further increases with exertion ### Management - **Avoid strenuous exercise** and sudden intense activity - **Frequent small meals** and **oral glucose before exercise** (to provide exogenous glucose) - **Adequate hydration** to prevent myoglobinuria-induced renal failure - **Genetic counselling** (autosomal recessive)