A 7-year-old girl from Tamil Nadu is brought to the paediatric clinic with a 2-year history of progressive muscle weakness, exercise intolerance, and recurrent episodes of dark-coloured urine after physical activity. Her mother reports that she cannot run or play like other children and becomes fatigued within minutes of exertion. On examination, there is mild proximal muscle weakness. Serum creatine kinase (CK) is markedly elevated at 3500 IU/L. Urine myoglobin is positive. A muscle biopsy shows normal glycogen structure but absent muscle phosphorylase activity. Which glycogen storage disorder is most likely?

Explanation

## Diagnosis: Glycogen Storage Disease Type V (McArdle Disease) ### Clinical Presentation Match **Key Point:** GSD Type V is caused by deficiency of **muscle phosphorylase**, the enzyme that catalyses the first step of glycogenolysis in skeletal muscle. This prevents muscle glycogen from being mobilised during exercise. ### Pathognomonic Features Present in This Case | Feature | GSD Type V | Clinical Finding | |---------|-----------|------------------| | **Exercise intolerance** | Hallmark symptom | Present (cannot run, fatigues quickly) | | **Muscle pain/cramping** | During exertion | Implied by exercise limitation | | **Myoglobinuria** | Characteristic (dark urine) | Present | | **Elevated CK** | Marked elevation | 3500 IU/L | | **Age of onset** | Childhood to adolescence | 7 years old | | **Glycogen structure** | Normal | Confirmed on biopsy | | **Muscle phosphorylase activity** | Absent | Confirmed on biopsy | | **Fasting hypoglycaemia** | **Absent** (key differentiator) | Not mentioned | ### Biochemical Mechanism 1. Muscle phosphorylase deficiency blocks glycogenolysis in skeletal muscle 2. During exercise, muscle cannot mobilise glycogen → no glucose-1-phosphate → no ATP production from glycolysis 3. Anaerobic metabolism and muscle damage ensue → rhabdomyolysis → myoglobinuria 4. Hepatic glucose production remains intact → no fasting hypoglycaemia **High-Yield:** GSD Type V is the **only glycogen storage disorder where fasting hypoglycaemia is absent**. This is the critical diagnostic clue. ### Second Wind Phenomenon **Clinical Pearl:** Patients with GSD Type V may experience a "second wind" during prolonged exercise—after 8–10 minutes, symptoms improve because the body switches to fatty acid and blood glucose oxidation. This is pathognomonic and helps confirm the diagnosis. ### Why This Is Type V and Not Type VII Both Type V and Type VII present with exercise intolerance and myoglobinuria, but: - **Type V:** Muscle phosphorylase deficiency (most common) - **Type VII:** Phosphofructokinase (PFK) deficiency (rare) The **normal glycogen structure** and **absent muscle phosphorylase activity** on biopsy definitively establish Type V. ### Management Implications - Avoid strenuous exercise - Educate on the second wind phenomenon - Genetic counselling (autosomal recessive) - Monitoring for rhabdomyolysis and acute kidney injury during exertion **Mnemonic:** **MCARDLE** = **M**uscle phosphorylase deficiency, **C**reatine kinase elevated, **A**bsent hypoglycaemia (fasting), **R**habdomyolysis (myoglobinuria), **D**ark urine, **L**imited exercise tolerance, **E**xercise intolerance