A 6-year-old girl presents with muscle pain and weakness after exercise, dark-coloured urine, and elevated creatine kinase (8000 U/L). Her parents report she cannot sustain physical activity. Which investigation is most appropriate to confirm glycogen storage disease type V (McArdle disease)?

Explanation

## Diagnostic Confirmation of GSD Type V (McArdle Disease) **Key Point:** The ischaemic forearm exercise test (non-ischaemic or ischaemic variant) is the most specific functional test for GSD Type V because it demonstrates the pathognomonic failure to produce lactate and ammonia during muscle contraction. ### Pathophysiology of GSD Type V **Mnemonic: MCARDLE** — **M**uscle **C**annot **A**ccumulate **R**ecycled **D**ue to **L**ack of **E**nzyme (glycogen phosphorylase) - Defect: Skeletal muscle glycogen phosphorylase (PYGL gene) - Result: Glycogen cannot be mobilized → no glucose-1-phosphate → no pyruvate → **no lactate production** - Consequence: Ammonia accumulates (alternative purine nucleotide cycle pathway) ### The Ischaemic Forearm Exercise Test | Finding | GSD Type V | Normal | |---|---|---| | **Lactate response to exercise** | Absent or minimal rise | 3–5× baseline | | **Ammonia response** | Exaggerated rise (>5× baseline) | Modest rise | | **Clinical correlate** | Second wind phenomenon | Normal fatigue recovery | **High-Yield:** The **second wind phenomenon** is pathognomonic—patients feel worse initially but improve after 10 minutes of rest, allowing alternative fuels (glucose, fatty acids) to mobilize. ### Why Other Tests Are Insufficient 1. **Myoglobinuria & elevated CK** — Indicate muscle necrosis but are non-specific (present in many myopathies) 2. **EMG/NCS** — Show myopathic pattern; do not identify the specific enzyme defect 3. **Muscle biopsy with PAS staining** — Shows glycogen accumulation (true in GSD Type V) but does NOT confirm the enzyme deficiency; requires enzyme histochemistry or molecular testing **Clinical Pearl:** Unlike GSD Type I, GSD Type V does NOT cause hepatomegaly, hypoglycemia, or lactic acidosis at rest—the defect is muscle-specific.