A 7-year-old girl from Bangalore presents with muscle pain and fatigue during physical education class. She reports that her symptoms improve with rest and a sugary snack. On examination during exercise testing, her serum creatine kinase rises to 2500 U/L (normal <200), and urine turns dark brown after exercise. Serum glucose and lactate remain normal during the exercise test. Muscle biopsy shows subsarcolemmal glycogen accumulation. Which enzyme deficiency is responsible for this disorder?

Explanation

## Diagnosis: Glycogen Storage Disease Type V (McArdle Disease) ### Clinical Presentation Match The vignette presents the classic features of GSD Type V: 1. **Exercise-induced myalgia and fatigue** — occurs during physical activity 2. **Improvement with rest and glucose** — "second wind" phenomenon 3. **Elevated creatine kinase** — indicates muscle damage 4. **Dark urine after exercise** — myoglobinuria (muscle breakdown products) 5. **Normal serum glucose and lactate during exercise** — key distinguishing feature ### Biochemical Defect **Key Point:** GSD Type V is caused by deficiency of **muscle phosphorylase**, the enzyme that catalyzes the first step of glycogenolysis in muscle: glycogen → glucose-1-phosphate. Without this enzyme: - Muscle cannot mobilize glycogen for energy during contraction - Muscle relies on blood glucose and fatty acid oxidation - Anaerobic metabolism during exercise causes muscle damage and myoglobinuria - **Lactate does NOT rise during exercise** (because no glucose-1-phosphate is generated from glycogen) ### Distinguishing Feature: The Ischemic Forearm Exercise Test | Finding | GSD Type I | GSD Type III | GSD Type V | GSD Type II | |---------|-----------|-------------|-----------|------------| | **Fasting hypoglycemia** | Severe | Mild–moderate | Absent | Absent | | **Lactate rise with exercise** | ↑↑↑ | ↑ | **Normal/absent** | Normal | | **Glucose rise with exercise** | ↑ | ↑ | ↑ | Normal | | **Myoglobinuria** | Absent | Absent | **Present** | Absent | | **CK elevation** | Absent | Absent | **Marked** | Absent | | **Muscle symptoms** | Absent | Absent | **Prominent** | Prominent | ### Clinical Pearl **High-Yield:** The **second wind phenomenon** is pathognomonic for GSD Type V. After 10 minutes of rest, blood glucose rises and symptoms resolve. This is because increased hepatic glucose output (from gluconeogenesis and glycogenolysis) provides substrate for muscle contraction via blood glucose uptake. ### Mnemonic **McArdle = Muscle Phosphorylase** — **M**uscle pain, **C**reatine kinase ↑, **A**naerobic metabolism, **R**est improves (second wind), **D**ark urine, **L**actate normal, **E**xercise intolerance. ### Pathophysiology Diagram ```mermaid flowchart TD A[Muscle contraction during exercise]:::action --> B{Muscle phosphorylase present?}:::decision B -->|Yes| C[Glycogen → Glucose-1-P]:::action B -->|No| D[Glycogen cannot be mobilized]:::urgent C --> E[Glycolysis → Pyruvate → Lactate]:::action E --> F[Lactate rises in serum]:::outcome D --> G[Reliance on blood glucose only]:::action G --> H[Anaerobic metabolism → lactic acid in muscle]:::action H --> I[Muscle damage, myoglobinuria, CK ↑]:::urgent F --> J[Normal lactate rise with exercise]:::outcome I --> K[Dark urine, myalgia, fatigue]:::outcome ``` ### Management - Avoid strenuous exercise - Frequent carbohydrate intake before and during activity - Oral glucose or sucrose during exercise (second wind effect) - Genetic counseling [cite:Robbins 10e Ch 5]