A 5-year-old girl from Delhi presents with progressive muscle weakness, myalgia, and dark urine after running in a school sports day 3 days ago. On examination, she has mild hepatomegaly and proximal muscle weakness. Serum creatine kinase is 8,500 U/L (normal <200), and urine myoglobin is positive. Her blood glucose during fasting is 85 mg/dL (normal). A forearm ischemic exercise test shows no rise in venous lactate but a normal rise in ammonia. Which glycogen storage disorder is most likely?

Explanation

## Diagnosis: Glycogen Storage Disease Type V (McArdle Disease) ### Clinical Recognition **Key Point:** GSD Type V (muscle phosphorylase deficiency) is the most common adult-onset glycogenosis, presenting with exercise-induced myalgia, myoglobinuria, and muscle cramps—but **normal fasting blood glucose**. ### Pathophysiology Muscle phosphorylase catalyzes the first step of glycogenolysis in skeletal muscle: $$\text{Glycogen} \xrightarrow{\text{Muscle phosphorylase}} \text{Glucose-1-phosphate}$$ Without this enzyme: 1. **Glycogen cannot be mobilized in muscle** → energy crisis during exercise 2. **No lactate production from muscle glycolysis** → **absent lactate rise on ischemic exercise test** (pathognomonic) 3. **Ammonia accumulates** (from AMP deamination as ATP is depleted) → **exaggerated ammonia rise** on exercise test 4. **Muscle ATP depletion** → rhabdomyolysis, myoglobinuria, acute kidney injury risk 5. **Fasting glucose normal** (liver phosphorylase is intact) ### Ischemic Forearm Exercise Test: Diagnostic Gold Standard | Test Result | GSD Type V | Normal | GSD Type I | GSD Type III | |-------------|-----------|--------|-----------|-------------| | **Venous lactate rise** | **Absent/minimal** | ↑↑ (2–5×) | ↓ or absent | ↑ (but less than normal) | | **Ammonia rise** | **Exaggerated** | ↑ (mild) | ↑ (mild) | ↑ (mild) | | **Fasting glucose** | Normal | Normal | **Severely low** | Low | | **Hepatomegaly** | Mild | None | Massive | Moderate | **High-Yield:** The **absence of lactate rise with exaggerated ammonia rise** on ischemic exercise is pathognomonic for muscle phosphorylase deficiency (GSD Type V). ### Clinical Features of GSD Type V (McArdle Disease) | Feature | Mechanism | |---------|----------| | **Exercise intolerance** | Cannot mobilize muscle glycogen | | **Myalgia and cramps** | Muscle energy crisis | | **Myoglobinuria (dark urine)** | Rhabdomyolysis from ATP depletion | | **Elevated CK** | Muscle necrosis | | **Normal fasting glucose** | Liver phosphorylase is normal | | **Mild hepatomegaly** | Some glycogen accumulation in liver | | **"Second wind" phenomenon** | Increased blood glucose/lactate from liver after ~10 min of exercise | | **Risk of acute kidney injury** | Myoglobin precipitation in renal tubules | **Clinical Pearl:** Patients often report a **"second wind"** after 10–15 minutes of exercise—as hepatic glucose output increases, blood glucose and lactate rise, providing alternative fuel and reducing muscle ATP crisis. ### Differential Diagnosis at a Glance | Feature | Type I | Type II | Type III | Type V | |---------|--------|--------|----------|--------| | **Fasting hypoglycemia** | **Severe** | Normal | Mild–moderate | **Normal** | | **Hepatomegaly** | **Massive** | None | Moderate | Mild | | **Exercise intolerance** | No | Yes (infantile) | Mild | **Severe** | | **Myoglobinuria** | No | No | No | **Yes** | | **Lactate on exercise** | Low | Normal | Normal | **Absent** | | **Ammonia on exercise** | Normal | Normal | Normal | **High** | | **Age of onset** | Infancy | Infancy | Childhood | **Adulthood** | ### Why This Patient Has GSD Type V 1. **Exercise-induced myalgia + myoglobinuria** → muscle-specific disorder 2. **Normal fasting glucose** → rules out hepatic glycogenoses (Types I, III) 3. **Absent lactate rise on ischemic exercise** → muscle phosphorylase deficiency (Type V) 4. **Exaggerated ammonia rise** → confirms ATP depletion in muscle 5. **Age 5 years** → consistent with childhood presentation of Type V **Mnemonic: "McArdle = No Lactate"** - **M**uscle phosphorylase - **A**mmonia rises - **C**ramps and myalgia - **A**bsent lactate on exercise - **R**habdomyolysis - **D**ark urine (myoglobin) - **L**ow ATP in muscle - **E**xercise intolerance ### Management 1. **Avoid intense exercise** (risk of rhabdomyolysis and AKI) 2. **Frequent carbohydrate intake** before/during activity 3. **Oral glucose or sucrose** during exercise (bypasses muscle glycogen block) 4. **Avoid fasting** 5. **Genetic counseling** (autosomal recessive) [cite:Robbins 10e Ch 5; Harrison 21e Ch 407]