A 24-year-old male presents to the emergency department with dark red-brown urine and severe myalgia following an intense gym session. He reports a lifelong history of exercise intolerance and painful muscle cramps that resolve after 10–15 minutes of rest, after which he can resume activity. His serum creatinine is elevated at 2.8 mg/dL. An ischemic forearm exercise test shows **failure of venous lactate to rise above baseline**, despite normal ammonia elevation. The structure marked **C** in the diagram is deficient in this patient. Which of the following best explains the pathophysiology of his presentation?

Explanation

## Why option 1 is correct The structure marked **C** is glycogen phosphorylase, the rate-limiting enzyme of glycogen breakdown. Deficiency of muscle glycogen phosphorylase causes McArdle disease (GSD type V), an autosomal recessive glycogenosis. The pathophysiology is straightforward: without glycogen phosphorylase, muscle cannot mobilize stored glycogen to glucose-1-phosphate, blocking entry into glycolysis and ATP generation during exercise. This explains exercise intolerance and cramps. The **ischemic forearm exercise test failure to produce lactate** is the diagnostic hallmark—lactate production requires glycolytic flux, which depends on glucose availability from glycogen breakdown. Once the patient rests, ATP levels recover and fatty acid oxidation becomes the primary fuel source (the "second wind" phenomenon), allowing brief resumption of activity. Myoglobinuria and acute kidney injury result from muscle necrosis due to severe energy depletion. This clinical picture and the diagnostic test finding are pathognomonic for muscle glycogen phosphorylase deficiency (Harper 32e Ch 19; Robbins 10e Ch 6). ## Why each distractor is wrong - **Option 2**: Describes branching enzyme deficiency (marked **B**, not **C**), which causes abnormal glycogen structure (polyglucosan accumulation) and presents in infancy with hepatomegaly and progressive cirrhosis—not exercise intolerance or myoglobinuria. - **Option 3**: Describes hepatic glycogen phosphorylase deficiency (Hers disease, GSD type VI), which presents with mild fasting hypoglycemia and hepatomegaly in childhood, not myoglobinuria, exercise intolerance, or abnormal lactate response to forearm exercise. - **Option 4**: Describes debranching enzyme deficiency (marked **D**, not **C**), which causes GSD type III (Cori disease) with hepatomegaly, fasting hypoglycemia, and myopathy—but the ischemic forearm exercise test would show *normal* lactate rise because debranching enzyme deficiency does not block glycolysis; it causes incomplete glycogenolysis and glycogen accumulation. **High-Yield:** McArdle disease = muscle glycogen phosphorylase deficiency = exercise intolerance + myoglobinuria + **absent lactate rise on ischemic forearm exercise test** (the diagnostic test). "Second wind" = recovery via fatty acid oxidation after rest. [cite: Harper 32e Ch 19; Robbins 10e Ch 6]