Correct Answer: C. Myophosphorylase
Myophosphorylase (muscle glycogen phosphorylase) deficiency causes McArdle disease (glycogen storage disease type V), the classic presentation of exercise-induced muscle cramps and pain. The discriminating feature is the second wind phenomenon: initial cramping during exertion that paradoxically improves after 10–15 minutes as alternative fuels (blood glucose, fatty acids) become available. Myophosphorylase catalyzes the first step of glycogenolysis in skeletal muscle—breakdown of glucose-1-phosphate from glycogen. Without this enzyme, muscles cannot mobilize their stored glycogen during exercise, leading to energy crisis, myoglobinuria, and rhabdomyolysis in severe cases. The adolescent presentation with exercise intolerance and cramps is pathognomonic. Unlike hepatic glycogenoses (which cause hypoglycemia and hepatomegaly), McArdle disease spares the liver and presents purely with muscle symptoms. Indian guidelines and Harrison's Principles emphasize that myophosphorylase deficiency is the most common symptomatic glycogenosis in young patients presenting with exertional myalgia.
Why the other options are wrong
A. Glucose-6-phosphatase — Glucose-6-phosphatase deficiency causes Von Gierke disease (GSD type I), characterized by severe fasting hypoglycemia, hepatomegaly, lactic acidosis, and growth retardation—not exercise-induced cramps. This enzyme is hepatic and essential for the final step of gluconeogenesis and glycogenolysis. Patients present in infancy with hypoglycemia, not adolescence with exertional symptoms. NBE may pair this with 'glycogen' to trap students unfamiliar with tissue-specific enzyme distribution. B. Hepatic glycogen phosphorylase — Hepatic glycogen phosphorylase deficiency causes Hers disease (GSD type VI), which presents with hepatomegaly, mild fasting hypoglycemia, and growth delay—not muscle cramps on exertion. The liver is the primary site affected; muscles retain normal glycogenolysis. Patients are typically younger children with hepatic symptoms, not adolescents with exercise intolerance. This is a common distractor because it involves glycogenolysis, but in the wrong tissue. D. Hexokinase — Hexokinase deficiency is extremely rare and causes hemolytic anemia and neurological symptoms, not myopathy or exercise intolerance. Hexokinase catalyzes the first step of glycolysis (glucose → glucose-6-phosphate), not glycogenolysis. Deficiency impairs glucose utilization globally, not specifically muscle energy metabolism during exertion. This option exploits confusion between glycolysis and glycogenolysis pathways.
High-Yield Facts
- McArdle disease (myophosphorylase deficiency) presents with exercise-induced muscle cramps, myoglobinuria, and the second wind phenomenon (cramps improve after 10–15 min of continued exertion).
- Myophosphorylase is muscle-specific; its deficiency does NOT cause hepatomegaly, hypoglycemia, or growth retardation—only muscle symptoms.
- Von Gierke disease (glucose-6-phosphatase deficiency) causes fasting hypoglycemia and hepatomegaly; Hers disease (hepatic phosphorylase deficiency) causes mild hepatomegaly—both present in infancy/early childhood, not adolescence.
- McArdle disease is the most common symptomatic glycogenosis in adolescents and young adults; diagnosis confirmed by ischemic forearm exercise test (no lactate rise, exaggerated ammonia rise) and muscle biopsy.
- Glycogenolysis in muscle requires myophosphorylase; glycogenolysis in liver requires hepatic phosphorylase—tissue-specific enzyme deficiencies produce distinct clinical phenotypes.
Mnemonics
GSD Tissue & Symptoms Muscle (myophosphorylase) → Myalgia/cramps; Liver (glucose-6-phosphatase, hepatic phosphorylase) → Liver enlargement & hypoglycemia. McArdle = muscle pain on exercise; Von Gierke/Hers = hepatic symptoms in infancy. Second Wind Phenomenon Second Wind = Skeletal muscle (myophosphorylase). Initial cramps → blood glucose/fatty acids kick in → symptoms improve. Pathognomonic for McArdle disease.
NBE Trap
NBE pairs 'glycogen' and 'enzyme deficiency' to lure students into choosing hepatic glycogenoses (options A, B) without discriminating between tissue-specific presentations. The key trap: confusing any glycogenosis with exercise intolerance, when only myophosphorylase deficiency causes exertional muscle symptoms.
Clinical Pearl
In Indian clinical practice, McArdle disease is often misdiagnosed as rhabdomyolysis or myositis because patients present with acute muscle pain and myoglobinuria after exertion. The diagnostic clue is the second wind phenomenon and normal fasting glucose—distinguishing it from hepatic glycogenoses. Ischemic forearm exercise test (no lactate rise) confirms the diagnosis and is the gold standard in Indian tertiary centers.
_Reference: Harrison's Principles of Internal Medicine, Ch. 356 (Glycogen Storage Diseases); Robbins & Cotran Pathologic Basis of Disease, Ch. 7 (Genetic Disorders)_