What is the diagnostic workup and management for a patient with suspected Glycogen Storage Disease type 5 (GSD5)?

Differential Diagnosis of GSD Type 5 (McArdle Disease)

Key Distinguishing Features of GSD5

GSD5 (myophosphorylase deficiency) presents with exercise-induced muscle cramps, myalgia, and the pathognomonic "second wind" phenomenon—symptoms that improve after a few minutes of rest during continued low-intensity exercise. 1, 2

Cardinal Clinical Features

• Exercise intolerance with muscle cramps and pain occurring during high-intensity or isometric exercise, typically beginning in childhood or adolescence 1, 2
• Second wind phenomenon (improvement in exercise tolerance after 8-10 minutes of continued low-intensity activity) reported in approximately 50% of patients 1
• Elevated resting serum CK levels (often 5-10 times normal even at baseline) 1, 2
• Exercise-induced rhabdomyolysis with myoglobinuria in 50% of patients during severe episodes 2
• Absence of hepatomegaly, hypoglycemia, or cardiac involvement—critical negative findings that distinguish GSD5 from hepatic GSDs 2, 3

Primary Differential Diagnoses

Other Muscle Glycogenoses

GSD Type VII (Phosphofructokinase Deficiency)

• Clinically nearly identical to GSD5 with exercise intolerance and cramps 2
• Key difference: Pre-exercise carbohydrate ingestion worsens symptoms in GSD7 but improves symptoms in GSD5 2
• Associated with mild hemolytic anemia and hyperuricemia (absent in GSD5) 2
• Forearm exercise test shows flat lactate response with exaggerated ammonia rise 2

GSD Type III (Debranching Enzyme Deficiency)

• Distinguishing features: Prominent hepatomegaly, childhood hypoglycemia, and elevated transaminases (AST often >500 U/L) 4
• Muscle involvement (GSD IIIa) presents as progressive fixed weakness rather than exercise-induced cramps 4
• Cardiomyopathy with left ventricular hypertrophy occurs in 30-80% of GSD IIIa patients 4
• CK elevation present but accompanied by liver dysfunction 4

GSD Type II (Pompe Disease)

• Presents with progressive proximal muscle weakness and respiratory insufficiency, not exercise-induced symptoms 4
• Diaphragm involvement is characteristic 4
• Lysosomal glycogen accumulation on muscle biopsy (not cytoplasmic as in GSD5) 4
• AST typically higher than ALT; no hypoglycemia 4

Other Muscle Glycogenoses with Exercise Intolerance

Phosphoglycerate Mutase Deficiency (GSD Type X)

• Exercise-induced cramps and rhabdomyolysis similar to GSD5 2
• CK can be normal between episodes (unlike persistently elevated CK in GSD5) 2
• Forearm exercise test shows flat lactate with elevated ammonia 2

Aldolase A Deficiency

• Exercise intolerance with rhabdomyolysis 2
• May have hemolytic anemia (not seen in GSD5) 2

β-Enolase Deficiency (GSD Type XIII)

• Exercise-induced symptoms with normal baseline CK 2
• CK rises only during rhabdomyolysis episodes 2

Non-Glycogenosis Muscle Disorders

Carnitine Palmitoyltransferase II (CPT2) Deficiency

• Exercise-induced rhabdomyolysis, but triggered by prolonged low-intensity exercise or fasting (opposite pattern from GSD5) 5, 6
• Hypoketotic hypoglycemia may occur with fasting 5
• Abnormal acylcarnitine profile with elevated long-chain acylcarnitines 5, 6
• No second wind phenomenon 2

Mitochondrial Myopathies

• Exercise intolerance with progressive fixed weakness rather than episodic cramps 2
• Elevated lactate at rest and with minimal exertion 2
• May have multisystem involvement (CNS, cardiac, endocrine) 2

Diagnostic Algorithm

Step 1: Clinical Pattern Recognition

• Exercise-induced cramps + second wind + elevated resting CK + no hepatomegaly = strongly suggests GSD5 1, 2
• Exercise intolerance worsened by pre-exercise carbohydrate = suggests GSD7 over GSD5 2
• Progressive fixed weakness + hepatomegaly = suggests GSD3 4

Step 2: Forearm Exercise Test

• Flat or minimal lactate rise (<3-fold increase) with exaggerated ammonia response (>5-fold increase) is characteristic of muscle glycogenoses including GSD5 1, 2
• Normal lactate rise (>3-fold) excludes glycogenolytic and glycolytic defects 2
• Critical caveat: Test is not invariably positive; false negatives occur in 10-20% of confirmed cases 2

Step 3: Genetic Testing (Gold Standard)

• Direct sequencing of PYGM gene is now the diagnostic gold standard, replacing the need for muscle biopsy in most cases 1
• Most common mutation: p.R50* (nonsense mutation) 1
• Biallelic pathogenic variants confirm diagnosis 1

Step 4: Muscle Biopsy (If Genetic Testing Inconclusive)

• Shows subsarcolemmal glycogen accumulation on periodic acid-Schiff (PAS) staining 2
• Absent myophosphorylase staining on histochemistry 2
• Avoid biopsy if genetic testing is diagnostic 1

Critical Pitfalls to Avoid

• Do not dismiss childhood-onset exercise intolerance as "deconditioning"—93% of GSD5 patients recall symptoms beginning in childhood, yet only 25% are diagnosed then, leading to decades of misdiagnosis 1
• Do not assume normal CK between episodes excludes muscle glycogenosis—GSD5 has persistently elevated CK, but GSD types X and XIII may have normal baseline CK 2
• Do not order carnitine/acylcarnitine profiles expecting diagnostic findings in GSD5—these are normal in muscle glycogenoses and serve only to exclude fatty acid oxidation disorders from the differential 5, 6
• Do not perform muscle biopsy before genetic testing—PYGM sequencing is less invasive and equally diagnostic 1
• Do not recommend pre-exercise carbohydrate without confirming the specific diagnosis—this helps GSD5 but worsens GSD7 2