Elevated Ammonia with Stable Lactate in GSD5 (McArdle Disease)
Metabolic Explanation
In GSD5 (McArdle disease), ammonia levels rise dramatically during exercise while lactate remains low or stable because myophosphorylase deficiency blocks glycogen breakdown to glucose-6-phosphate, preventing glycolysis and lactate production, but muscle still attempts to generate ATP through alternative pathways that produce ammonia as a byproduct. 1
The Biochemical Mechanism
Myophosphorylase deficiency prevents the first step of glycogenolysis, blocking the conversion of glycogen to glucose-1-phosphate, which means the glycolytic pathway cannot be fed from glycogen stores 2
Without glycolytic flux, lactate production is severely impaired because lactate is the end product of anaerobic glycolysis—a pathway that cannot function when its substrate supply is blocked 1
Muscles compensate by activating the purine nucleotide cycle (PNC) to generate ATP through adenosine monophosphate (AMP) deamination, which produces inosine monophosphate (IMP) and releases ammonia as a metabolic byproduct 3
The purine nucleotide cycle becomes hyperactive during exercise in GSD5 because the muscle is energy-starved and desperately attempting to maintain ATP levels through any available pathway 3, 4
Clinical Significance of Ammonia Accumulation
Plasma ammonia can exceed 250 μmol/L during exercise in glycogen storage diseases, far above normal exercise levels, while lactate remains inappropriately low 4
Ammonia crosses the blood-brain barrier and accumulates in cerebrospinal fluid during prolonged or intense exercise, with CSF ammonia reaching 16.1 μmol in studies of exercise-induced hyperammonemia 5
High ammonia levels correlate with exercise-induced symptoms including muscle cramping, exhaustion, motor incoordination, and perceived exertion during intense activity 4, 5
The brain takes up ammonia at a rate of 2.5-3.7 μmol/min during prolonged exercise when arterial ammonia is elevated, potentially affecting neurotransmitter metabolism and contributing to central fatigue 5
Distinguishing GSD5 from Other Glycogen Storage Diseases
GSD5 shows persistently low lactate during and after exercise, distinguishing it from normal individuals who show robust lactate elevation 1
GSD7 (Tarui disease) shows a late lactate rise 10-30 minutes post-exercise (approximately 3 times baseline), which is higher than GSD5 but lower than controls, providing a diagnostic distinction 1
Both GSD5 and GSD7 demonstrate elevated ammonia during exercise, but the lactate profile differs due to the specific enzyme deficiency location within the glycolytic pathway 1
Clinical Monitoring Implications
Serial CK measurements are required to monitor for rhabdomyolysis episodes, which occur recurrently in myophosphorylase deficiency 2
Exercise intolerance manifests as muscle contractures and cramping rather than progressive weakness, distinguishing GSD5 from GSD3 (debranching enzyme deficiency) 2
Cardiac evaluation with ECG and echocardiography is necessary to monitor for ventricular hypertrophy in muscle-affecting glycogenoses 2
Exercise Considerations
Patients with GSD5 experience dynamic exercise intolerance with contractures and recurrent rhabdomyolysis, requiring careful activity modification 2
The "second wind" phenomenon may occur in some GSD5 patients when alternative fuel sources (fatty acids, blood glucose) become available after initial exercise intolerance, though ammonia accumulation continues 3
Exhaustion during highly intensive endurance exercise occurs when plasma ammonia reaches peak individual values, suggesting ammonia toxicity contributes to the inability to continue exercise 4