Phosphoglucomutase (PGM 1) Deficiency: A Novel Defect of Muscle Glycogen Degradation and Synthesis (P07.200)

Objective: Evaluate the cause of exertional muscle fatigue, contractures and rhabdomyolysis in a young woman. Background An 18 year old woman reported lifelong fatigue with modest exercise and episodes of muscle contractures, pain and swelling with marked elevations in serum creatine kinase levels after more vigorous exercise. Design/Methods: Forearm and cycle exercise, muscle glycogen determinations, and relevant enzymatic and genetic evaluation were performed. Results: Ischemic forearm exercise resulted in no increase in lactate, an exaggerated increase in ammonia, rapid contractile fatigue and a finger flexor muscle contracture. Cycle exercise revealed low oxidative capacity and a spontaneous "second wind," associated with a 40 beat per minute (bpm) drop in exercise heart rate, from 159 (between minute 5-6) to 119 bpm at minute 14 of sustained exercise with a corresponding fall in perceived exertion, thus mirroring the response heretofore considered diagnostic of McArdle disease. However enzymatic activity of muscle phosphorylase and other known defects of muscle glycogenolysis were within normal limits and muscle glycogen levels were low normal as assessed biochemically (controls = 1.1±0.2%; patient = 0.7%) and with 13-C MRS in contrast to McArdle disease (2.5±0.4 %). Evaluation of other glycolytic enzymes revealed a complete absence of muscle phosphoglucomutase (PGM1) activity, the enzyme that catalyzes the conversion of phosphorylase-derived glucose-1-phosphate to glucose-6-phosphate for metabolism via glycolysis and the reverse reaction for glycogen synthesis from glucose. Genetic analysis revealed that the patient was a compound heterozygote for a nonsense mutation (Q530X in exon 10) and a missense mutation (R422W) in exon 8 of PGM1. Conclusions: This patient has a novel defect in phosphoglucomutase (PGM1) that mimics the clinical and physiological features of impaired muscle glycogenolysis due to muscle phosphorylase deficiency (McArdle disease). The finding of blocked muscle glycogenolysis in combination with low muscle glycogen implies that this enzymatic defect impairs both glycogen degradation and synthesis. Supported by: The Muscular Dystrophy Association and The Giant Tiger Foundation. Disclosure: Dr. Haller has nothing to disclose. Dr. Heinicke has nothing to disclose. Dr. Newby has nothing to disclose. Dr. Wyrick has nothing to disclose. Dr. Dimitrov has nothing to disclose. Dr. Mancias has nothing to disclose. Dr. Cohen has nothing to disclose.