Correspondence

Muscle Glycogenosis Due to Phosphoglucomutase 1 Deficiency

N Engl J Med 2009; 361:425-427July 23, 2009

Article

To the Editor:

Muscle glycogen storage diseases are rare inborn diseases caused by errors of metabolism associated with either dynamic, exercise-related symptoms or permanent muscle weakness. The most common glycogen storage disease, McArdle's disease (glycogen storage disease type V), is caused by myophosphorylase deficiency and characterized by cramps and muscle pain elicited by sudden vigorous exercise, which may lead to rhabdomyolysis and myoglobinuria. Diagnosis can be suggested by the absence or blunting of the increase in lactate level and the exaggeration of the ammonia response in venous effluent blood in the forearm of a person who is exercising. One exception is that lactate and ammonia responses may be normal in patients with phosphorylase b kinase deficiency (glycogen storage diseases type VIII).1

A 35-year-old man was referred for investigation of recurrent cramps provoked by exercise. He was the second child of nonconsanguineous, healthy parents who had no family history of a muscle disease. He had two episodes of dark-brown urine after strenuous exercise, suggesting rhabdomyolysis. No second wind occurred during exercise. Neurologic examination showed mild weakness of the pelvic-girdle muscles. The creatine kinase level at rest was 300 U per liter, but it increased by a factor of 10 to 20 after strenuous exercise. Needle electromyography showed a myopathic pattern in the vastus medialis. A standardized forearm-exercise test2 showed that the patient was able to perform isometric, nonischemic exercise at 70% of the maximum voluntary contraction force for 30 seconds. The increase in plasma lactate level was normal, but ammonia release was four times the expected increase (Figure 1A and 1BFigure 1Plasma Levels of Lactate and Ammonia and Heart Rate before and after Handgrip and Cycle-Ergometer Exercise.).

¹³C-magnetic resonance spectroscopy of the gastrocnemius muscle revealed a normal glycogen-to-creatine ratio. After performing 160 seconds of aerobic plantar flexion, producing 1680 joules, muscle acidification was normal.3 During recovery, the myoglobin reoxygenation rate was normal, as was the perfusion profile.

The patient performed a constant workload test for 20 minutes, followed by an incremental exercise test until exhaustion on a cycle ergometer (Tunturi Oy); normal increases in the plasma lactate level during submaximal and maximal exercise were observed, as compared with the levels in five healthy age-matched men (Figure 1C and 1D).

A muscle biopsy revealed abnormal subsarcolemmal and sarcoplasmic accumulations of normally structured, free glycogen (Fig. 2A through D in the Supplementary Appendix, available with the full text of this letter at NEJM.org). An in vitro muscle study of anaerobic glycogenolysis and glycolysis showed a metabolic block after formation of glucose-1-phosphate and before formation of glucose-6-phosphate, indicating phosphoglucomutase deficiency, which is responsible for this enzymatic step (Fig. 2E in the Supplementary Appendix). Biochemical investigation of muscle revealed a reduction of phosphoglucomutase activity to 1% of the value among controls (with values in the patient of 1.5 U per gram, vs. the control range of 115 to 130 U per gram),4 whereas total and active phosphorylase activities and phosphofructokinase activity were within the control range. Molecular analysis of the phosphoglucomutase 1 (PGM1) gene5 revealed two heterozygous mutations: a c.343A→G mutation inherited from the father, resulting in a change from threonine to alanine at position 115, affecting a highly conserved amino acid residue, and a c.1145-1G→C in an intron 7–8 splicing donor site, inherited from the mother. These mutations were absent in 65 controls of the same ethnic group as the patient.

Thus, this patient had biochemically and genetically proven phosphoglucomutase deficiency. This myopathy is characterized by exercise-induced intolerance with episodes of rhabdomyolysis, normal elevation of lactate, and hyperammonemia on a forearm-exercise test. Our findings suggest that phosphoglucomutase deficiency should be added to the list of rare glycolytic disorders and designated glycogenosis type XIV.

Tanya Stojkovic, M.D.
Groupe Hospitalier Pitié–Salpêtrière, 75651 Paris 13, France
tanya.stojkovic@psl.aphp.fr

John Vissing, M.D., Ph.D.
University of Copenhagen, DK-2100 Copenhagen, Denmark

François Petit, Ph.D.
Hôpital Antoine Béclère, 92140 Clamart, France

Monique Piraud, Ph.D.
Hospices Civils de Lyon, 69677 Bron, France

Mette C. Orngreen, B.Sc.
Grete Andersen, M.D.
University of Copenhagen, DK-2100 Copenhagen, Denmark

Kristl G. Claeys, M.D., Ph.D.
Claire Wary, Ph.D.
Jean-Yves Hogrel, Ph.D.
Institut de Myologie, 75651 Paris 13, France

Pascal Laforêt, M.D.
Groupe Hospitalier Pitié–Salpêtrière, 75651 Paris 13, France

Supported by the French Ministry of Health, Assistance Publique–Hôpitaux de Paris, the Association Française contre les Myopathies, the Sara and Ludvig Elsass Foundation, the Danish Medical Research Council, the NOVO Nordic Foundation, and the Copenhagen Hospital Community Foundation.

5 References

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   F. Maillot, D. Jacobi, C. Couet. 2011. Maladies innées du métabolisme chez l'adulte. , 293-302.
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   Salvatore DiMauro, Caterina Garone, Ali Naini. (2010) Metabolic Myopathies. Current Rheumatology Reports 12:5, 386-393
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