Tanya Stojkovic, neurologist, practices at the Institue of Myology in the reference centre for neuromuscular disorders of East of Paris pluridisciplinary consultation. In just a few months, a new disease caused by an enzyme deficiency was identified in one of her patient. The adult patient demonstrated exercise intolerance within a few minutes and had experienced two episodes of rhabdomyolysis. At the Institute, the close collaboration with the consultation department (P Laforet) and the Physiology and Neuromuscular Evaluation (JY Hogrel), Histopathology (K Claeys) and NMR laboratories (C Wary) in association with Danish and French (Lyon and Clamart) laboratories allowed the identification and characterization of this muscle glycogenosis. These results have just been published in the New England Journal of Medicine*.
What is the particular nature of this patient’s case?
We reported this patient’s case because this is the first case of this enzyme deficiency demonstrated by biochemical and genetic analysis, therefore, linked to the mutation of the phosphoglucomutase gene. This extremely rare deficiency has been reported in one adult case in 1992 in a Japanese publication ** but had not been genetically proven.
During consultation, we initially focused diagnosis for this patient to McArdle disease, but the normal elevation of lactate and the abnormal and significant increase in ammonia (at least 10 times above normal) in the grip test alerted us and refuted this hypothesis***. Keeping with the hypothesis of an enzyme deficiency during glycogenolysis, we assayed the enzymes at each step until we found the deficient enzyme. We then started the genetic study.
You insist on genetic evidence, what is its significance?
Given the rarity of the disease ****, we had to prove that there was, besides a profound deficiency in this enzyme, mutations in the gene. We were able to obtain DNA from the parents and in this patient we found a polymorphism inherited from his mother and two recessive pathogenic mutations, a missense mutation present in the patient's father and an intronic mutation (located on a donor splicing site), the other from his mother.
You've done other studies, what information did they provide?
The muscle biopsy was not very informative; there was very little accumulation of glycogen. NMR only showed a slightly higher level of creatine rephosphorylation. Measurements were made 10-15 minutes after exercise, which was probably too short to highlight more important anomalies.
However, in electromyography, the “long exercise” test, during which one measures the amplitude of the motor potential before and at different times after exercise (from 1 minute to 45 minutes after exercise) was interesting. The electromyogram showed a drop in the motor action potential after 20-25 minutes, directing us to an abnormality of muscle metabolism.
What have you concluded from this information?
We have concluded that this new disease was caused by the deficiency of phosphoglucomutase, an enzyme involved in glycogenolysis that catalyzes the transfer of a phosphate from position 1 to position 6 of glucose (see diagram below). In addition, this metabolic myopathy is characterized by exercise intolerance with episodes of rhabdomyolysis, a normal elevation of lactates during exercise, distinguishing it from McArdle disease. We therefore propose that this phosphoglucomutase deficiency be added to the list of glycogen storage diseases known as “glycogen storage disease type XIV”.