• muscle
• metabolism
• neuromuscular
• diagnosis

In a recent paper published in the Journal of Clinical Pathology,1 we raised the clinical significance of hyperammonaemia after the non-ischaemic forearm exercise test (NIFET) in detecting various glycogen storage diseases (GSD). The results of this work revealed that hyperammonaemia may occur in several GSD. In absence of lactate rise (less than 0.8 mmol/L), severe hyperammonaemia (defined as a rise of more than 141 µmol/L) is generally a hallmark of myophosphorylase deficiency (McArdle disease).2 In the presence of lactate rise (more than 0.8 mmol/L), hyperammonaemia was observed in deficiency in debranching enzyme, in phosphorylase b-kinase and in phosphoglucomutase 1. We would like to add another GSD to the list of possible diagnoses: phosphoglycerate kinase 1 (PGK1) deficiency.

A man diagnosed in 1979 with a PGK1 deficiency recently underwent the NIFET following several new recent episodes of rhabdomyolysis. The case was thoroughly described previously.3 The first symptoms appeared at the age of five, with muscle stiffness and nausea during short, intense efforts. He had difficulties participating in sport during his childhood and adolescence. At 21, after a sprint race, he experienced paralysis of the four limbs followed by a first episode of rhabdomyolysis. He underwent a muscle biopsy which was not contributive for the diagnosis. At the age of 24, a second episode of painful paralysis occurred during swimming training. Several other episodes have occurred over the years, including a severe episode with renal failure after a dance party. An assessment of the glycolysis enzymes on red blood cells led to a biochemical diagnosis of the disease, which was confirmed much later by genetic testing, which revealed a c.943G>A (p.Asp315Asn) on exon 9 of the gene.

At last follow-up, the patient was aged 69.6 years (weight: 76 kg; height: 173 cm; body mass index: 25.4 kg/m²). He described no permanent symptoms; he was able to walk for more than 2½ hours and to climb stairs without assistance. Manual muscle testing was normal and he displayed normal grip strength (41.8 kg). Heart and respiratory evaluations, including forced vital capacity, were normal. The NIFET revealed a normal lactate rise and a substantial hyperammonaemia (figure 1). Creatine kinase (CK) was 544 UI the day of the NIFET and increased to 1920 UI 24 hours after the test. Previous assessments had shown variable increases in CK activities, the lowest figures always being above normal values (around 1.5 times the upper limit of reference values).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Plasma lactate and ammonia concentrations before and after handgrip exercise (isometric grip contraction at 70% of the maximal grip strength sustained during 30 s). Dotted lines correspond to upper and lower normal limits. the grey area symbolises exercise.

PGK1 deficiency is an X-linked recessive, rare disorder. The clinical spectrum includes central nervous system involvement and haemolytic anaemia which were absent in this patient. His family history includes a single other case (a nephew aged 11 years who developed a rhabdomyolysis episode and complained about long-standing exercise muscle contractures), with no genetic at this stage. The patient’s two daughters (aged 15 and 12 years old) harbour the mutation and are thus asymptomatic carriers. His mother died at age 77 years with no muscle illness.

In such a case of probable glycogenosis, suspected from repeated rhabdomyolysis episodes and fluctuating CK activities almost never decreasing to normal values, NIFET offers a useful support: associated hyperammonaemia and hyperCKemia helps restrict the number of possible enzymes implicated in a patient’s condition, and thus brings an important clue to the diagnosis, which will be confirmed on enzymatic assessment and genetic testing, when available. This algorithm is all the more important as muscle biopsy may be inconclusive, as was the case in the patient reported here.