Diagnosis: Myopathy

Phosphofructokinase deficiency (GSD type VII; PFK deficiency or Tarui disease) might be underdiagnosed because it presents with nonspecific exercise intolerance and myalgias. Until recently, Tarui disease could only be diagnosed by functional enzyme testing requiring muscle biopsy. The diagnostic evaluation has been simplified with the recent availability of gene testing. The remaining disorders are quite rare, with the exception of McArdle’s disease (GSD type V), and typically produce dynamic symptoms. Given the relatively common occurrence and characteristic clinical presentation, we will discuss McArdle’s disease in more detail here.

Figure 2: Histopathology, Case 3. A) Prominent ragged red fibers detected by trichrome Gomori staining, fulfilling a major criterion of the modified Walker diagnostic criteria. B) Electron micrograph demonstrating the presence of numerous mitochondrial aggregates containing variable numbers of mitochondria (arrow). Clusters of many misshapen mitochondria were common within these aggregates (inset).

Case 1

A 22-year-old male presented to the neuromuscular clinic with exertional myalgia and recurrent myoglobinuria. When the patient was a young child, his first symptoms were painful, transient contractures of his forearm finger flexors noted when climbing trees. Attacks became more frequent with age, and he first noticed dark urine associated with muscle cramping as a high school student. He did not report symptomatic improvement following short periods of rest. Physical examination was normal in clinic. There was no weakness, and no fasciculations or fixed contractures. His medical history and family history were noncontributory. Laboratory examination revealed an elevated CK (8,404 U/L; normal, 30–220 U/L), mild elevations of aspartate aminotransferase (75 U/L; normal, 15–41 U/L), and alanine aminotransferase (82 U/L; normal, 17–63 U/L). Urinalysis was negative for myoglobin. Routine muscle histology was unremarkable, but histochemical stains were not performed. EMG demonstrated mild myopathic changes. Molecular genetic testing revealed homozygosity for the common p.R49X mutation in the myophosphorylase (PYGM) gene.

The patient was diagnosed with McArdle’s disease, instructed to avoid isometric exercises, and encouraged to engage in regular aerobic exercise with a brief warm-up period. He was also instructed to consume a high-protein, low-carbohydrate diet with frequent small meals throughout the day, to ingest the equivalent of 40 grams of sucrose 30 minutes before vigorous exercise and to avoid statin medications.

McArdle’s Disease

GSD type V (McArdle’s disease or myophosphorylase deficiency) is caused by homozygous mutations in the PYGM gene, which encodes the skeletal muscle isoform of glycogen phosphorylase, also known as myophosphorylase, an essential enzyme for glycogenolysis. Because the heart and liver isoforms are not affected, the disease exclusively affects skeletal muscle.5 The typical age of onset is in late childhood. Patients develop symptoms during brief, isometric exercise such as weightlifting or during prolonged moderate intensity exercise such as jogging or swimming. Improvement in symptoms after a brief rest, the so-called “second-wind” phenomenon, is frequently reported. Approximately 50% of patients develop fixed weakness and muscle atrophy with aging.⁶