Biochemical and molecular genetic identification of patients with phosphoglycerate mutase deficiency

Phosphoglycerate mutase (PGAM) deficiency is an autosomal recessive glycogenosis (type X) characterised by exercise induced cramps, myalgia, and myoglobinuria. Myohistological features are glycogen deposition and tubular aggregates. Biochemically there is low muscle PGAM activity (most patients below 10%) but few manifesting heterozygotes with 50% activity are reported. Molecular genetic investigations have revealed 4 mutations among 13 patients, so far. A nonsense mutation W78X is frequent in patients of African origin.

We performed biochemical and molecular genetic investigation (sequencing of the coding region of PGAM gene) in 10 patients with signs that are consistent with PGAM deficiency: exercise induced cramps/myalgia (n=10), glycogen accumulation (n=10), and tubular aggregates (n=5). Pompe and McArdle diseases were excluded.

PGAM activity was moderately reduced in 5 patients (57–70% of lower normal value) and severely reduced (4%) in 1 patient. The latter was a 37-year-old patient of African origin, who carried the W78X mutation in homozygous state. He suffered from exercise induced myalgia for 2 years. Muscle biopsy showed tubular aggregates. In a 67-year-old German patient with exercise induced cramps and myalgia for 1 year, a novel heterozygous missense mutation E154K was identified. This E154K mutation affects a highly conserved amino acid and was not present in 40 normal controls. No second mutation was identified. Residual activity of PGAM was 58% and there were tubular aggregates, too. In 3 other patients with reduced PGAM activity, no mutation was detected.

Our study confirms that tubular aggregates together with glycogen deposition are characteristic features of PGAM deficiency. However, these features are not highly specific for PGAM deficiency. Moreover, the study highlights that there are manifesting heterozygotes and very late-onset is possible. Undetected mutations in intronic or promoter regions might be responsible for PGAM deficiency in those patients without identified mutations.