β‐enolase deficiency, a new metabolic myopathy of distal glycolysis

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Abstract
A severe muscle enolase deficiency, with 5% of residual activity, was detected in a 47‐year‐old man affected with exercise intolerance and myalgias. No rise of serum lactate was observed with the ischemic forearm exercise. Ultrastructural analysis showed focal sarcoplasmic accumulation of glycogen β particles. The enzyme enolase catalyzes the interconversion of 2‐phosphoglycerate and phosphoenolpyruvate. In adult human muscle, over 90% of enolase activity is accounted for by the β‐enolase subunit, the protein product of the ENO3 gene. The β‐enolase protein was dramatically reduced in the muscle of our patient, by both immunohistochemistry and immunoblotting, while α‐enolase was normally represented. The ENO3 gene of our patient carries two heterozygous missense mutations affecting highly conserved amino acid residues: a G467A transition changing a glycine residue at position 156 to aspartate, in close proximity to the catalytic site, and a G1121A transition changing a glycine to glutamate at position 374. These mutations were probably inherited as autosomal recessive traits since the mother was heterozygous for the G467A and a sister was heterozygous for the G1121A transition. Our data suggest that ENO3 mutations result in decreased stability of mutant β‐enolase. Muscle β‐enolase deficiency should be considered in the differential diagnosis of metabolic myopathies due to inherited defects of distal glycolysis.