PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry

Mari Auranen; Johanna Palmio; Emil Ylikallio; Sanna Huovinen; Anders Paetau; Satu Sandell; Hannu Haapasalo; Kati Viitaniemi; Päivi Piirilä; Henna Tyynismaa; Bjarne Udd

doi:10.1212/NXG.0000000000000007

PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry

Neurol Genet. 2015 Jun 4;1(1):e7. doi: 10.1212/NXG.0000000000000007. eCollection 2015 Jun.

Authors

Affiliation

¹ Research Programs Unit (M.A., E.Y., H.T.), Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Clinical Neurosciences (M.A.), Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Neuromuscular Research Center (J.P., S.S., K.V., B.U.), Tampere University Hospital and University of Tampere, Tampere, Finland; Department of Pathology (S.H., H.H.), Fimlab Laboratories, University Hospital and University of Tampere, Tampere, Finland; Department of Pathology (A.P.), HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Neurology (S.S.), Seinäjoki Central Hospital, Seinäjoki, Finland; and Unit of Clinical Physiology (P.P.), HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland.

Abstract

Objective: To elaborate the diagnostic methods used as "gold standard" in one of the most common glycogen storage diseases (GSDs), Tarui disease (GSDVII).

Methods: Two siblings with disease suggestive of GSD underwent thorough clinical analysis, including muscle biopsy, muscle MRI, exercise tests, laboratory examinations, and whole-exome sequencing (WES).

Results: Both siblings had juvenile-onset exercise intolerance with cramping and infrequent myoglobinuria. Muscle biopsy showed extralysosomal glycogen accumulation, but because of normal phosphofructokinase histochemistry, GSDVII was thought to be excluded. However, WES revealed a causative homozygous PFKM gene defect, R39Q, in both siblings, establishing the diagnosis of GSDVII, which was confirmed by very low residual phosphofructo-1-kinase (PFK) enzyme activity in biochemical studies.

Conclusions: We suggest that in patients with suspicion of GSD and extralysosomal glycogen accumulation, biochemical activity assay of PFK followed by molecular genetics should be performed even when enzyme histochemistry is normal.