ARTICLE Level of residual enzyme activity modulates the phenotype in phosphoglycerate kinase deficiency John Vissing, MD, H. Orhan Akman, PhD, Jan Aasly, MD, Stephen G. Kahler, MD, Carlos A. Bacino, MD, Salvatore DiMauro, MD, and Ronald G. Haller, MD Neurology ® 2018;00:e1-e6. doi:10.1212/WNL.0000000000006165 Correspondence Dr. Vissing vissing@rh.dk Abstract Objective To study the variable clinical picture and exercise tolerance of patients with phosphoglycerate kinase (PGK) 1 deficiency and how it relates to residual PGK enzyme activity. Methods In this case series study, we evaluated 7 boys and men from 5 families with PGK1 deficiency. Five had pure muscle symptoms, while 2 also had mild intellectual disability with or without anemia. Muscle glycolytic and oxidative capacities were evaluated by an ischemic forearm exercise test and by cycle ergometry. Results Enzyme levels of PGK were 4% to 9% of normal in red cells and 5% to10% in muscle in pure myopathy patients and 2.6% in both muscle and red cells in the 2 patients with multisystem involvement. Patients with pure myopathy had greater increases in lactate with ischemic ex- ercise (2–3 mmol/L) vs the 2 multisystem-affected patients (<1 mmol/L). Myopathy patients had higher oxidative capacity in cycle exercise vs multisystem affected patients (≈30 vs ≈15 mL/kg per minute). One multisystem-affected patient developed frank myoglobinuria after the short exercise test. Conclusions This case series study of PGK1 deficiency suggests that the level of impaired glycolysis in PGK deficiency is a major determinant of phenotype. Lower glycolytic capacity in PGK1 deficiency seems to result in multisystem involvement and increased susceptibility to exertional rhabdomyolysis. From the Department of Neurology (J.V.), University of Copenhagen, Denmark; Department of Neurology (O.A., S.D.), Columbia University, New York, NY; Department of Neurology (J.A.), St. Olavs Hospital; NTNU (J.A.), Trondheim, Norway; Department of Pediatrics (S.G.K.), University of Arkansas School for Medical Sciences, Little Rock; Department of Molecular and Human Genetics (C.A.B.), Baylor College of Medicine, Houston, TX; Neuromuscular Center (R.G.H.), Institute for Exercise and Environmental Medicine of Texas Health Presbyterian Hospital; and Department of Neurology and Neurotherapeutics (R.G.H.), University of Texas Southwestern Medical Center, Dallas. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. Copyright © 2018 American Academy of Neurology e1 Copyright ª 2018 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Published Ahead of Print on August 15, 2018 as 10.1212/WNL.0000000000006165