Glucose tetrasaccharide as a biomarker for monitoring the therapeutic response to enzyme replacement therapy for Pompe disease

A tetraglucose oligomer, Glc alpha 1-6Glc alpha 1-4Glc alpha 1-4Glc, designated Glc(4), has been shown to be a putative biomarker for the diagnosis of Pompe disease. The purpose of this study was to assess whether Glc(4) could be used to monitor the therapeutic response to recombinant human acid alpha glucosidase (rhGAA) enzyme replacement therapy (ERT) in patients with Pompe disease. Urinary Glc(4) levels in I I patients receiving rhGAA therapy was determined by both HPLC-UV and stable isotope dilution ESI-MS/MS. Combined Glc(4) and maltotetraose, Glc alpha 1-4Glc alpha 1-4Glc alpha 1-4Glc, (M-4) concentrations, designated Hex(4), in plasma from these patients were measured by HPLC-UV only. Baseline urinary Glc4 and plasma Hex(4) in these patients (mean +/- SD: 34.2 +/- 11.3 mmol/mol creatinine and 1.7 +/- 0.8 mu M, respectively) were higher than age-matched control values (mean +/- SE), 6.1 +/- 5.1 mmol/mol creatinine and 0.22 +/- 0.15 mu M, respectively). Both urinary Glc4 and plasma Hex(4) levels decreased after initiation of ERT for all patients. In the four patients with the best overall clinical response in both skeletal and cardiac muscle, levels decreased to within, or near, normal levels during the first year of treatment. In contrast, levels fluctuated and were persistently elevated above the control ranges in those patients with a less favorable clinical response (good cardiac response but limited motor improvement). These results suggest that urinary Glc(4) and plasma Hex(4) could serve as a valuable adjunct to clinical endpoints for monitoring the efficacy of therapeutic interventions such as rhGAA ERT in Pompe disease. (c) 2005 Elsevier Inc. All rights reserved.