Individualized Assessment of Exercise Capacity in Response to Acute and Long-Term Enzyme Replacement Therapy in Pediatric Pompe Disease.

Ronen Bar-Yoseph,Galit Tal,Merav Zucker-Toledano,Mira Jahshan,Hanna Mandel,Gur Mainzer,Elena Dumin,Moneera Hanna,Lea Bentur,George Shallufi

doi:10.3390/jpm11111105

Abstract

Background: Enzyme replacement therapy (ERT) with alglucosidase alfa improves the prospect of patients with infantile-onset Pompe disease (IOPD). However, a progressive decline has been reported. Objective quantification of the response to ERT when assessing newer strategies is warranted. Methods: This combined retrospective-prospective study assessed the acute and long-term effects of ERT on exercise in IOPD patients. Evaluation included cardiopulmonary exercise testing (CPET), 6-min walking test (6MWT), spirometry, motor function test (GMFM-88) and enzyme blood levels. Results: Thirty-four CPETs (17 pre- and 17 two days-post ERT) over variable follow-up periods were performed in four patients. Two days following ERT, blood enzyme levels increased (median, 1.22 and 10.15 μmol/L/h (p = 0.003)). However, FEV1, FVC and GMFM-88, the median 6MWD and the peak VO2 were unchanged. Long-term evaluations showed stabilization in young patients but progressive deterioration in adolescents. Clinical deterioration was associated with more pronounced deterioration in peak VO2 followed in the decreasing order by 6MWD, FVC and GMFM-88. Conclusions: The peak VO2 and 6MWD might serve as more sensitive markers to assess clinical deterioration. More studies are needed to clarify the sensitivity of the peak VO2 and 6MWT for quantification of individualized response. This may be important when assessing newer strategies and formulations in IOPD.

Highlights

Pompe disease is an inherited autosomal recessive glycogen storage disease caused by partial or total deficiency of acid α-glucosidase (GAA), resulting in massive accumulation of glycogen in lysosomes of different tissues
Different factors are considered to contribute to the clinical course [5], including age at initiation of Enzyme replacement therapy (ERT), extent of the baseline pathology, antibodies formation, cross-reactive immunologic material (CRIM) status [6], as well as explanations related to ERT distribution in skeletal muscle or other pathomechanisms, such as abnormal autophagy
Of the 10 infantile-onset Pompe disease (IOPD) patients followed by the metabolic unit, six patients were excluded

Summary

Introduction

Pompe disease is an inherited autosomal recessive glycogen storage disease caused by partial or total deficiency of acid α-glucosidase (GAA), resulting in massive accumulation of glycogen in lysosomes of different tissues. In infantile-onset Pompe disease (IOPD), there is complete or near complete loss of GAA activity, and patients present early in life with severe hypotony, hypertrophic cardiomyopathy and early death without treatment. Clinical studies in infants have shown that ERT led to complete resolution of cardiomyopathy and improvement in skeletal muscle functions with achievement of independent walking, higher levels of physical activity and survival beyond infancy [3,4]. Enzyme replacement therapy (ERT) with alglucosidase alfa improves the prospect of patients with infantile-onset Pompe disease (IOPD). More studies are needed to clarify the sensitivity of the peak VO2 and 6MWT for quantification of individualized response. This may be important when assessing newer strategies and formulations in IOPD

Methods

Results

Discussion

Conclusion