T.P.24: Alglucosidase alfa reduces lysosomal glycogen in skeletal muscle biopsies of patients with late-onset Pompe disease (LOPD)

• Published in: Neuromuscular disorders : NMD Vol. 24; no. 9-10; pp. 871 - 872
• Main Authors: Thurberg, B.L., van der Ploeg, A., Kissel, J.T., Schoser, B., Pestronk, A., Barohn, R.J., Goker-Alpan, O., Mozaffar, T., Pena, L.D.M., Simmons, Z., Straub, V., Young, P., Bjartmar, C.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2014
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2014.06.260

Clearance of lysosomal glycogen has been shown after treatment with ERT (alglucosidase alfa) in LOPD patients. However, there is little data assessing glycogen clearance in ERT-treated LOPD patients. This Phase 4, controlled, prospective study evaluated skeletal muscle pathology and ERT response in ERT-naïve LOPD patients. Methods: 15 LOPD patients received alglucosidase alfa 20mg/kg bi-weekly for 24weeks. Quadriceps and deltoid biopsies were taken at baseline and week 26. Biopsies were prepared by HRLM and electron microscopy and assessed for glycogen accumulation and secondary pathology. Results: Evaluable baseline and 6-month quadriceps and deltoid biopsies were available for 13 and 10 patients, respectively. Baseline total glycogen (lysosomal plus cytoplasmic glycogen) levels were consistently higher in quadriceps than deltoid muscles. Total glycogen levels in most post-treatment quadriceps and deltoid biopsies were reduced or stable at 6months vs. baseline. Baseline biopsy examination showed that glycogen was present within lysosomes and in cytoplasm. Post-treatment biopsies revealed that remaining glycogen was overwhelmingly extra-lysosomal and lysosomal glycogen was qualitatively reduced. Secondary changes included occasional foci of autophagic debris. No fibrosis, inflammation or fatty replacement was observed. Conclusions: This is the first proof-of-concept assessment of the histopathologic effects of ERT in LOPD patients. ERT reduced lysosomal glycogen; extra-lysosomal, cytoplasmic glycogen remained in biopsies after 6months of ERT. This extra-lysosomal glycogen may evolve from the disruption of the lysosomal membrane and leakage of glycogen into the cytoplasm by the repetitive biomechanical forces of muscle contraction which occur in LOPD patients, but less so in IOPD patients. Early diagnosis and treatment of LOPD may translate into lysosomal glycogen clearance and prevention of further accumulation of cytoplasmic glycogen and cellular damage.