Effects of short-to-long term enzyme replacement therapy (ERT) on skeletal muscle tissue in late onset Pompe disease (LOPD)

Neuropathol Appl Neurobiol 2018 Aug;44(5):449-462. doi: 10.1111/nan.12414. Epub 2017 Jul 4.

PMID: 28574618

M Ripolone, R Violano, D Ronchi

Highlights: The goal of this study was to look at ERT-related skeletal muscle alterations as well as the connection between morphological/biochemical changes and clinical outcomes in patients with late-onset Pompe disease (LOPD). In the majority of LOPD patients, ERT improved skeletal muscle pathology, as well as motor and respiratory outcomes.

Abstract

Aims: The deficiency of the acid α-glucosidase (GAA) enzyme causes Pompe disease, which is an autosomal recessive lysosomal storage disorder. Fibre vacuolization and autophagy are histopathological markers in skeletal muscle tissue. With human recombinant GAA alglucosidase alfa, enzyme replacement therapy (ERT) has been the only approved treatment since 2006. The goal of this study was to look at ERT-related skeletal muscle alterations in 18 individuals with late-onset Pompe disease (LOPD) who were mildly to moderately affected, as well as the connection between morphological/biochemical changes and clinical outcomes. Treatment duration was short-to-long term.

Methods: Muscle biopsies from 18 individuals with LOPD were evaluated histopathologically and biochemically. Before and after ERT treatment, all patients received two muscle biopsies. Because the initial biopsies were collected before the study was designed, the study is partially retrospective, whereas the second biopsy was always conducted after at least 6 months of ERT treatment.

Results: After ERT, 15 of 18 patients improved on the 6-minute walking test (6MWT; P = 0.0007), and the majority of them achieved respiratory stabilization. Muscle samples taken before to therapy revealed a wide range of histological patterns, ranging from nearly normal to severe vacuolar myopathy. We found morphological improvement in 15 patients after therapy and deterioration in three cases. In all patients, post-ERT GAA enzymatic activity was slightly higher than pretreatment values. The mature enzyme protein levels increased in 14 of the 18 patients (mean increase = 35%; P=0.05). According to additional studies, autophagic flux improved following ERT in some patients.

Conclusions: In the majority of LOPD patients, ERT improved skeletal muscle pathology, as well as motor and respiratory outcomes.

Keywords: Pompe disease, acid alpha-glucosidase deficiency, autophagy, enzyme replacement therapy