T.P.18: Late-onset Pompe disease: Histopathological, biochemical and clinical assessment before and after ERT

Abstract

Glycogenosis type II (OMIM 23230) is an autosomal recessive lysosomal storage disorder resulting from a deficiency in the glucosidase alpha acid (GAA) enzyme. The disease is characterized by progressive accumulation of lysosomal glycogen in various tissues, primarily heart and skeletal muscle, and it is clinically classified into three forms: infantile, juvenile, and late-onset. The histopathological hallmarks in muscle tissue are fiber vacuolization and autophagy. Recombinant human GAA is the only approved enzyme replacement therapy (ERT) available for disease treatment. It is effective in most infantile patients, whereas the improvement is quite variable in adults. We analyzed muscle biopsies from 14 late-onset patients at molecular, biochemical, and histopathological level before and after ERT. We evaluated the following morphological parameters: CSA, number of vacuolated fibers, degree of glycogen accumulation, percentage of vacuolization in type I and II fibers. Pre-treatment muscle biopsies showed marked histopathological variability ranging from almost normal morphology to severe vacuolar myopathy. Post-treatment muscle biopsies morphologically improved in seven patients, worsened in two patients and were unchanged in all the other subjects. Immunohistochemical analysis of the autophagic/lysosomal markers EEA1 (early endosome antigen 1), LC3 (microtubule-associated protein 1 light chain 3), and LAMP2 (lysosome associated membrane protein 2) showed a variable binding in both the first and the second biopsies. GAA enzymatic activity, tested by a fluorimetric assay in both lymphocytes and muscle tissue from 5 patients after ERT, was mildly increased in skeletal muscle compared with pre-treatment levels. Also, GAA expression assessed by immunoblotting slightly increased in a few patients. All patients clinically improved or remained stable after ERT.