A Comprehensive Update on Late-Onset Pompe Disease

Abstract

Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments.

Keywords: chaperone; diagnosis; enzyme replacement therapy; gene therapy; late-onset Pompe disease; multi-system disease; myopathy.

Figure 1

Quadriceps muscle biopsy in patients with LOPD. (A) Hematoxylin-eosin staining showing the presence of intracytoplasmic vacuolization with a “rimmed” appearance (arrow). (B) Periodic acid-Schiff (PAS) staining on semi-fine section showing the presence of abnormal accumulation of intrafibral glycogen. (C,D) Acid phosphatase staining showing the presence of lysosomal activation in scattered fibers.