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Abstract Background Pompe disease is a rare lysosomal storage disorder characterized by muscle weakness and wasting. The majority of adult patients have slowly progressive disease, which gradually impairs mobility and respiratory function and may lead to wheelchair and ventilator dependency. It is as yet unknown to what extent the disease reduces the life span of these patients. Our objective was to determine the survival of adults with Pompe disease not receiving ERT and to identify prognostic factors associated with survival. Methods Data of 268 patients were collected in a prospective international observational study conducted between 2002 and 2009. Survival analyses from time of diagnosis and from time of study entry were performed using Kaplan-Meier curves and Cox-proportional-hazards regression. Results Median age at study entry was 48 years (range 19-79 years). Median survival after diagnosis was 27 years, while median age at diagnosis was 38 years. During follow-up, twenty-three patients died prior to ERT, with a median age at death of 55 (range 23-77 years). Use of wheelchair and/or respiratory support and patients' score on the Rotterdam Handicap Scale (RHS) were identified as prognostic factors for survival. Five-year survival for patients without a wheelchair or respiratory support was 95% compared to 74% in patients who were wheelchair-bound and used respiratory support. In a Dutch subgroup of 99 patients, we compared the observed number of deaths to the expected number of deaths in the age- and sex-matched general population. During a median follow-up of 2.3 years, the number of deaths among the Dutch Pompe patients was higher than the expected number of deaths in the general population. Conclusion Our study shows for the first time that untreated adults with Pompe disease have a higher mortality than the general population and that their levels of disability and handicap/participation are the most important factors associated with mortality. These results may be of relevance when addressing the effect of ERT or other potential treatment options on survival.

Background: Pompe disease is a rare metabolic myopathy for which disease-specific enzyme replacement therapy (ERT) has been available since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients. However, no data on the effect of ERT on the survival of adult patients are currently available. The aim of this study was to assess the effect of ERT on survival in adult patients with Pompe disease. Methods: Data were collected as part of an international observational study conducted between 2002 and 2011, in which patients were followed on an annual basis. Time-dependent Cox's proportional hazards models were used for univariable and multivariable analyses. Results: Overall, 283 adult patients with a median age of 48 years (range, 19 to 81 years) were included in the study. Seventy-two percent of patients started ERT at some time during follow-up, and 28% never received ERT. During follow-up (median, 6 years; range, 0.04 to 9 years), 46 patients died, 28 (61%) of whom had never received ERT. After adjustment for age, sex, country of residence, and disease severity (based on wheelchair and ventilator use), ERT was positively associated with survival (hazard ratio, 0.41; 95% CI, 0.19 to 0.87). Conclusion: This prospective study was the first to demonstrate the positive effect of ERT on survival in adults with Pompe disease. Given the relatively recent registration of ERT for Pompe disease, these findings further support its beneficial impact in adult patients. [ABSTRACT FROM AUTHOR]

Pompe disease is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), resulting in glycogen accumulation with profound pathology in skeletal muscle. We recently developed an optimized form of lentiviral gene therapy for Pompe disease in which a codon-optimized version of the GAA transgene (LV-GAAco) was fused to an insulin-like growth factor 2 (IGF2) peptide (LV-IGF2.GAAco), to promote cellular uptake via the cation-independent mannose-6-phosphate/IGF2 receptor. Lentiviral gene therapy with LV-IGF2.GAAco showed superior efficacy in heart, skeletal muscle, and brain of Gaa −/− mice compared to gene therapy with untagged LV-GAAco. Here, we used quantitative mass spectrometry using TMT labeling to analyze the muscle proteome and the response to gene therapy in Gaa −/− mice. We found that muscle of Gaa −/− mice displayed altered levels of proteins including those with functions in the CLEAR signaling pathway, autophagy, cytoplasmic glycogen metabolism, calcium homeostasis, redox signaling, mitochondrial function, fatty acid transport, muscle contraction, cytoskeletal organization, phagosome maturation, and inflammation. Gene therapy with LV-GAAco resulted in partial correction of the muscle proteome, while gene therapy with LV-IGF2.GAAco resulted in a near-complete restoration to wild type levels without inducing extra proteomic changes, supporting clinical development of lentiviral gene therapy for Pompe disease. Lysosomal glycogen accumulation is the primary cause of Pompe disease, and leads to a cascade of pathological events in cardiac and skeletal muscle and in the central nervous system. In this study, we identified the proteomic changes that are caused by Pompe disease in skeletal muscle of a mouse model. We showed that lentiviral gene therapy with LV-IGF2.GAAco nearly completely corrects disease-associated proteomic changes. This study supports the future clinical development of lentiviral gene therapy with LV-IGF2.GAAco as a new treatment option for Pompe disease. [Display omitted] • Quantitative mass spectrometry using TMT labelling of murine skeletal muscle. • Correction of Pompe disease proteome after ex vivo lentiviral gene therapy. • Efficacy and safety of IGF2-tagged GAA as a transgene for lentiviral gene therapy. [ABSTRACT FROM AUTHOR]

Abstract: We present a case of adult Pompe disease (acid maltase deficiency) with an uncommon clinical presentation characterized by severe fatigue and myalgia prior to the onset of limb girdle weakness. Remarkably, the muscle biopsy demonstrated selective involvement of type 1 muscle fibers. The cause and clinical effects of fiber type specific involvement are currently unknown, but the phenomenon might contribute to the clinical heterogeneity in Pompe disease and the variable response to enzyme replacement therapy. [Copyright &y& Elsevier]