{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:32:17Z","timestamp":1790098337068,"version":"4.0.1"},"reference-count":103,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scholarship Galician Innovation Agency-GAIN","award":["IN607B 2025\/02"],"award-info":[{"award-number":["IN607B 2025\/02"]}]},{"name":"MPS-Lysosomal Families Association"},{"DOI":"10.13039\/501100004587","name":"\u201cInstituto de Salud Carlos III\u201d","doi-asserted-by":"crossref","award":["CP25\/00066"],"award-info":[{"award-number":["CP25\/00066"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"award":["CP25\/00066"],"award-info":[{"award-number":["CP25\/00066"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pompe disease (PD) is a rare, autosomal recessive neuromuscular disorder caused by mutations in the gene encoding acid alpha-glucosidase (GAA). The resulting deficiency in GAA, a lysosomal enzyme, leads to the pathological accumulation of glycogen, primarily in cardiac and skeletal muscles. PD presents as a clinical continuum spanning two major phenotypes: infantile-onset Pompe disease (IOPD), the most severe form, typically characterized by onset before 12 months of age, rapid hypertrophic cardiomyopathy, and severe hypotonia; and late-onset Pompe disease (LOPD), which manifests between 12 months of age and adulthood, and is characterized by progressive axial and proximal muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT), available since 2006, has improved survival, particularly in IOPD, but is limited by variable efficacy and limited penetration of the blood\u2013brain barrier, necessitating new approaches. In this comprehensive review, we focus on advances in the understanding and management of PD. First, we explore recent diagnostic advances and the characterization of multisystem involvement in PD. Next, we critically discuss the advantages and limitations of current ERT approaches, and advances achieved with next-generation ERT (avalglucosidase alfa, cipaglucosidase alfa + miglustat). Finally, we summarize cutting-edge, potentially curative strategies, including substrate reduction therapy and novel experimental therapies (e.g., gene therapy) that seek to circumvent the limitations of ERT, provide durable effects, and potentially penetrate the central nervous system.<\/jats:p>","DOI":"10.3390\/ijms27135726","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T08:14:12Z","timestamp":1782375252000},"page":"5726","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Comprehensive Update on Pompe Disease: From Existing Therapies to Emerging Curative Strategies"],"prefix":"10.3390","volume":"27","author":[{"given":"Rebeca","family":"Estevez Barcia","sequence":"first","affiliation":[{"name":"IDIS\u2014Health Research Institute of Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9711-2812","authenticated-orcid":false,"given":"Crist\u00f3bal","family":"Col\u00f3n","sequence":"additional","affiliation":[{"name":"IDIS\u2014Health Research Institute of Santiago de Compostela, 15706 Santiago de Compostela, Spain"},{"name":"Metabolic Unit, Clinical University Hospital of Santiago de Compostela, CIBERER, MetabERN, RICORS, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3757-262X","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Hermida-Ameijeiras","sequence":"additional","affiliation":[{"name":"Department of Forensic Sciences, Pathology, Gynecology and Obstetrics, Pediatrics, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2504-6008","authenticated-orcid":false,"given":"Laura","family":"L\u00f3pez-Valverde","sequence":"additional","affiliation":[{"name":"IDIS\u2014Health Research Institute of Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"IDIS\u2014Health Research Institute of Santiago de Compostela, 15706 Santiago de Compostela, Spain"},{"name":"Metabolic Unit, Clinical University Hospital of Santiago de Compostela, CIBERER, MetabERN, RICORS, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5151-988X","authenticated-orcid":false,"given":"Cristina","family":"Dom\u00ednguez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, Department of Neurology, Research Institute Imas12, Biomedical Network Research Centre on Rare Diseases (CIBERER), Hospital Universitario 12 de Octubre, Instituto de Salud Carlos III, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2941-7988","authenticated-orcid":false,"given":"Jordi","family":"D\u00edaz-Manera","sequence":"additional","affiliation":[{"name":"The John Walton Muscular Dystrophy Research Center, Newcastle University, Newcastle Upon Tyne NHS Trust, Newcastle upon Tyne NE1 3BZ, UK"},{"name":"Neuromuscular Disorders Laboratory, Insitut de Recerca de l\u2019Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Raras (CIBERER), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4861-9905","authenticated-orcid":false,"given":"Maria L.","family":"Couce","sequence":"additional","affiliation":[{"name":"IDIS\u2014Health Research Institute of Santiago de Compostela, 15706 Santiago de Compostela, Spain"},{"name":"Metabolic Unit, Clinical University Hospital of Santiago de Compostela, CIBERER, MetabERN, RICORS, 15706 Santiago de Compostela, Spain"},{"name":"Department of Forensic Sciences, Pathology, Gynecology and Obstetrics, Pediatrics, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3735-1341","authenticated-orcid":false,"given":"Jos\u00e9 Victor","family":"Alvarez","sequence":"additional","affiliation":[{"name":"IDIS\u2014Health Research Institute of Santiago de Compostela, 15706 Santiago de Compostela, Spain"},{"name":"Metabolic Unit, Clinical University Hospital of Santiago de Compostela, CIBERER, MetabERN, RICORS, 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Labella, B., Cotti Piccinelli, S., Risi, B., Caria, F., Damioli, S., Bertella, E., Poli, L., Padovani, A., and Filosto, M. 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