{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T11:36:35Z","timestamp":1793878595586,"version":"4.7.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T00:00:00Z","timestamp":1572220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T00:00:00Z","timestamp":1572220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004923","name":"AFM-T\u00e9l\u00e9thon","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-17-CE18-0014"],"award-info":[{"award-number":["ANR-17-CE18-0014"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Association Francophone des Glycog\u00e9noses"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n              <jats:p>Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by <jats:italic>AGL<\/jats:italic> gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene.<\/jats:p>\n              <jats:p>In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1\/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1\/p62 was also found in the GSDIII mouse model.<\/jats:p>\n              <jats:p>In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.<\/jats:p>\n              <jats:p>These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.<\/jats:p>","DOI":"10.1186\/s40478-019-0815-2","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T17:05:08Z","timestamp":1572282308000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment"],"prefix":"10.1186","volume":"7","author":[{"given":"Pascal","family":"Lafor\u00eat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michio","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyne","family":"Goillot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Lefeuvre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umut","family":"Cagin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Streichenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Leonard-Louis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Brochier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeline","family":"Madelaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemence","family":"Labasse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Hedberg-Oldfors","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Krag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa","family":"Jauze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Fabregue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Labrune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Milisenda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Nadaj-Pakleza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Sacconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Mingozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ronzitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Petit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Schoser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Oldfors","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Vissing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norma B.","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichizo","family":"Nishino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7871-8600","authenticated-orcid":false,"given":"Edoardo","family":"Malfatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,28]]},"reference":[{"key":"815_CR1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0076-6879(08)03612-4","volume":"452","author":"G Bj\u00f8rk\u00f8y","year":"2009","unstructured":"Bj\u00f8rk\u00f8y G, Lamark T, Pankiv S, \u00d8vervatn A, Brech A, Johansen T (2009) Monitoring autophagic degradation of p62\/SQSTM1. Methods Enzymol 452:181\u2013197. \n                    https:\/\/doi.org\/10.1016\/S0076-6879(08)03612-4","journal-title":"Methods Enzymol"},{"key":"815_CR2","doi-asserted-by":"publisher","unstructured":"Brambilla A, Mannarino S, Pretese R, Gasperini S, Galimberti C, Parini R. Improvement of cardiomyopathy after high-fat diet in two siblings with glycogen storage disease type III. JIMD Rep 2014;17:91\u201395. \n                    https:\/\/doi.org\/10.1007\/8904_2014_343","DOI":"10.1007\/8904_2014_343"},{"key":"815_CR3","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ymgme.2017.08.010","volume":"122","author":"V Decostre","year":"2017","unstructured":"Decostre V, Lafor\u00eat P, De Antonio M, Kachetel K, Canal A, Ollivier G, Nadaj-Pakleza A, Petit FM, Wahbi K, Fayssoil A, Eymard B, Behin A, Labrune P, Hogrel J-Y (2017) Long term longitudinal study of muscle function in patients with glycogen storage disease type IIIa. Mol Genet Metab 122:108\u2013116. \n                    https:\/\/doi.org\/10.1016\/j.ymgme.2017.08.010","journal-title":"Mol Genet Metab"},{"key":"815_CR4","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1002\/ana.410050504","volume":"5","author":"S DiMauro","year":"1979","unstructured":"DiMauro S, Hartwig GB, Hays A, Eastwood AB, Franco R, Olarte M, Chang M, Roses AD, Fetell M, Schoenfeldt RS, Stern LZ (1979) Debrancher deficiency: neuromuscular disorder in 5 adults. Ann Neurol 5:422\u2013436. \n                    https:\/\/doi.org\/10.1002\/ana.410050504","journal-title":"Ann Neurol"},{"key":"815_CR5","first-page":"1535","volume-title":"Myology","author":"S DiMauro","year":"2004","unstructured":"DiMauro S, Tsujino SHA (2004) Metabolic disorders affecting muscle. In: Myology. mcGraw-Hill, New York, pp 1535\u20131558"},{"key":"815_CR6","volume-title":"Muscle biopsy: a practical approach","author":"V Dubowitz","year":"2013","unstructured":"Dubowitz V, Sewry C, Oldfors A (2013) Muscle biopsy: a practical approach. Saunders Ltd., Philadelphia"},{"issue":"23","key":"815_CR7","doi-asserted-by":"publisher","first-page":"19094","DOI":"10.1074\/jbc.M111.322933","volume":"287","author":"RA Hanna","year":"2012","unstructured":"Hanna RA, Quinsay MN, Orogo AM, Giang K, Rikka S (2012) Gustafsson \u00c5B (2012) microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem 287(23):19094\u201319104. \n                    https:\/\/doi.org\/10.1074\/jbc.M111.322933","journal-title":"J Biol Chem"},{"key":"815_CR8","volume-title":"The metabolic and molecular bases of inherited diseases","author":"RRA Hirschhorn","year":"2001","unstructured":"Hirschhorn RRA (2001) Glycogen storage disease type II: acida-glucosidase(acid maltase) deficiency. n. In: Scriver CR, Beaudet AL, Valle D, Sly WS (eds) The metabolic and molecular bases of inherited diseases. McGraw-hill, New York"},{"key":"815_CR9","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/8904_2015_511","volume":"28","author":"IJ Hoogeveen","year":"2016","unstructured":"Hoogeveen IJ, van der Ende RM, van Spronsen FJ, de Boer F, Heiner-Fokkema MR, Derks TGJ (2016) (2015) Normoglycemic Ketonemia as biochemical presentation in Ketotic glycogen storage disease. JIMD Rep. 28:41\u201347","journal-title":"JIMD Rep."},{"key":"815_CR10","doi-asserted-by":"publisher","first-page":"8397","DOI":"10.1073\/pnas.1813351116","volume":"116","author":"L-J Kepser","year":"2019","unstructured":"Kepser L-J, Damar F, De Cicco T, Chaponnier C, Pr\u00f3szy\u0144ski TJ, Pagenstecher A, Rust MB (2019) CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function. Proc Natl Acad Sci 116:8397\u20138402. \n                    https:\/\/doi.org\/10.1073\/pnas.1813351116","journal-title":"Proc Natl Acad Sci"},{"key":"815_CR11","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1212\/WNL.55.8.1122","volume":"55","author":"P Laforet","year":"2000","unstructured":"Laforet P, Nicolino M, Eymard B, Puech JP, Caillaud C, Poenaru L, Fardeau M (2000) Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 55:1122\u20131128. \n                    https:\/\/doi.org\/10.1212\/WNL.55.8.1122","journal-title":"Neurology"},{"key":"815_CR12","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.nmd.2014.03.009","volume":"24","author":"L Merlini","year":"2014","unstructured":"Merlini L, Nishino I, Consortium for Autophagy in Muscular Dystrophies (2014) 201st ENMC international workshop: autophagy in muscular dystrophies--translational approach, 1-3 November 2013, Bussum, the Netherlands. Neuromuscul Disord 24:546\u2013561. \n                    https:\/\/doi.org\/10.1016\/j.nmd.2014.03.009","journal-title":"Neuromuscul Disord"},{"key":"815_CR13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.bbrc.2014.01.134","volume":"445","author":"L Min-ho","year":"2014","unstructured":"Min-ho L, Hyung-Nam S, Ji-Eun C, Lan TP, Sunghoon P, Jong-Tae P, Eui-Jeon W (2014) Association of bi-functional activity in the N-terminal domain of glycogen debranching enzyme. Biochem Biophys Res Commun 445:107\u2013112. \n                    https:\/\/doi.org\/10.1016\/j.bbrc.2014.01.134","journal-title":"Biochem Biophys Res Commun"},{"issue":"10","key":"815_CR14","doi-asserted-by":"publisher","first-page":"1698","DOI":"10.1038\/cdd.2012.52","volume":"19","author":"AC Nascimbeni","year":"2012","unstructured":"Nascimbeni AC, Fanin M, Masiero E, Angelini C, Sandri M (2012) The role of autophagy in the pathogenesis of glycogen storage disease type II (GSDII). Cell Death Differ 19(10):1698\u20131708. \n                    https:\/\/doi.org\/10.1038\/cdd.2012.52","journal-title":"Cell Death Differ"},{"key":"815_CR15","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1111\/nan.12414","volume":"44","author":"M Ripolone","year":"2018","unstructured":"Ripolone M, Violano R, Ronchi D, Mondello S, Nascimbeni A, Colombo I, Fagiolari G, Bordoni A, Fortunato F, Lucchini V, Saredi S, Filosto M, Musumeci O, Tonin P, Mongini T, Previtali S, Morandi L, Angelini C, Mora M, Sandri M, Sciacco M, Toscano A, Comi GP, Moggio M (2018) Effects of short-to-long term enzyme replacement therapy (ERT) on skeletal muscle tissue in late onset Pompe disease (LOPD). Neuropathol Appl Neurobiol 44:449\u2013462. \n                    https:\/\/doi.org\/10.1111\/nan.12414","journal-title":"Neuropathol Appl Neurobiol"},{"key":"815_CR16","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1001\/archneur.1973.00490220055008","volume":"28","author":"N Sakuragawa","year":"1973","unstructured":"Sakuragawa N (1973) Scanning Electron microscopic study of skeletal muscle. Arch Neurol 28:247. \n                    https:\/\/doi.org\/10.1001\/archneur.1973.00490220055008","journal-title":"Arch Neurol"},{"key":"815_CR17","first-page":"29","volume":"29","author":"E Sawicka","year":"1991","unstructured":"Sawicka E (1991) Origin of the ring muscle fibers in neuromuscular diseases. Neuropatol Pol 29:29\u201340","journal-title":"Neuropatol Pol"},{"key":"815_CR18","doi-asserted-by":"publisher","first-page":"2911","DOI":"10.1002\/ajmg.a.32529","volume":"146A","author":"B Schoser","year":"2008","unstructured":"Schoser B, Gl\u00e4ser D, M\u00fcller-H\u00f6cker J (2008) Clinicopathological analysis of the homozygous p.W1327X AGL mutation in glycogen storage disease type 3. Am J Med Genet Part A 146A:2911\u20132915. \n                    https:\/\/doi.org\/10.1002\/ajmg.a.32529","journal-title":"Am J Med Genet Part A"},{"key":"815_CR19","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1007\/s10545-016-9932-2","volume":"39","author":"CP Sentner","year":"2016","unstructured":"Sentner CP, Hoogeveen IJ, Weinstein DA, Santer R, Murphy E, McKiernan PJ, Steuerwald U, Beauchamp NJ, Taybert J, Lafor\u00eat P, Petit FM, Hubert A, Labrune P, Smit GPA, Derks TGJ (2016) Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome. J Inherit Metab Dis 39:697\u2013704. \n                    https:\/\/doi.org\/10.1007\/s10545-016-9932-2","journal-title":"J Inherit Metab Dis"},{"issue":"2","key":"815_CR20","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.ymgme.2012.12.002","volume":"108","author":"B Sun","year":"2013","unstructured":"Sun B, Fredrickson K, Austin S, Tolun AA, Thurberg BL, Kraus WE, Bali D, Chen YT, Kishnani PS (2013) Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III. Mol Genet Metab 108(2):145\u2013147. \n                    https:\/\/doi.org\/10.1016\/j.ymgme.2012.12.002\n                    \n                   Epub 2012 Dec 27","journal-title":"Mol Genet Metab"},{"key":"815_CR21","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1203\/PDR.0b013e318232154f","volume":"70","author":"V Valayannopoulos","year":"2011","unstructured":"Valayannopoulos V, Bajolle F, Arnoux J-B, Dubois S, Sannier N, Baussan C, Petit F, Labrune P, Rabier D, Ottolenghi C, Vassault A, Broissand C, Bonnet D, de Lonlay P (2011) Successful Treatment of Severe Cardiomyopathy in Glycogen Storage Disease Type III With D,L-3-Hydroxybutyrate, Ketogenic and High-Protein Diet. Pediatr Res 70:638\u2013641. \n                    https:\/\/doi.org\/10.1203\/PDR.0b013e318232154f","journal-title":"Pediatr Res"},{"key":"815_CR22","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.ymthe.2017.12.019","volume":"26","author":"P Vidal","year":"2018","unstructured":"Vidal P, Pagliarani S, Colella P, Costa Verdera H, Jauze L, Gjorgjieva M, Puzzo F, Marmier S, Collaud F, Simon Sola M, Charles S, Lucchiari S, van Wittenberghe L, Vignaud A, Gjata B, Richard I, Laforet P, Malfatti E, Mithieux G, Rajas F, Pietro CG, Ronzitti G, Mingozzi F (2018) Rescue of GSDIII phenotype with gene transfer requires liver- and muscle-targeted GDE expression. Mol Ther 26:890\u2013901. \n                    https:\/\/doi.org\/10.1016\/j.ymthe.2017.12.019","journal-title":"Mol Ther"},{"key":"815_CR23","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1007\/s00109-014-1127-4","volume":"92","author":"H Yi","year":"2014","unstructured":"Yi H, Brooks ED, Thurberg BL, Fyfe JC, Kishnani PS, Sun B (2014) Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med 92:641\u2013650. \n                    https:\/\/doi.org\/10.1007\/s00109-014-1127-4","journal-title":"J Mol Med"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-019-0815-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s40478-019-0815-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-019-0815-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T00:47:09Z","timestamp":1603759629000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-019-0815-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,28]]},"references-count":23,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["815"],"URL":"https:\/\/doi.org\/10.1186\/s40478-019-0815-2","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,28]]},"assertion":[{"value":"24 July 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"We confirm that we have read the Journal\u2019s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All patients gave informed consent prior to having a muscle biopsy performed.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"G.R. and F.M. are inventors in patents related to the development of gene therapy strategies for GSDIII. All other authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"167"}}