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Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment

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Laforêt, P, Inoue, M, Goillot, E, Lefeuvre, C, Cagin, U, Streichenberger, N, Leonard-Louis, S, Brochier, G, Madelaine, A, Labasse, C, Hedberg-Oldfors, C, Krag, T, Jauze, L, Fabregue, J, Labrune, P, Milisenda, J, Nadaj-Pakleza, A, Sacconi, S, Mingozzi, F, Ronzitti, G, Petit, F, Schoser, B, Oldfors, A, Vissing, J, Romero, NB, Nishino, I & Malfatti, E 2019, 'Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment' Acta neuropathologica communications, bind 7, nr. 1, s. 167. https://doi.org/10.1186/s40478-019-0815-2

APA

CBE

Laforêt P, Inoue M, Goillot E, Lefeuvre C, Cagin U, Streichenberger N, Leonard-Louis S, Brochier G, Madelaine A, Labasse C, Hedberg-Oldfors C, Krag T, Jauze L, Fabregue J, Labrune P, Milisenda J, Nadaj-Pakleza A, Sacconi S, Mingozzi F, Ronzitti G, Petit F, Schoser B, Oldfors A, Vissing J, Romero NB, Nishino I, Malfatti E. 2019. Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment. Acta neuropathologica communications. 7(1):167. https://doi.org/10.1186/s40478-019-0815-2

MLA

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Author

Laforêt, Pascal ; Inoue, Michio ; Goillot, Evelyne ; Lefeuvre, Claire ; Cagin, Umut ; Streichenberger, Nathalie ; Leonard-Louis, Sarah ; Brochier, Guy ; Madelaine, Angeline ; Labasse, Clemence ; Hedberg-Oldfors, Carola ; Krag, Thomas ; Jauze, Louisa ; Fabregue, Julien ; Labrune, Philippe ; Milisenda, Jose ; Nadaj-Pakleza, Aleksandra ; Sacconi, Sabrina ; Mingozzi, Federico ; Ronzitti, Giuseppe ; Petit, François ; Schoser, Benedikt ; Oldfors, Anders ; Vissing, John ; Romero, Norma B ; Nishino, Ichizo ; Malfatti, Edoardo. / Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment. I: Acta neuropathologica communications. 2019 ; Bind 7, Nr. 1. s. 167.

Bibtex

@article{b43f4cf26c7745b0902601070756c924,
title = "Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment",
abstract = "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 AGL 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.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.In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.",
author = "Pascal Lafor{\^e}t and Michio Inoue and Evelyne Goillot and Claire Lefeuvre and Umut Cagin and Nathalie Streichenberger and Sarah Leonard-Louis and Guy Brochier and Angeline Madelaine and Clemence Labasse and Carola Hedberg-Oldfors and Thomas Krag and Louisa Jauze and Julien Fabregue and Philippe Labrune and Jose Milisenda and Aleksandra Nadaj-Pakleza and Sabrina Sacconi and Federico Mingozzi and Giuseppe Ronzitti and Fran{\cc}ois Petit and Benedikt Schoser and Anders Oldfors and John Vissing and Romero, {Norma B} and Ichizo Nishino and Edoardo Malfatti",
year = "2019",
month = "10",
day = "28",
doi = "10.1186/s40478-019-0815-2",
language = "English",
volume = "7",
pages = "167",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",

}

RIS

TY - JOUR

T1 - Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment

AU - Laforêt, Pascal

AU - Inoue, Michio

AU - Goillot, Evelyne

AU - Lefeuvre, Claire

AU - Cagin, Umut

AU - Streichenberger, Nathalie

AU - Leonard-Louis, Sarah

AU - Brochier, Guy

AU - Madelaine, Angeline

AU - Labasse, Clemence

AU - Hedberg-Oldfors, Carola

AU - Krag, Thomas

AU - Jauze, Louisa

AU - Fabregue, Julien

AU - Labrune, Philippe

AU - Milisenda, Jose

AU - Nadaj-Pakleza, Aleksandra

AU - Sacconi, Sabrina

AU - Mingozzi, Federico

AU - Ronzitti, Giuseppe

AU - Petit, François

AU - Schoser, Benedikt

AU - Oldfors, Anders

AU - Vissing, John

AU - Romero, Norma B

AU - Nishino, Ichizo

AU - Malfatti, Edoardo

PY - 2019/10/28

Y1 - 2019/10/28

N2 - 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 AGL 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.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.In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

AB - 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 AGL 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.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.In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

U2 - 10.1186/s40478-019-0815-2

DO - 10.1186/s40478-019-0815-2

M3 - Journal article

VL - 7

SP - 167

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

IS - 1

ER -

ID: 58350333