Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.
[en] Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.
Disciplines :
Neurology Pediatrics
Author, co-author :
Labasse, Clémence; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France
Brochier, Guy; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France
Taratuto, Ana-Lia; Neuropathology and Neuromuscular Diseases Laboratory, Buenos Aires, Argentina
Cadot, Bruno; Sorbonne Université, INSERM, Center for Research in Myology, Myology Institute, APHP, GHU Pitié-Salpêtrière, Paris, France
Rendu, John; Laboratoire de Biochimie Et Génétique Moléculaire, Pôle de Biologie, CHU Grenoble Alpes, Grenoble, France ; Université Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France
Monges, Soledad; Servucio de Neurología Et Neuropatología, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina
Biancalana, Valérie; Institut de Génétique Et de Biologie Moléculaire Et Cellulaire (IGBMC), Inserm U 1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France ; Laboratoire de Diagnostic Génétique, Faculté de Médecine, CHRU, Strasbourg, France
Quijano-Roy, Susana; APHP Université Paris-Saclay, Pediatric Neuromuscular Unit, Hôpital Universitaire Raymond-Poincaré, Université de Versailles Saint-Quentin-en-Yvelines, Garches, France
Bui, Mai Thao; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France
Chanut, Anaïs; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France
Madelaine, Angéline; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France
Lacène, Emmanuelle; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France
Beuvin, Maud; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France ; Sorbonne Université, INSERM, Center for Research in Myology, Myology Institute, APHP, GHU Pitié-Salpêtrière, Paris, France
Amthor, Helge; APHP Université Paris-Saclay, Pediatric Neuromuscular Unit, Hôpital Universitaire Raymond-Poincaré, Université de Versailles Saint-Quentin-en-Yvelines, Garches, France
Servais, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; Department of Paediatrics, MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
de Feraudy, Yvan; Institut de Génétique Et de Biologie Moléculaire Et Cellulaire (IGBMC), Inserm U 1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France ; Department of Neuropediatrics, Strasbourg University Hospital, Strasbourg, France
Erro, Marcela; Gutierrez Pediatric Hospital, Buenos Aires, Argentina
Saccoliti, Maria; Neuropathology and Neuromuscular Diseases Laboratory, Buenos Aires, Argentina
Neto, Osorio Abath; Institut de Génétique Et de Biologie Moléculaire Et Cellulaire (IGBMC), Inserm U 1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
Fauré, Julien; Laboratoire de Biochimie Et Génétique Moléculaire, Pôle de Biologie, CHU Grenoble Alpes, Grenoble, France ; Université Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neurosciences, Grenoble, France
Lannes, Béatrice; Department of Pathology, Strasbourg University Hospital, Strasbourg, France
Laugel, Vincent; Department of Neuropediatrics, Strasbourg University Hospital, Strasbourg, France
Coppens, Sandra; Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium
Lubieniecki, Fabiana; Servucio de Neurología Et Neuropatología, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina
Bello, Ana Buj; Université Paris-Saclay, Integrare Research Unit UMR S951, Inserm, Evry, France ; Généthon, Université Evry, Evry, France
Laing, Nigel; Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, Australia
Evangelista, Teresinha; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France ; Sorbonne Université, INSERM, Center for Research in Myology, Myology Institute, APHP, GHU Pitié-Salpêtrière, Paris, France
Laporte, Jocelyn; Institut de Génétique Et de Biologie Moléculaire Et Cellulaire (IGBMC), Inserm U 1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
Böhm, Johann; Institut de Génétique Et de Biologie Moléculaire Et Cellulaire (IGBMC), Inserm U 1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France
Romero, Norma B ; Myology Institute, Neuromuscular Morphology Unit, Reference Center of Neuromuscular Diseases Nord-Est-IDF, GHU Pitié-Salpêtrière, Paris, France. nb.romero@institut-myologie.org ; Sorbonne Université, INSERM, Center for Research in Myology, Myology Institute, APHP, GHU Pitié-Salpêtrière, Paris, France. nb.romero@institut-myologie.org
Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.
AFM - Association Française contre les Myopathies Institute of Myology Fondation Maladies Rares France Génomique NHMRC - National Health and Medical Research Council INSERM - French Institute of Health and Medical Research AISB - Society for the Study of Artificial Intelligence and Simulation of Behaviour University of Strasbourg CNRS - Centre National de la Recherche Scientifique
Funding text :
We thank Anne Boland and Jean-François Deleuze for their technical support in exome sequencing, Nicolas Dondaine in MYOdiagHTS sequencing, and Favienne Levy-Borsato for retrieving clinical data from ancient records. This work was supported by the Association Institute of Myology (AIM), Inserm, CNRS, University of Strasbourg, Labex INRT (ANR-10-LABX-0030, ANR-10-IDEX-0002-02), Association Française contre les Myopathies (AFM-22734), France Génomique (ANR-10-INBS-09) and Fondation Maladies Rares within the frame of the “Myocapture” sequencing project, and AFM-16992 and CREGEMES for the MYOdiagHTS sequencing. NGL was supported by Australian National Health and Medical Research Council Fellowship APP1117510.
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