Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies
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Published:2022-07-09
Issue:1
Volume:10
Page:
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ISSN:2051-5960
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Container-title:Acta Neuropathologica Communications
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language:en
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Short-container-title:acta neuropathol commun
Author:
Labasse Clémence, Brochier Guy, Taratuto Ana-Lia, Cadot Bruno, Rendu John, Monges Soledad, Biancalana Valérie, Quijano-Roy Susana, Bui Mai Thao, Chanut Anaïs, Madelaine Angéline, Lacène Emmanuelle, Beuvin Maud, Amthor Helge, Servais Laurent, de Feraudy Yvan, Erro Marcela, Saccoliti Maria, Neto Osorio Abath, Fauré Julien, Lannes Béatrice, Laugel Vincent, Coppens Sandra, Lubieniecki Fabiana, Bello Ana Buj, Laing Nigel, Evangelista Teresinha, Laporte Jocelyn, Böhm Johann, Romero Norma B.ORCID
Abstract
AbstractNemaline 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.
Funder
Association Française contre les Myopathies Association Institute of Myology Fondation Maladies Rares France Génomique Australian National Health and Medical Research Council Inserm, CNRS, University of Strasbourg Society for the Study of Artificial Intelligence and the Simulation of Behaviour
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
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