Journal article
Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies
Acta neuropathologica communications, Vol.10(1), pp.1-19
07/01/2022
DOI: 10.1186/s40478-022-01400-0
PMCID: PMC9271256
PMID: 35810298
Abstract
Abstract 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.
Details
- Title: Subtitle
- Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies
- Creators
- Clémence Labasse - Institut de MyologieGuy Brochier - Institut de MyologieAna-Lia Taratuto - Neuropathology and Neuromuscular Diseases Laboratory, Buenos Aires, Argentina.Bruno Cadot - Institut de MyologieJohn Rendu - Université Grenoble AlpesSoledad Monges - Garrahan HospitalValérie Biancalana - Université de StrasbourgSusana Quijano-Roy - Université de Versailles Saint-Quentin-en-YvelinesMai Thao Bui - Institut de MyologieAnaïs Chanut - Institut de MyologieAngéline Madelaine - Institut de MyologieEmmanuelle Lacène - Institut de MyologieMaud Beuvin - Institut de MyologieHelge Amthor - Université de Versailles Saint-Quentin-en-YvelinesLaurent Servais - University of LiègeYvan de Feraudy - Université de StrasbourgMarcela Erro - Hospital General de Niños Ricardo GutierrezMaria Saccoliti - Neuropathology and Neuromuscular Diseases Laboratory, Buenos Aires, Argentina.Osorio Abath Neto - PathologyJulien Fauré - Université Grenoble AlpesBéatrice Lannes - Université de StrasbourgVincent Laugel - Université de StrasbourgSandra Coppens - Université Libre de BruxellesFabiana Lubieniecki - Garrahan HospitalAna Buj Bello - Université Paris-SaclayNigel Laing - Harry Perkins Institute of Medical ResearchTeresinha Evangelista - Institut de MyologieJocelyn Laporte - Université de StrasbourgJohann Böhm - Université de StrasbourgNorma B. Romero - Institut de Myologie
- Resource Type
- Journal article
- Publication Details
- Acta neuropathologica communications, Vol.10(1), pp.1-19
- DOI
- 10.1186/s40478-022-01400-0
- PMID
- 35810298
- PMCID
- PMC9271256
- NLM abbreviation
- Acta Neuropathol Commun
- ISSN
- 2051-5960
- eISSN
- 2051-5960
- Publisher
- BMC
- Grant note
- DOI: 10.13039/100007393, name: Association Française contre les Myopathies, award: AFM-22734; name: Association Institute of Myology; DOI: 10.13039/100014865, name: Fondation Maladies Rares; name: France Génomique, award: (ANR-10-INBS-09); name: Australian National Health and Medical Research Council; name: Inserm, CNRS, University of Strasbourg; DOI: 10.13039/100014655, name: Society for the Study of Artificial Intelligence and the Simulation of Behaviour
- Language
- English
- Date published
- 07/01/2022
- Academic Unit
- Pathology
- Record Identifier
- 9984276455702771
Metrics
8 Record Views