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J Neuropathol Exp Neurol. 2018 Dec 1;77(12):1101-1114. doi: 10.1093/jnen/nly095.

Loss of Sarcomeric Scaffolding as a Common Baseline Histopathologic Lesion in Titin-Related Myopathies.

Author information

1
Neuromuscular Morphology Unit, Myology Institute, GHU Pitié-Salpêtrière, Paris, France.
2
FISEVI-UGC Anatomía Patológica-HU Virgen del Rocío, Sevilla, Spain.
3
University of Granada, Granada, Spain.
4
AP-HP, GHU Pitié-Salpêtrière, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Paris, France.
5
Department of Translational Medicine, IGBMC, INSERM U1258, UMR7104, Strasbourg University, Illkirch, France.
6
Sorbonne University, INSERM UMRS974, GHU Pitié-Salpêtrière, Paris, France.
7
Assistance Publique-Hôpitaux de Paris (AP-HP), GH Cochin-Broca-Hôtel Dieu, Laboratoire de Biochimie et Génétique Moléculaire, Paris, France.
8
Complex Systems and Translational Bioinformatics, ICube, Strasbourg University, CNRS UMR7357, Illkirch, France.
9
Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
10
Hospital Nacional de Pediatría J.P. Garrahan and Instituto de Investigaciones Neurológicas FLENI, Buenos Aires, Argentina.
11
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Evry, France.
12
Genethon Institute, Evry, France.
13
Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland.
14
Folkhalsan Institute of Genetics, Helsinki University, Helsinki, Finland.

Abstract

Titin-related myopathies are heterogeneous clinical conditions associated with mutations in TTN. To define their histopathologic boundaries and try to overcome the difficulty in assessing the pathogenic role of TTN variants, we performed a thorough morphological skeletal muscle analysis including light and electron microscopy in 23 patients with different clinical phenotypes presenting pathogenic autosomal dominant or autosomal recessive (AR) mutations located in different TTN domains. We identified a consistent pattern characterized by diverse defects in oxidative staining with prominent nuclear internalization in congenital phenotypes (AR-CM) (n = 10), ± necrotic/regenerative fibers, associated with endomysial fibrosis and rimmed vacuoles (RVs) in AR early-onset Emery-Dreifuss-like (AR-ED) (n = 4) and AR adult-onset distal myopathies (n = 4), and cytoplasmic bodies (CBs) as predominant finding in hereditary myopathy with early respiratory failure (HMERF) patients (n = 5). Ultrastructurally, the most significant abnormalities, particularly in AR-CM, were multiple narrow core lesions and/or clear small areas of disorganizations affecting one or a few sarcomeres with M-band and sometimes A-band disruption and loss of thick filaments. CBs were noted in some AR-CM and associated with RVs in HMERF and some AR-ED cases. As a whole, we described recognizable histopathological patterns and structural alterations that could point toward considering the pathogenicity of TTN mutations.

PMID:
30365001
DOI:
10.1093/jnen/nly095

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