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Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.

Biancalana, Valérie and Scheidecker, Sophie and Miguet, Marguerite and Laquerrière, Annie and Romero, Norma B and Stojkovic, Tanya and Abath Neto, Osorio and Mercier, Sandra and Voermans, Nicol and Tanner, Laura and Rogers, Curtis and Ollagnon-Roman, Elisabeth and Roper, Helen and Boutte, Célia and Ben-Shachar, Shay and Lornage, Xavière and Vasli, Nasim and Schaefer, Elise and Laforet, Pascal and Pouget, Jean and Moerman, Alexandre and Pasquier, Laurent and Marcorelle, Pascale and Magot, Armelle and Küsters, Benno and Streichenberger, Nathalie and Tranchant, Christine and Dondaine, Nicolas and Schneider, Raphael and Gasnier, Claire and Calmels, Nadège and Kremer, Valérie and Nguyen, Karine and Perrier, Julie and Kamsteeg, Erik Jan and Carlier, Pierre and Carlier, Robert-Yves and Thompson, Julie and Boland, Anne and Deleuze, Jean-François and Fardeau, Michel and Zanoteli, Edmar and Eymard, Bruno and Laporte, Jocelyn (2017) Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues. Acta neuropathologica, 134 (6). pp. 889-904. ISSN 1432-0533. This article is available to all HEFT staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their HEFT Athens login IDs

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Official URL: https://link.springer.com/article/10.1007%2Fs00401...

Abstract

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

Item Type: Article
Additional Information: This article is available to all HEFT staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their HEFT Athens login IDs
Subjects: QZ Pathology. Oncology
Divisions: Clinical Support > Pathology
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Depositing User: Mrs Caroline Tranter
Date Deposited: 28 Jun 2018 14:48
Last Modified: 28 Jun 2018 14:48
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/1674

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