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


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.

DOI: 10.1007/s00401-017-1748-0

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@article{Biancalana2017AffectedFC, title={Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues}, author={Val{\'e}rie Biancalana and Sophie Scheidecker and Marguerite Miguet and Annie Laqu{\'e}rriere and Norma Beatriz Romero and Tanya Stojkovic and Os{\'o}rio Lopes Abath Neto and Sandra Mercier and Nicol C. Voermans and Laura M. Tanner and Curtis R Rogers and Elisabeth Ollagnon-Roman and Helen Roper and C{\'e}lia Boutte and Shay Ben-Shachar and Xavi{\`e}re Lornage and Nasim Vasli and Elise Schaefer and Pascal Laf{\^o}ret and Jean Pouget and Alexandre Moerman and Laurent Pasquier and Pascale Marcorelle and Armelle Magot and Benno Kuesters and Nathalie Streichenberger and Christine Tranchant and Nicolas Dondaine and Raphael Schneider and Claire Gasnier and Nad{\`e}ge Calmels and Val{\'e}rie Kremer and Karine Nguyen and Julie Perrier and Erik Jan Kamsteeg and Pierre G. Carlier and Robert Carlier and Julie Dawn Thompson and Anne Boland and J Deleuze and Michel Fardeau and Edmar Zanoteli and Bruno Eymard and Jocelyn Laporte}, journal={Acta Neuropathologica}, year={2017}, volume={134}, pages={889-904} }