French study published on largest ever cohort of x-linked female carriers. Read the full publication here.

It was thought that female carriers are usually asymptomatic but seldom show muscle weakness. The molecular, pathological and phenotypic spectrum of female carriers was thus unclear. The number of affected females is most probably underestimated and the absence of molecular diagnosis precludes better health care and genetic counselling to potentially assess the risk of having severely affected boys.
To clarify the spectrum of female carriers, the team of Biancalana et al analysed the largest cohort to date and compared new data to previously published cases.  Their key findings were :
-MTM1 carrier females display a recognisable myopathy, independently of the presence of affected males in the family.
-They show a wide spectrum of clinical severity ranging from severe neonatal and generalised weakness, similar to affected males, to milder adult forms.
-Several display a typical asymmetric muscle weakness but also skeletal asymmetry suggesting extra-muscular involvement. Additional diagnosis clues were identified using MRI and muscle biopsy.
These findings should assist the recognition, diagnosis and therefore the clinical management and genetic counselling of MTM1 carrier females. Furthermore, this data and population may be taken into account in therapeutic projects engaged by different biotechs on myotubular myopathy.

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 generalised 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 centralised nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganisation 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 counselling 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.

Dr Jocelyn Laporte
Department of Translational Medicine and Neurogentics