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.

X连锁肌管肌病（XLMTM）是一种严重的先天性肌病，是由MTM1中的突变引起的基因位于X染色体上。大多数受影响的男性在产后早期死亡，而女性携带者通常无症状。然而，据报道有几位受影响的女性。为了评估携带者雌性的表型和病理光谱并描述诊断线索，我们鉴定了17位新的不相关的受影响雌性，并在临床，肌肉成像，组织学，超微结构和分子水平上与先前报道的病例进行了详细比较。综上所述，对这一庞大的43例队列的分析突出显示了广泛的临床严重程度，从严重的新生儿和全身虚弱（类似于XLMTM男性）到较轻度的成人形式。几位女性表现出呼吸功能下降。非对称性肌无力是一个值得注意的常见特定特征，可能与高度偏斜的X失活的患病率增加有关。还注意到增长的不对称性。其他诊断线索包括面部无力，上睑下垂和眼肌麻痹，骨骼和关节异常，以及作为中央核肌病特征的组织病理学迹象，例如中央核和项链纤维。组织病理学发现还表明，除了这些特定特征外，肌肉结构也普遍紊乱。因此，以及中心核肌病的标志性组织病理学标志，例如中央核和项链纤维。组织病理学发现还表明，除了这些特定特征外，肌肉结构也普遍紊乱。因此，以及中心核肌病的标志性组织病理学标志，例如中央核和项链纤维。组织病理学发现还表明，除了这些特定特征外，肌肉结构也普遍紊乱。因此，携带者雌性中的MTM1突变定义了一种特定的肌病，它可能与家族中XLMTM雄性的存在无关。由于一些报告的受影响女性携带通过Sanger测序无法检测到的大杂合MTM1缺失，并且由于存在较轻的表型作为成年发作的肢带肌病，该肌病的患病率很可能被低估了。该报告应有助于MTM1携带者女性的诊断，进而协助其临床管理和遗传咨询。此外，该队列的临床和病理史可能对XLMTM男性患者的治疗计划有用，因为它说明了长期存活的患者疾病可能演变的范围。