Congenital myopathies – centronuclear myopathies

The mode of inheritance of X-linked myotubular myopathy (XL-MTM) is currently considered recessive and the proportion of manifesting carriers is assumed low. We aimed to characterize the spectrum of clinical signs and symptoms in a cohort of female XL-MTM carriers, including prevalence, genetic features and associated disease burden. We performed a cross-sectional online questionnaire study among XL-MTM carriers, recruiting from patient associations, medical centres and registries in the United Kingdom, Germany and the Netherlands. We used a custom-made questionnaire, the checklist individual strength (CIS), the Frenchay activities index (FAI), the SF-12 health survey and the McGill pain questionnaire (MPQ). Carriers were classified as manifesting or non-manifesting, based on self-reported ambulation and muscle weakness. The prevalence of manifesting carriers in this study population (n=76) was 51%, subdivided into mild (independent ambulation, 39%), moderate (assisted ambulation, 9%) and severe (wheelchair-dependent, 3%) phenotypes. In addition to muscle weakness, manifesting carriers often reported fatigue (70%) and exercise intolerance (49%). Manifesting carriers scored higher on the overall CIS (p=0.001), the fatigue sub-scale (p<0.001) and least severe pain sub-scale (p=0.005) than non-manifesting carriers. They scored lower on the FAI (p=0.005) and the physical component of the SF-12 Health survey (p<0.001). The prevalence of manifesting female XL-MTM carriers may be higher than currently assumed, most having a mild phenotype and a wide variety of symptoms. Manifesting carriers are significantly affected by fatigue, limitations of daily activities, pain and reduced quality of life. The large percentage of manifesting carriers may indicate that inheritance of this X-linked disorder is not strictly recessive and symptomatic carriers are to be considered. Our findings should raise awareness and offer useful information for health care providers and clinical trials.