Objective: To characterize the spectrum of clinical features in a cohort of X-linked myotubular myopathy (XL-MTM) carriers, including prevalence, genetic features, clinical symptoms and signs, as well as associated disease burden.

Methods: We performed a cross-sectional online questionnaire study among XL-MTM carriers. Participants were recruited from patient associations, medical centers 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.

Results: 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 frequently 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).

Conclusions: The prevalence of manifesting XL-MTM carriers may be higher than currently assumed, most having a mild phenotype and a wide variety of symptoms. Manifesting carriers are particularly affected by fatigue, limitations of daily activities, pain and reduced quality of life. Our findings should increase awareness and provide useful information for health care providers and future clinical trials.