Objectives: As X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcomes measures. Methods: We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored. Results: Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), seven had an intermediate phenotype (ventilation support less than 12 hours a day), and twenty-five had a severe phenotype (ventilation support equal to or greater than 12 hours a day). Most strength and motor function assessments could be performed even in very weak patients. MFM32 total score, grip and pinch strengths, and FVC, FEV1 and PCF measures discriminated the three groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients shown a MFM32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti-AAV8 neutralizing activity was detected in 26% with two patients having an inhibitory titer >1:10. Conclusions: Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population. NCT02057705.

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