An international, prospective study on the natural history of X-linked myotubular myopathy

An article published in April in Neurology reports the work of a team of international experts including I-Motion clinicians and researchers from the Institute of Myology. The authors designed an international, prospective and longitudinal study of the natural history of patients with X-lined myotubular myopathy. Interview with Melanie Annoussamy, the first author of the article.

In what context was this international study designed?
The natural history study of patients with Myotubular Myopathy (NatHis-MTM) (centronuclear myopathy linked to a mutation of the MTM1 gene) was initiated in 2014. This study, carried out in the USA, Canada and Europe (France, Germany, Italy, Spain, Belgium) was financed for 3 years by Valerion Therapeutics and Genethon. In Europe, we wanted to continue this study and Dynacure accepted to finance 3 supplementary years with the hope of enlarging the study to include patients with centronuclear myopathy linked to a mutation of the MTM1 gene. In total, 60 patients were included in Europe and 52 are still part of the ongoing study.

What are the objectives?
We have 5 objectives for this study. First to characterize the history of the disease in patients with centronuclear myopathy (CNM) by way of standardized analysis. Then to identify the prognostic variables of the disease; also identify the best evaluation criteria for future therapeutic approaches. Then evaluate the immune response against AAV (for patients included between May 2014 and May 2017). Finally, to participate in the development of treatments against central-nuclear myopathy by collecting blood samples for biomarker research and the development of medicines in the CNM conducted under the responsibility of Dynacure or an eventual third party to whom the research activities in the CNM of Dynacure will be transferred (for patients included from June 2017).

How and to what aim(s) were the evaluation criteria determined? Specifically, why were the AAV8 immune responses monitored in a natural history study in which patients are not undergoing treatment?
Evaluation criteria were selected to evaluate the strength of the superior dominant member, muscular function, liver function and quality of life in a standardized manner. The analyses were chosen from evaluations commonly used in neuro-muscular diseases. Concerning the AAV8 immune response, we wish to conduct the evaluations in light of gene therapy trials.

What was the role of I-Motion in the study?
During the first 3 years of the study, Valerion therapeutics was the sponsor of the study. Valerion delegated the complete responsibility of the promotion of the study in Europe to AIM. Nevertheless, the I-motion team, initially based at the Pitié hospital, designed the study with Valerion, wrote the protocol, conducted the regulatory submissions in France, Germany, Italy, Spain, and Belgium, set up the study, ensured the follow-up and quality control, analyzed the data and wrote the article.

Is a continuation of the study planned?
The study is still in ongoing in Europe with 60 patients included and 52 patients still undergoing evaluation in the study.


X-linked myotubular myopathy: A prospective international natural history study. Annoussamy M, Lilien C, Gidaro T, Gargaun E, Chê V, Schara U, Gangfuß A, D’Amico A, Dowling JJ, Darras BT, Daron A, Hernandez A, de Lattre C, Arnal JM, Mayer M, Cuisset JM, Vuillerot C, Fontaine S, Bellance R, Biancalana V, Buj-Bello A, Hogrel JY, Landy H, Servais L. Neurology. 2019 Mar 22. pii: 10.1212/WNL.0000000000007319. doi: 10.1212/WNL.0000000000007319. [Epub ahead of print]


On NCT02057705