P.105INCEPTUS pre-phase 1, prospective, non-interventional, natural history run-in study to evaluate subjects aged 4 years and younger with X-linked myotubular myopathy (XLMTM)

2019 ◽  
Vol 29 ◽  
pp. S79 ◽  
Author(s):  
L. Servais ◽  
P. Shieh ◽  
J. Dowling ◽  
N. Kuntz ◽  
W. Müller-Felber ◽  
...  
2015 ◽  
Vol 25 ◽  
pp. S274
Author(s):  
N. R'guiba ◽  
M. Annoussamy ◽  
R. Cardas ◽  
C. Lilien ◽  
G. Ollivier ◽  
...  

Neurology ◽  
2019 ◽  
Vol 92 (16) ◽  
pp. e1852-e1867 ◽  
Author(s):  
Mélanie Annoussamy ◽  
Charlotte Lilien ◽  
Teresa Gidaro ◽  
Elena Gargaun ◽  
Virginie Chê ◽  
...  

ObjectivesBecause 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 outcome measures.MethodsWe 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.ResultsForty-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), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti–adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.ConclusionsOur 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.ClinicalTrials.gov identifierNCT02057705.


2021 ◽  
pp. 1-10
Author(s):  
Cristina Molera ◽  
Tinatin Sarishvili ◽  
Andrés Nascimento ◽  
Irakli Rtskhiladze ◽  
Gema Muñoz Bartolo ◽  
...  

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy characterized by profound skeletal muscle weakness, respiratory distress, and motor dysfunction. However, pathology is not limited to muscle and can be associated with life-threatening hepatic peliosis. Hepatobiliary disease has been reported in up to 17% of XLMTM patients but has not been extensively characterized. We report on five XLMTM patients who experienced intrahepatic cholestasis in their disease natural history, illustrating the need to further investigate these manifestations. These patients shared presentations that included pruritus, hypertransaminemia, and hyperbilirubinemia with normal gamma-glutamyl transferase, following infection or vaccination. Three patients who had genetic testing showed no evidence of genetic mutations associated with familial cholestasis. In one patient, progression to cirrhotic, decompensated liver disease occurred. Further investigations into the molecular pathomechanism underpinning these clinical observations in XLMTM patients will be important for informing patient care.


2021 ◽  
Author(s):  
A. Blaschek ◽  
J. J. Dowling ◽  
W. Müller-Felber ◽  
W. Miller ◽  
B. Sepulveda ◽  
...  

2016 ◽  
Vol 26 ◽  
pp. S116-S117
Author(s):  
M. Annoussamy ◽  
C. Lilien ◽  
T. Gidaro ◽  
E. Gargaun ◽  
V. Chê ◽  
...  

2017 ◽  
Vol 27 ◽  
pp. S170
Author(s):  
M. Annoussamy ◽  
C. Lilien ◽  
T. Gidaro ◽  
E. Gargaun ◽  
V. Chê ◽  
...  

Author(s):  
Elizabeth R. Ellwood ◽  
Andrew Bentley ◽  
Jutta Buschbom ◽  
Alex Hardisty ◽  
Austin Mast ◽  
...  

International collaboration between collections, aggregators, and researchers within the biodiversity community and beyond is becoming increasingly important in our efforts to support biodiversity, conservation and the life of the planet. The social, technical, logistical and financial aspects of an equitable biodiversity data landscape – from workforce training and mobilization of linked specimen data, to data integration, use and publication – must be considered globally and within the context of a growing biodiversity crisis. In recent years, several initiatives have outlined paths forward that describe how digital versions of natural history specimens can be extended and linked with associated data. In the United States, Webster (2017) presented the “extended specimen”, which was expanded upon by Lendemer et al. (2019) through the work of the Biodiversity Collections Network (BCoN). At the same time, a “digital specimen” concept was developed by DiSSCo in Europe (Hardisty 2020). Both the extended and digital specimen concepts depict a digital proxy of an analog natural history specimen, whose digital nature provides greater capabilities such as being machine-processable, linkages with associated data, globally accessible information-rich biodiversity data, improved tracking, attribution and annotation, additional opportunities for data use and cross-disciplinary collaborations forming the basis for FAIR (Findable, Accessible, Interoperable, Reproducible) and equitable sharing of benefits worldwide, and innumerable other advantages, with slight variation in how an extended or digital specimen model would be executed. Recognizing the need to align the two closely-related concepts, and to provide a place for open discussion around various topics of the Digital Extended Specimen (DES; the current working name for the joined concepts), we initiated a virtual consultation on the discourse platform hosted by the Alliance for Biodiversity Knowledge through GBIF. This platform provided a forum for threaded discussions around topics related and relevant to the DES. The goals of the consultation align with the goals of the Alliance for Biodiversity Knowledge: expand participation in the process, build support for further collaboration, identify use cases, identify significant challenges and obstacles, and develop a comprehensive roadmap towards achieving the vision for a global specification for data integration. In early 2021, Phase 1 launched with five topics: Making FAIR data for specimens accessible; Extending, enriching and integrating data; Annotating specimens and other data; Data attribution; and Analyzing/mining specimen data for novel applications. This round of full discussion was productive and engaged dozens of contributors, with hundreds of posts and thousands of views. During Phase 1, several deeper, more technical, or additional topics of relevance were identified and formed the foundation for Phase 2 which began in May 2021 with the following topics: Robust access points and data infrastructure alignment; Persistent identifier (PID) scheme(s); Meeting legal/regulatory, ethical and sensitive data obligations; Workforce capacity development and inclusivity; Transactional mechanisms and provenance; and Partnerships to collaborate more effectively. In Phase 2 fruitful progress was made towards solutions to some of these complex functional and technical long-term goals. Simultaneously, our commitment to open participation was reinforced, through increased efforts to involve new voices from allied and complementary fields. Among a wealth of ideas expressed, the community highlighted the need for unambiguous persistent identifiers and a dedicated agent to assign them, support for a fully linked system that includes robust publishing mechanisms, strong support for social structures that build trustworthiness of the system, appropriate attribution of legacy and new work, a system that is inclusive, removed from colonial practices, and supportive of creative use of biodiversity data, building a truly global data infrastructure, balancing open access with legal obligations and ethical responsibilities, and the partnerships necessary for success. These two consultation periods, and the myriad activities surrounding the online discussion, produced a wide variety of perspectives, strategies, and approaches to converging the digital and extended specimen concepts, and progressing plans for the DES -- steps necessary to improve access to research-ready data to advance our understanding of the diversity and distribution of life. Discussions continue and we hope to include your contributions to the DES in future implementation plans.


2021 ◽  
Vol 8 (1) ◽  
pp. 79-90
Author(s):  
Andrea Gangfuss ◽  
Dirk Schmitt ◽  
Andreas Roos ◽  
Frederik Braun ◽  
Melanie Annoussamy ◽  
...  

X-linked myotubular myopathy (XLMTM) is a life-threatening rare neuromuscular disease, which is caused by pathogenic variants in the MTM1 gene. It has a large phenotypic heterogeneity, ranging from patients, who are able to walk independently to immobile patients who are only able to bring hand to mouth and depend on a respirator 24 hours a day every day. This suggests that ventilator requirements may not illustrate the full clinical picture of patients with XLMTM. At present, there is no curative therapy available, despite first promising results from ongoing gene therapy studies. In this study, we evaluated in detail the data from 13 German XLMTM patients, which was collected over a period of up to 20 years in our university hospital. We compared it to the international prospective longitudinal natural history study (NHS) data from 45 patients (containing 11 German patients). To highlight the broad phenotypic spectrum of the disease, we additionally focused on the clinical presentation of three cases at a glance. Comparing our data with the above mentioned natural history study, it appears the patients of the present German cohort seem to be more often severely affected, with higher frequency of non-ambulatory patients and patients on ventilation (and for longer time) and a higher proportion of patients needing a percutaneous endoscopic gastrostomy. Another key finding is a potential gap in time between first clinical presentation and final diagnosis, showing a need for patients to be treated in a specialized center for neuromuscular diseases.


2021 ◽  
Author(s):  
Ege Sarikaya ◽  
Jonathan Volpatti ◽  
Nesrin Sabha ◽  
Nika Maani ◽  
Hernan D. Gonorazky ◽  
...  

AbstractX-linked myotubular myopathy is a severe monogenetic disorder of the skeletal muscle caused by loss of expression/function mutations in the MTM1 (myotubularin) gene. There is a growing understanding of the pathologic and molecular abnormalities associated with loss of MTM1, and emerging therapeutic strategies that are in the process of translation to patients. Much of these data have been uncovered through experimentation in pre-clinical animal models of the disease. The most widely used model is an Mtm1 gene knockout mouse line; this line faithfully recapitulates the salient genetic and pathologic features of the disease. Despite the advances in aspects of XLMTM, there remain many unknowns related to disease pathomechanisms and to understanding of MTM1’s function in normal muscle development, and a continued need for therapy identification and development. To address these barriers, and to lay the groundwork for future study, we performed a natural history study of the Mtm1 knockout mouse model of XLMTM. We show that certain molecular and pathologic changes precede overt phenotypic changes, while others, including abnormalities in triad structure, occur more coincident with muscle weakness in the mouse. In total, we provide a comprehensive longitudinal assessment of molecular and structural features of the murine XLMTM disease process.


2013 ◽  
Vol 23 (9-10) ◽  
pp. 761 ◽  
Author(s):  
K. Amburgey ◽  
D. Julian ◽  
E. Howell ◽  
M. Britt ◽  
J.J. Dowling

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