INCEPTUS Multinational, Prospective, Natural History, Run-in Study of Males with X-Linked Myotubular Myopathy

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.

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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)

Neuromuscular Disorders ◽

10.1016/j.nmd.2019.06.161 ◽

2019 ◽

Vol 29 ◽

pp. S79 ◽

Cited By ~ 1

Author(s):

L. Servais ◽

P. Shieh ◽

J. Dowling ◽

N. Kuntz ◽

W. Müller-Felber ◽

...

Keyword(s):

Natural History ◽

Phase 1 ◽

Myotubular Myopathy

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Intrahepatic Cholestasis Is a Clinically Significant Feature Associated with Natural History of X-Linked Myotubular Myopathy (XLMTM): A Case Series and Biopsy Report

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210712 ◽

2021 ◽

pp. 1-10

Author(s):

Cristina Molera ◽

Tinatin Sarishvili ◽

Andrés Nascimento ◽

Irakli Rtskhiladze ◽

Gema Muñoz Bartolo ◽

...

Keyword(s):

Natural History ◽

Intrahepatic Cholestasis ◽

Case Series ◽

Motor Dysfunction ◽

Significant Feature ◽

Gamma Glutamyl Transferase ◽

Myotubular Myopathy ◽

Biopsy Report ◽

Life Threatening ◽

Glutamyl Transferase

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.

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Baseline data from patients with myotubular myopathy enrolled in a European prospective and longitudinal natural history study

Neuromuscular Disorders ◽

10.1016/j.nmd.2016.06.114 ◽

2016 ◽

Vol 26 ◽

pp. S116-S117

Author(s):

M. Annoussamy ◽

C. Lilien ◽

T. Gidaro ◽

E. Gargaun ◽

V. Chê ◽

...

Keyword(s):

Natural History ◽

Baseline Data ◽

Natural History Study ◽

Myotubular Myopathy

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Longitudinal data of patients with myotubular myopathy enrolled in a European prospective and longitudinal natural history study

Neuromuscular Disorders ◽

10.1016/j.nmd.2017.06.280 ◽

2017 ◽

Vol 27 ◽

pp. S170

Author(s):

M. Annoussamy ◽

C. Lilien ◽

T. Gidaro ◽

E. Gargaun ◽

V. Chê ◽

...

Keyword(s):

Natural History ◽

Longitudinal Data ◽

Natural History Study ◽

Myotubular Myopathy

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Diagnosing X-linked Myotubular Myopathy – A German 20-year Follow Up Experience

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200539 ◽

2021 ◽

Vol 8 (1) ◽

pp. 79-90

Author(s):

Andrea Gangfuss ◽

Dirk Schmitt ◽

Andreas Roos ◽

Frederik Braun ◽

Melanie Annoussamy ◽

...

Keyword(s):

Natural History ◽

Clinical Presentation ◽

Neuromuscular Diseases ◽

Final Diagnosis ◽

University Hospital ◽

Natural History Study ◽

Myotubular Myopathy ◽

Curative Therapy ◽

Endoscopic Gastrostomy ◽

Prospective Longitudinal

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.

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Natural history of a mouse model of X-linked myotubular myopathy

10.1101/2021.10.11.463940 ◽

2021 ◽

Author(s):

Ege Sarikaya ◽

Jonathan Volpatti ◽

Nesrin Sabha ◽

Nika Maani ◽

Hernan D. Gonorazky ◽

...

Keyword(s):

Natural History ◽

Mouse Model ◽

Knockout Mouse ◽

Muscle Development ◽

Gene Knockout ◽

Disease Process ◽

Longitudinal Assessment ◽

Myotubular Myopathy ◽

Molecular Abnormalities ◽

Pathologic Features

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.

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P.4.7 The natural history of myotubular myopathy, summary of the first year of enrollment

Neuromuscular Disorders ◽

10.1016/j.nmd.2013.06.445 ◽

2013 ◽

Vol 23 (9-10) ◽

pp. 761 ◽

Cited By ~ 1

Author(s):

K. Amburgey ◽

D. Julian ◽

E. Howell ◽

M. Britt ◽

J.J. Dowling

Keyword(s):

Natural History ◽

First Year ◽

Myotubular Myopathy ◽

History Of

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A natural history study of X-linked myotubular myopathy

Neurology ◽

10.1212/wnl.0000000000004415 ◽

2017 ◽

Vol 89 (13) ◽

pp. 1355-1364 ◽

Cited By ~ 26

Author(s):

Kimberly Amburgey ◽

Etsuko Tsuchiya ◽

Sabine de Chastonay ◽

Michael Glueck ◽

Rachel Alverez ◽

...

Keyword(s):

Natural History ◽

Online Survey ◽

Neuromuscular Disorders ◽

Cross Sectional Study ◽

Disease Course ◽

Cross Sectional ◽

Myotubular Myopathy ◽

Phone Survey ◽

History Of ◽

Infancy And Early Childhood

Objective:To define the natural history of X-linked myotubular myopathy (MTM).Methods:We performed a cross-sectional study that included an online survey (n = 35) and a prospective, 1-year longitudinal investigation using a phone survey (n = 33).Results:We ascertained data from 50 male patients with MTM and performed longitudinal assessments on 33 affected individuals. Consistent with existing knowledge, we found that MTM is a disorder associated with extensive morbidities, including wheelchair (86.7% nonambulant) and ventilator (75% requiring >16 hours of support) dependence. However, unlike previous reports and despite the high burden of disease, mortality was lower than anticipated (approximate rate 10%/y). Seventy-six percent of patients with MTM enrolled (mean age 10 years 11 months) were alive at the end of the study. Nearly all deaths in the study were associated with respiratory failure. In addition, the disease course was more stable than expected, with few adverse events reported during the prospective survey. Few non–muscle-related morbidities were identified, although an unexpectedly high incidence of learning disability (43%) was noted. Conversely, MTM was associated with substantial burdens on patient and caregiver daily living, reflected by missed days of school and lost workdays.Conclusions:MTM is one of the most severe neuromuscular disorders, with affected individuals requiring extensive mechanical interventions for survival. However, among study participants, the disease course was more stable than predicted, with more individuals surviving infancy and early childhood. These data reflect the disease burden of MTM but offer hope in terms of future therapeutic intervention.

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