X-linked myotubular myopathy: A prospective international natural history study

Mélanie Annoussamy; Charlotte Lilien; Teresa Gidaro; Elena Gargaun; Virginie Chê; Ulrike Schara; Andrea Gangfuß; Adele D'Amico; James J Dowling; Basil T Darras; Aurore Daron; Arturo Hernandez; Capucine de Lattre; Jean-Michel Arnal; Michèle Mayer; Jean-Marie Cuisset; Carole Vuillerot; Stéphanie Fontaine; Rémi Bellance; Valérie Biancalana; Ana Buj-Bello; Jean-Yves Hogrel; Hal Landy; Laurent Servais

doi:10.1212/WNL.0000000000007319

X-linked myotubular myopathy: A prospective international natural history study

Mélanie Annoussamy, Charlotte Lilien, Teresa Gidaro, Elena Gargaun, Virginie Chê, Ulrike Schara, Andrea Gangfuß, Adele D'Amico, James J Dowling, Basil T Darras, Aurore Daron, Arturo Hernandez, Capucine de Lattre, Jean-Michel Arnal, Michèle Mayer, Jean-Marie Cuisset, Carole Vuillerot, Stéphanie Fontaine, Rémi Bellance, Valérie BiancalanaAna Buj-Bello, Jean-Yves Hogrel, Hal Landy, Laurent Servais

Ospedale Pediatrico Bambino Gesu

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVES: Because 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.

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), 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.

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.

CLINICALTRIALSGOV IDENTIFIER: NCT02057705.

Original language	English
Pages (from-to)	e1852-e1867
Journal	Neurology
Volume	92
Issue number	16
DOIs	https://doi.org/10.1212/WNL.0000000000007319
Publication status	Published - Apr 16 2019

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Annoussamy, M., Lilien, C., Gidaro, T., Gargaun, E., Chê, V., Schara, U., Gangfuß, A., D'Amico, A., Dowling, J. J., Darras, B. T., Daron, A., Hernandez, A., de Lattre, C., Arnal, J-M., Mayer, M., Cuisset, J-M., Vuillerot, C., Fontaine, S., Bellance, R., ... Servais, L. (2019). X-linked myotubular myopathy: A prospective international natural history study. Neurology, 92(16), e1852-e1867. https://doi.org/10.1212/WNL.0000000000007319

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, J-M, Mayer, M, Cuisset, J-M, Vuillerot, C, Fontaine, S, Bellance, R, Biancalana, V, Buj-Bello, A, Hogrel, J-Y, Landy, H & Servais, L 2019, 'X-linked myotubular myopathy: A prospective international natural history study', Neurology, vol. 92, no. 16, pp. e1852-e1867. https://doi.org/10.1212/WNL.0000000000007319

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title = "X-linked myotubular myopathy: A prospective international natural history study",

abstract = "OBJECTIVES: Because 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.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), 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.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.CLINICALTRIALSGOV IDENTIFIER: NCT02057705.",

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doi = "10.1212/WNL.0000000000007319",

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TY - JOUR

T1 - X-linked myotubular myopathy

T2 - A prospective international natural history study

AU - Annoussamy, Mélanie

AU - Lilien, Charlotte

AU - Gidaro, Teresa

AU - Gargaun, Elena

AU - Chê, Virginie

AU - Schara, Ulrike

AU - Gangfuß, Andrea

AU - D'Amico, Adele

AU - Dowling, James J

AU - Darras, Basil T

AU - Daron, Aurore

AU - Hernandez, Arturo

AU - de Lattre, Capucine

AU - Arnal, Jean-Michel

AU - Mayer, Michèle

AU - Cuisset, Jean-Marie

AU - Vuillerot, Carole

AU - Fontaine, Stéphanie

AU - Bellance, Rémi

AU - Biancalana, Valérie

AU - Buj-Bello, Ana

AU - Hogrel, Jean-Yves

AU - Landy, Hal

AU - Servais, Laurent

PY - 2019/4/16

Y1 - 2019/4/16

N2 - OBJECTIVES: Because 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.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), 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.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.CLINICALTRIALSGOV IDENTIFIER: NCT02057705.

AB - OBJECTIVES: Because 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.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), 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.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.CLINICALTRIALSGOV IDENTIFIER: NCT02057705.

U2 - 10.1212/WNL.0000000000007319

DO - 10.1212/WNL.0000000000007319

M3 - Article

C2 - 30902907

SN - 0028-3878

VL - 92

SP - e1852-e1867

JO - Neurology

JF - Neurology

IS - 16

ER -

X-linked myotubular myopathy: A prospective international natural history study

Abstract

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