X-linked myotubular myopathy

Annoussamy, M.; Lilien, C.; Gidaro, T.; Gargaun, E.; Chê, V.; Schara, Ulrike; Gangfuß, Andrea; D’Amico, Adele; Dowling, James J.; Darras, Basil T.; Daron, Aurore; Hernández, Arturo; Lattre, Capucine de; Arnal, Jean-Michel; Mayer, M.; Cuisset, Jean‐Marie; Vuillerot, Carole; Fontaine, S.; Bellance, Rémi; Biancalana, Valérie; Buj‐Bello, Ana; Hogrel, Jean‐Yves; Landy, Hal

doi:10.1212/wnl.0000000000007319

Cited by 70 publications

(35 citation statements)

References 49 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NHS population consisted of 59 patients recruited in Europe [ 22 ]. Of the 59 patients, 15 have a DNM2 mutation and 44 patients have a mutation in the MTM1 gene (Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…Our NHS was a prospective international study on X-linked and autosomal dominant centronuclear myopathy, which followed Good Clinical Practice and systematic source data verification. Patient forced expiratory volume in 1 s (FEV1), assessed according to EU and US recommendations, and time on ventilator were recorded at every visit [ 22 ]. The Bayesian model reduced the necessary sample size while controlling overall Type I error.…”

Section: Introductionmentioning

confidence: 99%

“…The main causal mutations are distributed throughout the genes encoding myotubularin ( MTM1 ) for XLMTM (OMIM: 310400) [ 24 ], dynamin 2 ( DNM2 ) [ 25 ] and amphiphysin 2 ( BIN1 ) [ 26 ] for the autosomal dominant form (OMIM: 160150), and amphiphysin 2 ( BIN1 ) [ 27 ] for the autosomal recessive form (OMIM: 255200). The clinical traits of CNM include hypotonia, external ophthalmoplegia, and respiratory deficiency, which can be severe and life-threatening in the XLMTM congenital form [ 22 , 28 ]. Patients who survive beyond the neonatal period live with a high disease burden: a majority require the use of a wheelchair, feeding tube, and ventilation support.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy

Fouarge

Monseur²,

Boulanger³

et al. 2021

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

Background Centronuclear myopathies are severe rare congenital diseases. The clinical variability and genetic heterogeneity of these myopathies result in major challenges in clinical trial design. Alternative strategies to large placebo-controlled trials that have been used in other rare diseases (e.g., the use of surrogate markers or of historical controls) have limitations that Bayesian statistics may address. Here we present a Bayesian model that uses each patient’s own natural history study data to predict progression in the absence of treatment. This prospective multicentre natural history evaluated 4-year follow-up data from 59 patients carrying mutations in the MTM1 or DNM2 genes. Methods Our approach focused on evaluation of forced expiratory volume in 1 s (FEV1) in 6- to 18-year-old children. A patient was defined as a responder if an improvement was observed after treatment and the predictive probability of such improvement in absence of intervention was less than 0.01. An FEV1 response was considered clinically relevant if it corresponded to an increase of more than 8%. Results The key endpoint of a clinical trial using this model is the rate of response. The power of the study is based on the posterior probability that the rate of response observed is greater than the rate of response that would be observed in the absence of treatment predicted based on the individual patient’s previous natural history. In order to appropriately control for Type 1 error, the threshold probability by which the difference in response rates exceeds zero was adapted to 91%, ensuring a 5% overall Type 1 error rate for the trial. Conclusions Bayesian statistical analysis of natural history data allowed us to reliably simulate the evolution of symptoms for individual patients over time and to probabilistically compare these simulated trajectories to actual observed post-treatment outcomes. The proposed model adequately predicted the natural evolution of patients over the duration of the study and will facilitate a sufficiently powerful trial design that can cope with the disease’s rarity. Further research and ongoing dialog with regulatory authorities are needed to allow for more applications of Bayesian statistics in orphan disease research.

show abstract

“…The NHS population consisted of 59 patients recruited in Europe [ 22 ]. Of the 59 patients, 15 have a DNM2 mutation and 44 patients have a mutation in the MTM1 gene (Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy

Fouarge

Monseur²,

Boulanger³

et al. 2021

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…This prompted a phase 1/2 study (NCT03199469) in children with XLMTM ranging in age from 0-5 years. While the first six patients dosed at 1 ×•10 14 genome copies/kg also showed very encouraging results, all 3 patients administered a 3-fold higher dose (3 × 10 14 ) experienced severe hepatotoxicity and two of them died (85). Further development of this product is currently on hold pending further evaluation of these serious adverse events (86).…”

Section: Congenital Myopathiesmentioning

confidence: 97%

New Therapeutics Options for Pediatric Neuromuscular Disorders

Flotats‐Bastardas

Hahn

2020

Front. Pediatr.

View full text Add to dashboard Cite

Neuromuscular disorders (NMDs) of Childhood onset are a genetically heterogeneous group of diseases affecting the anterior horn cell, the peripheral nerve, the neuromuscular junction, or the muscle. For many decades, treatment of NMDs has been exclusively symptomatic. But this has changed fundamentally in recent years due to the development of new drugs attempting either to ameliorate secondary pathophysiologic consequences or to modify the underlying genetic defect itself. While the effects on the course of disease are still modest in some NMDs (e.g., Duchenne muscular dystrophy), new therapies have substantially prolonged life expectancy and improved motor function in others (e.g., spinal muscular atrophy and infantile onset Pompe disease). This review summarizes recently approved medicaments and provides an outlook for new therapies that are on the horizon in this field.

show abstract

“…Motor strength was quantitatively measured using a handheld dynamometer (MicroFET®2 [hogganhealth.net]) for knee, hip, and elbow strength with distal strength measured using grip and pinch dynamometers (MyoGrip and MyoPinch (Ateliers Laumonier, France) (Hogrel, 2015). Handheld dynamometry results were expressed as the percentage of the highest value compared to age/weight/sex-based norms (Beenakker, van der Hoeven, Fock, & Maurits, 2001), and distal strength results were expressed as the percentage of the highest value compared to agebased norms (Annoussamy et al, 2019). A single pediatric physical therapist completed all motor capacity and strength assessments at both visits using standard positions and instructions.…”

Section: Motor Assessmentsmentioning

confidence: 99%

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

Donkervoort

Mohassel

Laugwitz

et al. 2020

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin‐2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant‐negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS‐disease gene and expands its clinical and genetic spectrum to include recessive loss‐of‐function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

show abstract

X-linked myotubular myopathy

Cited by 70 publications

References 49 publications

Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy

Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy

New Therapeutics Options for Pediatric Neuromuscular Disorders

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

Contact Info

Product

Resources

About