Centronuclear myopathies under attack: A plethora of therapeutic targets

Tasfaout, Hichem; Cowling, Belinda S.; Laporte, Jocelyn

doi:10.3233/jnd-180309

Cited by 35 publications

(32 citation statements)

References 165 publications

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“…Additionally, respiratory function is also altered in patients who do not need ventilator support and respiratory complications are the most frequent cause of death [ 29 , 30 ]. Despite their rarity and their heterogeneous genotype and phenotype, CNMs are currently the targets of several clinical and pre-clinical development efforts that make them a paradigm for the need of alternative statistical strategies in clinical trials [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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

Fouarge

Monseur²,

Boulanger³

et al. 2021

Orphanet J Rare Dis

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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.

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Section: Introductionmentioning

confidence: 99%

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

Fouarge

Monseur²,

Boulanger³

et al. 2021

Orphanet J Rare Dis

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“…For example, L-type VGCCs function in hematopoietic cells such as macrophages and B, T, and dendritic cells (17)(18)(19)(20). Several syndromes, such as hypokalemic periodic paralysis, centronuclear myopathy, and malignant hyperthermia susceptibility (MHS) type 5, have been linked to mutations in the CACNA1S gene encoding the α1S subunit (21)(22)(23).…”

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confidence: 99%

CACNA1S haploinsufficiency confers resistance to New World arenavirus infection

Sarute

Ross

2020

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the genetics of susceptibility to infectious agents is of great importance to our ability to combat disease. Here, we show that voltage-gated calcium channels (VGCCs) are critical for cellular binding and entry of the New World arenaviruses Junín and Tacaribe virus, suggesting that zoonosis via these receptors could occur. Moreover, we demonstrate that α1s haploinsufficiency renders cells and mice more resistant to infection by these viruses. In addition to being more resistant to infection, haploinsufficient cells and mice required a lower dosage of VGCC antagonists to block infection. These studies underscore the importance of genetic variation in susceptibility to both viruses and pharmaceutics.

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“…At present, the treatment of CNM is not unique, and possible treatment options at the cellular and molecular and genetic levels are under study [ 19 ]. At present, symptomatic treatment, such as feeding support for chewing weakness, rehabilitation training for limb weakness, drug treatment for heart involvement, and surgery for joint contracture or scoliosis, is most often recommended [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic analysis of a case with centronuclear myopathy caused by SPEG gene mutation: a case report and literature review

Zhang

Huang

et al. 2021

BMC Pediatr

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Background Centronuclear myopathy (CNM), a subtype of congenital myopathy (CM), is a group of clinical and genetically heterogeneous muscle disorders. Since the discovery of the SPEG gene and disease-causing variants, only a few additional patients have been reported. Case presentation The child, a 13-year-old female, had delayed motor development since childhood, weakness of both lower extremities for 10 years, gait swinging, and a positive Gower sign. Her distal muscle strength of both lower extremities was grade IV. The electromyography showed myogenic damage and electromyographic changes. Her 11-year-old sister had a similar muscle weakness phenotype. Gene sequencing revealed that both sisters had SPEG compound heterozygous mutations, and the mutation sites were c.3715 + 4C > T and c.3588delC, which were derived from their parents. These variant sites have not been reported before. The muscle biopsy showed the nucleic (> 20% of fibers) were located in the center of the cell, the average diameter of type I myofibers was slightly smaller than that of type II myofibers, and the pathology of type I myofibers was dominant, which agreed with the pathological changes of centronuclear myopathy. Conclusions The clinical phenotypes of CNM patients caused by mutations at different sites of the SPEG gene are also different. In this case, there was no cardiomyopathy. This study expanded the number of CNM cases and the mutation spectrum of the SPEG gene to provide references for prenatal diagnosis and genetic counseling.

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Centronuclear myopathies under attack: A plethora of therapeutic targets

Cited by 35 publications

References 165 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

CACNA1S haploinsufficiency confers resistance to New World arenavirus infection

Clinical and genetic analysis of a case with centronuclear myopathy caused by SPEG gene mutation: a case report and literature review

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