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Myology research highlights

Discover our weekly selection of scientific and medical publications in the field of myology and of neuromuscular diseases :  summary of each publication aimed at the general reader, highlighting the main points of the article and the authors’ conclusions
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26/08/2014 - Missing protein restored in patients with muscular dystrophy

No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell's quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. Here, the authors treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. The authors conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases.


26/08/2014 - New protein offers novel therapeutic approach for patients with DMD


Most mutations that truncate the reading frame of the DMD gene cause loss of dystrophin expression and lead to Duchenne muscular dystrophy. However, amelioration of disease severity has been shown to result from alternative translation initiation beginning in DMD exon 6 that leads to expression of a highly functional N-truncated dystrophin. Here, the authors demonstrate that this isoform results from usage of an internal ribosome entry site (IRES) within exon 5 that is glucocorticoid inducible. They confirmed IRES activity by both peptide sequencing and ribosome profiling in muscle from individuals with minimal symptoms despite the presence of truncating mutations. A truncated reading frame upstream of the IRES was generated by exon skipping, which led to synthesis of a functional N-truncated isoform in both human subject-derived cell lines and in a new DMD mouse model, where expression of the truncated isoform protected muscle from contraction-induced injury and corrected muscle force to the same level as that observed in control mice. These results support a potential therapeutic approach for patients with mutations within the 5' exons of DMD.


Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Wein N, Vulin A, Falzarano MS, et al. Nat Med. 2014 Aug 10. doi: 10.1038/nm.3628. [Epub ahead of print]


26/08/2014 - ISIS SMN-Rx advances into Phase III trial in infants with Spinal Muscular Atrophy


Isis Pharmaceuticals has initiated a pivotal Phase III study evaluating ISIS-SMNRx in infants with spinal muscular atrophy (SMA), the most common genetic cause of infant mortality. The Phase III study entitled ENDEAR, is the first of several planned studies in a broad and comprehensive late-stage clinical development program for ISIS-SMNRx.  ENDEAR is a randomized, double-blind, sham-procedure controlled thirteen month study in approximately 110 infants diagnosed with SMA.  The study will evaluate the efficacy and safety of a 12 mg dose of ISIS-SMNRx with a primary endpoint of survival or permanent ventilation.  Additional efficacy endpoints are also included in the study. Isis plans to initiate a second pivotal study in children with SMA later this year. The company is continuing the development of ISIS-SMNRx and is in the planning stages for clinical studies in additional patient populations. The clinical and preclinical data generated to date, including data in multiple open-label clinical studies, across multiple measures with ISIS-SMNRx, support the initiation of these studies, which fully assess the safety and efficacy benefits of this experimental treatment.


26/08/2014 - Validating diagnostic criteria for sensory neuronopathies


There are no validated criteria for the diagnosis of sensory neuronopathy (SNN) yet. In a preliminary monocenter study, a set of criteria relying on clinical and electrophysiological data showed good sensitivity and specificity for a diagnosis of probable SNN. The aim of this study was to test these criteria in a French multicenter study. A total of 210 patients with sensory neuropathies from 15 francophone reference centers for neuromuscular diseases were included in the study with an expert diagnosis of non-SNN, SNN or suspected SNN according to the investigations performed in these centers. Diagnosis was obtained independently from the set of criteria to be tested. The expert diagnosis was taken as the reference against which the proposed SNN criteria were tested. The set relied on clinical and electrophysiological data easily obtainable with routine investigations. Nine out of sixty one (16.4 %) non-SNN patients, 23/36 (63.9 %) of suspected SNN, and 102/113 (90.3 %) of SNN patients according to the expert diagnosis were classified as SNN by the criteria. The SNN criteria tested against the expert diagnosis in the SNN and non-SNN groups had 90.3 % (102/113) sensitivity, 85.2 % (52/61) specificity, 91.9 % (102/111) positive predictive value, and 82.5 % (52/63) negative predictive value. Discordance between the expert diagnosis and the SNN criteria occurred in 20 cases. After analysis of these cases, 11 could be reallocated to a correct diagnosis in accordance with the SNN criteria. The proposed criteria may be useful for the diagnosis of probable SNN in patients with sensory neuropathy. They can be reached with simple clinical and paraclinical investigations.


26/08/2014 - SPEG mutations results in Centronuclear Myopathy

Centronuclear myopathies (CNMs) are characterized by muscle weakness and increased numbers of central nuclei within myofibers. X-linked myotubular myopathy, the most common severe form of CNM, is caused by mutations in MTM1, encoding myotubularin (MTM1), a lipid phosphatase. To increase understanding of MTM1 function, the authors of this study conducted a yeast two-hybrid screen to identify MTM1-interacting proteins. Striated muscle preferentially expressed protein kinase (SPEG), the product of SPEG complex locus (SPEG), was identified as an MTM1-interacting protein, confirmed by immunoprecipitation and immunofluorescence studies. SPEG knockout has been previously associated with severe dilated cardiomyopathy in a mouse model. Using whole-exome sequencing, they identified three unrelated CNM-affected probands, including two with documented dilated cardiomyopathy, carrying homozygous or compound-heterozygous SPEG mutations. SPEG was markedly reduced or absent in two individuals whose muscle was available for immunofluorescence and immunoblot studies. Examination of muscle samples from Speg-knockout mice revealed an increased frequency of central nuclei, as seen in human subjects. SPEG localizes in a double line, flanking desmin over the Z lines, and is apparently in alignment with the terminal cisternae of the sarcoplasmic reticulum. Examination of human and murine MTM1-deficient muscles revealed similar abnormalities in staining patterns for both desmin and SPEG. These results suggest that mutations in SPEG, encoding SPEG, cause a CNM phenotype as a result of its interaction with MTM1. SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy.


26/08/2014 - Diagnosing patients with Pompe disease

Pompe disease is a rare, autosomal recessive disorder characterized by deficiency of lysosomal acid alpha-glucosidase and accumulation of lysosomal glycogen in many tissues. The variable clinical manifestations, broad phenotypic spectrum, and overlap of signs and symptoms with other neuromuscular diseases make diagnosis challenging. In the past, the diagnosis of Pompe disease was based on enzyme activity assay in skin fibroblasts or muscle tissue. In 2004, methods for measuring acid alpha-glucosidase activity in blood were published. To compare how diagnostic methods changed over time and whether they differed by geographic region and clinical phenotype, diagnostic methods used for 1059 patients enrolled in the Pompe Registry in three onset categories (Group A: onset of signs/symptoms ≤12months of age with cardiomyopathy; Group B: onset ≤12months without cardiomyopathy and onset >1year to ≤12years; Group C: onset >12years) were examined. Enzyme activity-based assays were used more frequently than other diagnostic methods. Measuring acid alpha-glucosidase activity in blood (leukocytes, lymphocytes, or dried-blood spot) increased over time; use of muscle biopsy decreased. The increased use of blood-based assays for diagnosis may result in a more timely diagnosis in patients across the clinical spectrum of Pompe disease.


26/08/2014 - New insights on contraction efficiency in patients with Duchenne muscular dystrophy


The decrease in muscle strength in patients with Duchenne muscular dystrophy (DMD) is mainly explained by a decrease in the number of active contractile elements. Nevertheless, it is possible that other electro-chemical and force transmission processes may contribute. The present study aimed to quantify the effect of DMD on the relative contribution of electro-chemical and force transmission components of the electromechanical delay (i.e., time lag between the onset of muscle activation and force production) in humans using very high frame rate ultrasound. Fourteen patients with DMD and thirteen control subjects underwent two electrically-evoked contractions of the biceps brachii with the ultrasound probe over the muscle belly. The electromechanical delay was significantly longer in DMD patients compared to controls (18.5±3.9 ms vs. 12.5±1.4 ms, p<0.0001). More precisely, DMD patients exhibited a longer delay between the onset of muscle fascicles motion and force production (13.6±3.1 ms vs. 7.9±2.0 ms, p<0.0001). This delay was correlated to the chronological age of the DMD patients (r=0.66; p=0.01) but not of the controls (r=-0.45; p=0.10). No significant difference was found for the delay between the onset of muscle stimulation and the onset of muscle fascicles motion. These results highlight the role of the alteration of muscle force transmission (delay between the onset of fascicle motion and force production) in the impairments of the contraction efficiency in patients with DMD.


26/08/2014 - Evaluation of primary and secondary clinical outcome measures in Charcot-Marie-Tooth

This study evaluated primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, four significant clusters of patients were identified according to clinical severity. The authors then tested the impact of each of the CMTNS components and of the secondary clinical parameters with regard to their power to differentiate these four clusters. The CMTNS components ulnar sensory nerve action potential (SNAP), pin sensibility, vibration and strength of arms did not increase the discriminant value of the remaining five CMTNS components (Ulnar compound motor action potential [CMAP], leg motor symptoms, arm motor symptoms, leg strength and sensory symptoms). However, three of the six additional clinical outcome measures - the 10m-timed walking test (T10MW), 9 hole-peg test (9HPT), and foot dorsal flexion dynamometry - further improved discrimination between severely and mildly affected patients. From these findings, three different composite measures were identified as score hypotheses and their discriminant power was compared with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. To conclude, five items from the CMTNS and three secondary clinical outcome measures improved the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials.



26/08/2014 - A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function

The goal of this study was to describe a novel mutation in TRK-fused gene (TFG) as a new cause of dominant axonal Charcot-Marie-Tooth disease (CMT) identified by exome sequencing and further characterized by in vitro functional studies. Exome sequencing and linkage analysis were used to investigate a large Taiwanese family with a dominantly inherited adult-onset motor and sensory axonal neuropathy in which mutations in common CMT2-implicated genes had been previously excluded. Functional effects of the mutant gene products were investigated in vitro. Exome sequencing of 2 affected individuals in this family revealed a novel heterozygous mutation, c.806G>T (p.Gly269Val), in TFG that perfectly cosegregates with the CMT2 phenotype in all 27 family members. This mutation occurs at an evolutionarily conserved residue and is absent in the 1,140 ethnically matched control chromosomes. Genome-wide linkage study also supported its disease-causative role. Cell transfection studies showed that the TFG p.Gly269Val mutation increased the propensity of TFG proteins to form aggregates, resulting in sequestration of both mutant and wild-type TFG proteins and might thus deplete functional TFG molecules. The secreted Gaussia luciferase reporter assay demonstrated that inhibition of endogenous TFG compromised the protein secretion pathways, which could only be rescued by expressing wild-type TFG but not the p.Gly269Val altered proteins. TFG mutation was not found in 55 additional unrelated patients with CMT2, suggesting its rarity.


26/08/2014 - Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia

Nondystrophic myotonias are characterized by muscle stiffness triggered by voluntary movement. They are caused by mutations in either the CLCN1 gene in myotonia congenita or in the SCN4A gene in paramyotonia congenita and sodium channel myotonias. Clinical and electrophysiological phenotypes of these disorders have been well described. No concomitant mutations in both genes have been reported yet. This study reports five patients from three families showing myotonia with both chloride and sodium channel mutations. Their clinical and electrophysiological phenotypes did not fit with the phenotype known to be associated with the mutation initially found in SCN4A gene, which led the authors to screen and find an additional mutation in CLCN1 gene. The electrophysiological and clinical observations suggest that heterozygous CLCN1 mutations can modify the clinical and electrophysiological expression of SCN4A mutation.



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