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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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30/04/2013 - "State-of-the-heart" of cardiac laminopathies

The LMNA gene encodes the nuclear A-type lamins. LMNA mutations are associated with more than 10 clinical entities and represent one of the first causes of inherited dilated cardiomyopathy. LMNA-dilated cardiomyopathy is associated with conduction disease (DCM-CD) and is a severe and aggressive form of DCM. However, pathogenesis remains largely unknown and no specific treatment is currently available for the patients. This review presents recent discoveries that improve the understanding of the cardiac pathophysiological roles of A-type lamins and shed light on potential therapeutic targets. In the last decade, many efforts have been made to elucidate how mutations in A-type lamins, ubiquitous proteins, lead to DCM-CD. No clear genotype/phenotype correlations have been found to help in elucidating those mechanisms. Analysis of several mouse models has helped in deciphering critical pathomechanisms. Among those, Mitogen-activated protein kinases (MAPK) and Akt/mTOR appear to be key early-activated signaling pathways in LMNA DCM-CD in both humans and mice. Inhibition of these signaling pathways has shown encouraging beneficial effects upon cardiac evolution of DCM-CD. These recent findings suggest that targeting MAPK and Akt/mTOR pathways with potent and specific compounds represents a promising intervention for the treatment of LMNA DCM-CD.

30/04/2013 - Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease

A recently proposed therapeutic approach for lysosomal storage disorders (LSDs) relies upon the ability of transcription factor EB (TFEB) to stimulate autophagy and induce lysosomal exocytosis leading to cellular clearance. This approach is particularly attractive in glycogen storage disease type II [a severe metabolic myopathy, Pompe disease (PD)] as the currently available therapy, replacement of the missing enzyme acid alpha-glucosidase, fails to reverse skeletal muscle pathology. PD, a paradigm for LSDs, is characterized by both lysosomal abnormality and dysfunctional autophagy. Here, the authors show that TFEB is a viable therapeutic target in PD: overexpression of TFEB in a new muscle cell culture system and in mouse models of the disease reduced glycogen load and lysosomal size, improved autophagosome processing, and alleviated excessive accumulation of autophagic vacuoles. Unexpectedly, the exocytosed vesicles were labelled with lysosomal and autophagosomal membrane markers, suggesting that TFEB induces exocytosis of autophagolysosomes. Furthermore, the effects of TFEB were almost abrogated in the setting of genetically suppressed autophagy, supporting the role of autophagy in TFEB-mediated cellular clearance.

30/04/2013 - Motor Function Measure: validation of a short form for young children with neuromuscular diseases

This prospective, two-cohort study was carried out in French-speaking rehabilitation departments from France, Belgium and Switzerland. It aimed to validate a version of the Motor Function Measure (MFM) useful in neuromuscular children aged between 2 and 7 years old. A total of 194 healthy children and 88 children with a neuromuscular disease participated in the study. MFM was rated by trained medical professionals, either once or twice, with a delay between the two MFM ranging between 8 and 30 days, The main outcome measure was the intra- and inter-rater reliability of the MFM. The subtests making up the MFM-32, a scale monitoring severity and progression of motor function in patients with a neuromuscular disease in 3 functional domains, were carried out in healthy children aged 2-7 years. Twenty items of the MFM-32 were successfully completed by these children and were used to constitute the MFM-20. Principal component analysis of the MFM-20 confirmed the 3 functional domains. Inter- and intra-rater reliability of the 3 sub-scores and total score were high (ICC > 0.90) and discriminant validity was good. The authors conclude that the MFM-20 can be used as an outcome measure for assessment of motor function in young children with a neuromuscular disease.

30/04/2013 - Safety and ventilatory outcomes in a phase I/II trial of AAV-mediated GAA gene therapy in Pompe disease

Pompe Disease is an inherited neuromuscular disease due to deficiency of lysosomal acid alpha-glucosidase (GAA) leading to glycogen accumulation in muscle and motoneurons. Cardiopulmonary failure in infancy leads to early mortality and GAA enzyme replacement therapy (ERT) results in improved survival, reduction of cardiac hypertrophy and developmental gains. However, many children have progressive ventilatory insufficiency and need additional support. Preclinical work shows that gene transfer restores phrenic neural activity and corrects ventilatory deficits. Here, the authors present 180-day safety and ventilatory outcomes for five ventilator-dependent children in a phase I/II clinical trial of AAV-mediated GAA gene therapy (rAAV1-hGAA) following intradiaphragmatic delivery. They assessed if rAAV1-hGAA results in acceptable safety outcome and detectable functional changes, using general safety measures, immunological studies and pulmonary functional testing. All subjects required chronic, full-time mechanical ventilation due to respiratory failure that was unresponsive to both ERT and pre-operative muscle conditioning exercises. After receiving a dose of either 1 x 1012 vg (n=3) or 5 x 1012 vg (n=2) of rAAV1-hGAA, the subjects' unassisted tidal volume was significantly larger (median, IQR: 28.8% increase, 15.2-35.2, p<0.05). Further, most patients tolerated appreciably longer periods of unassisted breathing (425% increase, 103-851%, p=0.08). Gene transfer did not improve maximal inspiratory pressure. Expected levels of circulating antibodies and no T cell-mediated immune responses to the vector (capsids) were observed. One subject demonstrated a slight increase in anti-GAA antibody that was not considered clinically significant. These results indicate that rAAV1-hGAA was safe and may lead to modest improvements in volitional ventilatory performance measures. Evaluation of the next five patients will determine if earlier intervention can further enhance the functional benefit.


Phase I/II trial of AAV1-GAA gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Smith BK, Collins S, Conlon T, et al. Hum Gene Ther. 2013 Apr 9. [Epub ahead of print]


30/04/2013 - Development of a national Japanese registry of muscular dystrophy

Currently, clinical trials for new therapeutic strategies are being planned for Duchenne and Becker muscular dystrophies (DMD/BMD). However, it is difficult to obtain adequate numbers of patients in clinical trials. As solutions to these problems, patient registries are an important resource worldwide, especially in rare diseases such as DMD/BMD. Herein, the authors developed a national registry of Japanese DMD/BMD patients in collaboration with TREAT-NMD. The registry includes male Japanese DMD/BMD patients whose genetic status has been confirmed by genetic analysis. The registry includes patients throughout Japan. As of February 2012, 583 DMD and 105 BMD patients were registered. Most individuals were aged less than 20 years. In terms of genetic mutations of registrants of DMD and BMD, deletion of exons was the most frequent (61.4% and 79.0%) followed by point mutations (24.5% and 14.3%) and duplications (13.6% and 4.8%), respectively. 43.6% of DMD patients are capable of walking, and 76.2% of BMD registrants are able to walk. 41.1% of DMD registrants in the database were treated using steroids. 29.5% of DMD and 23.8% of BMD registrants were prescribed one cardiac medicine at least. 22% of DMD used ventilator support, and non-invasive support was common. Small numbers of DMD and BMD registrants, only 3.9% and 1.0%, have received scoliosis surgery. 57 (9.8%) patients were eligible for a clinical trial focussed on 'skipping' exon 51. The Remudy has already demonstrated utility in clinical researches and standardization of patients care for DMD/BMD. This new DMD/BMD patient registry facilitates the synchronization of clinical drug development in Japan with that in other countries.

25/04/2013 - PPMD white paper lists several recommendations to speed up orphan drug approval

Parent Project Muscular Dystrophy (PPMD) is a patient advocacy foundation focused on advancing research that will lead to treatments for Duchenne and Becker muscular dystrophy  (DMD and BMD). PPMD has released Putting Patients First, a white paper outlining recommendations to speed responsible access to new treatments for DMD and other, rare, serious, and life-threatening neurological disorders. This white paper was developed in collaboration with an expert Advisory Committee on Policies to Promote Responsible Access to New Therapies, made up of leading authorities from the nonprofit, academic, medical, legal, and pharmaceutical sectors. Putting Patients First urges the U.S. Food and Drug Administration (FDA) to work with PPMD and the rare disease community to take advantage of opportunities created by the 2012 passage of the Food and Drug Administration Safety and Innovation Act to enhance patient access to new therapies for serious and life-threatening disorders.  In implementing the law, PPMD and the Advisory Committee encourage the FDA to “strike a more appropriate balance between clinical certainty and patient access to potentially life-saving treatments.”

25/04/2013 - Mutations in GFPT1 that underlie limb-girdle congenital myasthenic syndrome result in reduced cell-surface expression of muscle AChR

Mutations in GFPT1 underlie a congenital myasthenic syndrome characterised by a limb-girdle pattern of muscle weakness. Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is a key rate-limiting enzyme in the hexosamine biosynthetic pathway providing building blocks for the glycosylation of proteins and lipids. It is expressed ubiquitously and it is not readily apparent why mutations in this gene should cause a syndrome with symptoms restricted to muscle and in particular to the neuromuscular junction. Data from a muscle biopsy obtained from a patient with GFPT1mutations indicated that there were reduced endplate acetylcholine receptors. The authors therefore further investigated the relationship between identified mutations in GFPT1 and expression of muscle acetylcholine receptor. Cultured myotubes derived from two patients with GFPT1 mutations showed a significant reduction of cell-surface AChR expression (Pt1 p<0.0001; Pt2 p=0.0097). Inhibition of GFPT1 enzymatic activity or siRNA silencing of GFPT1 expression both resulted in reduced AChR cell-surface expression. Western blot and gene silencing experiments indicate this is due to reduced steady-state levels of AChR α, δ, ε, but not β subunits rather than altered transcription of AChR-subunit RNA. UDP-GlcNAc, a product of the hexosamine synthetic pathway, acts as a substrate at an early in the N-linked glycosylation pathway. Similarity between congenital myasthenic syndrome due to GFPT1 mutations and congenital myasthenic syndrome due to DPAGT1 mutations would suggest that reduced endplate AChR due to defective N-linked glycosylation is a primary disease mechanism in this disorder.

25/04/2013 - Non-surgical prevention and management of scoliosis for children with Duchenne muscular dystrophy: What is the evidence?

This review was performed to examine the evidence for non-surgical interventions for preventing scoliosis and the need for scoliosis surgery in children with Duchenne muscular dystrophy. Medline and Embase databases and reference lists from key articles were searched. After the inclusion and exclusion criteria were applied, 13 studies were critically appraised independently by two reviewers. The included studies examined spinal orthoses and steroid therapy. There were no studies with high levels of evidence (randomised or other controlled trials). The studies with the highest level of evidence were non-randomised experimental trials. There is some evidence that children with Duchenne muscular dystrophy who receive steroid therapy might have delayed onset of scoliosis, but more evidence is required about the long-term risks versus benefits of this intervention. There is weak evidence that spinal orthoses do not prevent and only minimally delay the onset of scoliosis.

25/04/2013 - A mutation in the transportin 3 gene results in LGMD 1F

In 2001, the authors of the present study reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, they identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Their results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies.

25/04/2013 - Identification of the genetic cause of HMSN-P

Hereditary motor and sensory neuropathy with proximal dominance (HMSN-P) has been reported as a rare type of autosomal dominant adult-onset Charcot-Marie-Tooth disease. HMSN-P has been described only in Japanese descendants since 1997, and the causative gene has not been found. In this genetic and observational analysis study, the authors aimed to identify the genetic cause of HMSN-P in a Korean family and determine the pathogenic mechanism. The study was carried out in a translational research centre for rare neurologic disease and included 28 individuals (12 men and 16 women) from a Korean family with HMSN-P. The main outcome measures were whole-exome sequencing, linkage analysis, and magnetic resonance imaging. Through whole-exome sequencing, the authors revealed that HMSN-P is caused by a mutation in the TRK-fused gene (TFG). Clinical heterogeneities were revealed in HMSN-P between Korean and Japanese patients. The patients in the present report showed faster progression of the disease compared with the Japanese patients, and sensory nerve action potentials of the sural nerve were lost in the early stages of the disease. Moreover, tremor and hyperlipidemia were frequently found. Magnetic resonance imaging of the lower extremity revealed a distinct proximal dominant and sequential pattern of muscular involvement with a clearly different pattern than patients with Charcot-Marie-Tooth disease type 1A. Particularly, endoneural blood vessels revealed marked narrowing of the lumen with swollen vesicular endothelial cells. The authors conclude that the underlying cause of HMSN-P proves to be a mutation in TFG that lies on chromosome 3q13.2. This disease is not limited to Japanese descendants, and marked narrowing of endoneural blood vessels was noted in the present study. The authors suggest that TFG can affect the peripheral nerve tissue.

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