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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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For your information, there are at present more than 1250 news items on myology online.
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21/11/2014 - An unusual case of carotid-cavernous fistula mimicking myasthenia gravis

A carotid-cavernous fistula (CCF) is an abnormal communication between the carotid arterial system and the cavernous sinus. Common symptoms of CCFs include proptosis and ophthalmoplegia, but fluctuating diplopia and presence of ptosis are not typical. Here, the authors present an unusual case of CCF with fluctuating binocular diplopia and ptosis, mimicking myasthenia gravis. Electrodiagnostic testing, which included repetitive nerve stimulation and single-fiber electromyography, was normal. Magnetic resonance imaging of the brain and orbits was initially normal, but later magnetic resonance angiography revealed enlargement of the left superior ophthalmic vein along with a left CCF. Patient underwent a successful left cavernous sinus embolization. Fluctuating ophthalmic symptoms are a typical presentation of myasthenia gravis; however, there may be an association of these symptoms with a CCF. Repetitive nerve stimulation and single-fiber electromyography played a key role in diagnosis of this case, as the normal result led to further investigations revealing a CCF.


21/11/2014 - Direct interplay between DUX4 and FRG1 contributes to FSHD pathogenesis

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The major form of the disease (FSHD1) is linked to decrease in copy number of a 3.3-kb tandem repeated macrosatellite (D4Z4), located on chromosome 4q35. D4Z4 deletion alters chromatin structure of the locus leading to aberrant expression of nearby 4q35 genes. Given the high variability in disease onset and progression, multiple factors could contribute to the pathogenesis of FSHD. Among the FSHD candidate genes are DUX4 (double homeobox 4), encoded by the most telomeric D4Z4 unit, and FRG1 (FSHD region gene 1). DUX4 is a sequence-specific transcription factor. Here, the authors located putative DUX4 binding sites in the human FRG1 genomic area and show specific DUX4 association to these regions. They also found that ectopically expressed DUX4 up-regulates the endogenous human FRG1 gene in healthy muscle cells, while DUX4 knockdown leads to a decrease in FRG1 expression in FSHD muscle cells. Moreover, DUX4 binds directly and specifically to its binding site located in the human FRG1 gene and transactivates constructs containing FRG1 genomic regions. Intriguingly, the mouse Frg1 genomic area lacks DUX4 binding sites and DUX4 is unable to activate the endogenous mouse Frg1 gene providing a possible explanation for the lack of muscle phenotype in DUX4 transgenic mice. Altogether, these results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to FSHD.


21/11/2014 - Dystrophin deficient rats: a new and promising model for DMD

Few animal models of Duchenne muscular dystrophy (DMD) are available: large models such as pigs or dogs are expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals from both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. Dmdmdx rats thus represent a new faithful small animal model of DMD.