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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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20/03/2015 - Diagnostic value of the non-ischaemic forearm exercise test in detecting glycogenosis type V

The study is a retrospective diagnostic study over 15 years (1999-2013) on a referred sample of patients suffering from exercise intolerance and various muscle complaints, generally with elevated creatine kinase (CK). In all, 1226 patients underwent the non-ischaemic forearm exercise test. Blood lactate, ammonia and CK levels were analyzed. DNA analyses and/or muscle biopsies were assessed to confirm the diagnosis of McArdle's disease. The results of 60 volunteers were used to compare with the results of study subjects. In this cohort, 40 patients were finally diagnosed with McArdle's disease. Absolute values of lactate and ammonia rise were used to discriminate all McArdle patients from healthy patients. A sensitivity and specificity of respectively 100% and 99.7% were calculated. The 24-h CK level showed no significant difference from the CK level at the day of the test and confirms the safety of the test. This study has formally assessed the diagnostic value of the non-ischaemic forearm exercise test in the detection of McArdle's disease. Very high sensitivity and specificity were observed. Furthermore, the test is easy to set up and to perform, it is non-traumatic and cost effective. It may circumvent a muscle biopsy in McArdle patients presenting the most common mutations. Hence, it is a perfect and safe screening instrument to detect patients with McArdle's disease. Glycogen storage disease type III patients, however, may show similar patterns to McArdle patients.


20/03/2015 - Zebra body myopathy: 40 years later

This study presents follow up data on the original case of 'zebra body myopathy' published by Lake and Wilson in 1975. Pathological features in a second biopsy performed at the age of 29 years included a wide variation in fibre size, multiple split fibres, excess internal nuclei and endomysial connective tissue, rimmed vacuoles, accumulation of myofibrillar material and large 'wiped out' areas lacking stain for oxidative enzymes. The presence of nemaline rods and actin-like filaments in addition to small zebra bodies suggested ACTA1 as a candidate gene. This has been confirmed by the identification of a novel c.1043T.p.Leu348Gln mutation, which probably occurred de novo. This case illustrates that the myopathy associated with zebra bodies is part of the spectrum of myopathies associated with the ACTA1 gene. It also highlights that accumulation of actin filaments is not confined to severe neonatal ACTA1 cases and that progression of weakness can occur in congenital myopathies, as the patient is now wheelchair bound and can only stand with the aid of a walking frame.


20/03/2015 - Skeletal muscle quantitative nuclear magnetic resonance imaging follow-up of adult Pompe patients

Adult late-onset Pompe disease is most often a slowly progressive limb-girdle and spine extensor muscle dystrophy, due to defective lysosomal acid maltase. With the exception of the few patients who present with a dramatically accelerated clinical course, standard diagnostic imaging fail to detect and evaluate disease progression between two successive visits. In muscle dystrophy of very rapid evolution, like the Duchenne disease, quantitative NMR imaging has successfully demonstrated its capacity to objectivate both disease activity and degenerative changes progression over short follow-up periods. The purpose of this retrospective monocentric open-label study was to investigate whether quantitative NMR imaging can monitor disease progression in adult Pompe patients despite its very slow nature. Quantitative imaging of Pompe patients succeeded in demonstrating that muscle fatty infiltration increased on average by 0.9 %/year, with the hamstring and adductor muscles showing the fastest degradation. Muscle water T2 mapping revealed that 32 % of all muscles had abnormally high T2 in at least one of two successive examinations. When muscle water T2 was abnormal, fatty degenerative changes were further increased by 0.61 %/year. Enzyme replacement therapy resulted in 0.68 %/year slowdown of the muscle fatty infiltration, in both muscles with normal and high T2s.


20/03/2015 - Relationship between the ventilatory response to CO2 and the impairment of lung function in DM1 patients

Myotonic dystrophy Type 1 (DM1) is the most common muscular dystrophy in adults. Respiratory failure is common but clinical findings support a dysregulation of the control of breathing at central level, furthermore contributing to alveolar hypoventilation independently of the severity of respiratory weakness. Here, the authors investigated the relationship between the ventilatory response to CO2 and the impairment of lung function in DM1 patients. Sixty-nine DM1 patients were prospectively investigated (43.5 ± 12.7 years). Systematic pulmonary lung function evaluation including spirometry, plethysmography, measurements of respiratory muscle strength, arterial blood gas analysis and ventilatory response to CO2 were performed. Thirty-one DM1 patients (45%) presented a ventilatory restriction, 38 (55%) were hypoxaemic and 15 (22%) were hypercapnic. Total lung capacity decline was correlated to hypoxaemia (p = 0.0008) and hypercapnia (p = 0.0013), but not to a decrease in ventilatory response to CO2 (p = 0.194). Ventilatory response to CO2 was reduced to 0.85 ± 0.67 L/min/mmHg and not correlated to respiratory muscle weakness. Ventilatory response to CO2 was neither different among restricted/non-restricted patients (p = 0.2395) nor among normoxaemic/hypoxaemic subjects (p = 0.6380). The reduced ventilatory response to CO2 in DM1 patients appeared independent of lung function impairment and respiratory muscle weakness, suggesting a central cause of CO2 insensitivity.


20/03/2015 - Genome modification to reverse DM1 phenotypes

Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the 3'-untranslated region (3' UTR) of the DMPK gene. Correcting the mutation in DM1 stem cells would be an important step towards autologous stem cell therapy. The objective of this study is to demonstrate in vitro genome editing to prevent production of toxic mutant transcripts and reverse phenotypes in DM1 stem cells. Genome editing was performed in DM1 neural stem cells (NSCs) derived from human DM1 iPS cells. An editing cassette containing SV40/bGH polyA signals was integrated upstream of the CTG repeats by TALEN-mediated homologous recombination (HR). The expression of mutant CUG repeats transcript was monitored by nuclear RNA foci, the molecular hallmarks of DM1, using RNA fluorescence in situ hybridization (RNA-FISH). Alternative splicing of microtubule-associated protein tau (MAPT) and muscleblind-like (MBNL) proteins were analyzed to further monitor the phenotype reversal after genome modification. The cassette was successfully inserted into DMPK intron 9 and this genomic modification led to complete disappearance of nuclear RNA foci. MAPT and MBNL 1, 2 aberrant splicing in DM1 NSCs was reversed to normal pattern in genome-modified NSCs. Interpretation: Genome modification by integration of exogenous polyA signals upstream of the DMPK CTG repeat expansion prevents the production of toxic RNA and leads to phenotype reversal in human DM1 iPS-cells derived stem cells. These data provide proof-of-principle evidence that genome modification may be used to generate genetically modified progenitor cells as a first step toward autologous cell transfer therapy for DM1. 


20/03/2015 - FSHD pathology: role of miRNA

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder and is one of the most common forms of muscular dystrophy. The authors have recently shown that some hallmarks of FSHD are already expressed in fetal FSHD biopsies, thus opening a new field of investigation for mechanisms leading to FSHD. As microRNAs (miRNAs) play an important role in myogenesis and muscle disorders,  miRNAs expression levels were compared during normal and FSHD muscle development. Muscle biopsies were obtained from quadriceps of both healthy control and FSHD1 fetuses with ages ranging from 14 to 33 weeks of development. miRNA expression profiles were analyzed using TaqMan Human MicroRNA Arrays. During human skeletal muscle development, in control muscle biopsies changes for 4 miRNAs potentially involved in secondary muscle fiber formation and 5 miRNAs potentially involved in fiber maturation were observed. When the miRNA profiles obtained from control and FSHD biopsies were compared, no differences in the muscle specific miRNAs were observed. However, 8 miRNAs exclusively expressed in FSHD1 samples (miR-330, miR-331-5p, miR-34a, miR-380-3p, miR-516b, miR-582-5p, miR-517* and miR-625) were observed, which could represent new biomarkers for this disease. Their putative targets are mainly involved in muscle development and morphogenesis. Interestingly, these FSHD1 specific miRNAs do not target the genes previously described to be involved in FSHD. This work provides new candidate mechanisms potentially involved in the onset of FSHD pathology. Whether these FSHD specific miRNAs cause deregulations during fetal development, or protect against the appearance of the FSHD phenotype until the second decade of life still needs to be investigated.


20/03/2015 - Prevalence of Duchenne and Becker Muscular Dystrophies in the United States

This study aimed to estimate the prevalence of childhood-onset Duchenne and Becker muscular dystrophies (DBMD) in 6 sites in the United States by race/ethnicity and phenotype (Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD). In 2002, the Centers for Disease Control and Prevention established the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) to conduct longitudinal, population-based surveillance and research of DBMD in the United States. Six sites conducted active, multiple-source case finding and record ion to identify MD STARnet cases born January 1982 to December 2011. We used cross-sectional analyses to estimate prevalence of DBMD per 10 000 boys, ages 5 to 9 years, for 4 quinquennia (1991-1995, 1996-2000, 2001-2005, and 2006-2010) and prevalence per 10 000 male individuals, ages 5 to 24 years, in 2010. Prevalence was also estimated by race/ethnicity and phenotype. Overall, 649 cases resided in an MD STARnet site during ≥1 quinquennia. Prevalence estimates per 10 000 boys, ages 5 to 9 years, were 1.93, 2.05, 2.04, and 1.51, respectively, for 1991-1995, 1996-2000, 2001-2005, and 2006-2010. Prevalence tended to be higher for Hispanic individuals than non-Hispanic white or black individuals, and higher for DMD than BMD. In 2010, prevalence of DBMD was 1.38 per 10 000 male individuals, ages 5 to 24 years. The authors present population-based prevalence estimates for DBMD in 6 US sites. Prevalence differed by race/ethnicity, suggesting potential cultural and socioeconomic influences in the diagnosis of DBMD. Prevalence also was higher for DMD than BMD. Continued longitudinal surveillance will permit us to examine racial/ethnic and socioeconomic differences in treatment and outcomes for MD STARnet cases.



20/03/2015 - Multiplex CRISPR/Cas9 facilitates correction of DMD mutations

The CRISPR/Cas9 genome-editing platform is a promising technology to correct the genetic basis of hereditary diseases. The versatility, efficiency and multiplexing capabilities of the CRISPR/Cas9 system enable a variety of otherwise challenging gene correction strategies. Here, the authors use the CRISPR/Cas9 system to restore the expression of the dystrophin gene in cells carrying dystrophin mutations that cause Duchenne muscular dystrophy (DMD). Single or multiplexed sgRNAs were designed to restore the dystrophin reading frame by targeting the mutational hotspot at exons 45-55 and introducing shifts within exons or deleting one or more exons. Following gene editing in DMD patient myoblasts, dystrophin expression is restored in vitro. Human dystrophin is also detected in vivo after transplantation of genetically corrected patient cells into immunodeficient mice. Importantly, the unique multiplex gene-editing capabilities of the CRISPR/Cas9 system facilitate the generation of a single large deletion that can correct up to 62% of DMD mutations.


20/03/2015 - Predicting the cardiac phenotype correlations in DMD and BMD

Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype-cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. The authors performed dystrophin genotype-cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. The authors conclude that genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype-phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies.


20/03/2015 - Effect of voluntary physical activity on skeletal and cardiac muscle

The effects of voluntary activity initiated in adult mdx (C57BL/10ScSc-DMDmdx /J) mice on skeletal and cardiac muscle function have not been studied extensively. Here, the authors studied the effects of 3 months of voluntary wheel running initiated at age 7 months on hindlimb muscle weakness, increased susceptibility to muscle contraction-induced injury, and left ventricular function in mdx mice. Voluntary wheel running did not worsen the deficit in force generating capacity and the force drop following lengthening contractions in both mdx mouse genders. It increased the absolute maximal force of skeletal muscle in female mdx mice. Moreover, it did not affect left ventricular function, structural heart dimensions, cardiac gene expression of inflammation, fibrosis, or remodeling markers. These results indicate that voluntary activity initiated at age 7 months has no detrimental effects on skeletal or cardiac muscles in both mdx mouse genders.



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