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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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21/07/2014 - Routine newborn screening for Duchenne Muscular Dystrophy

In this article, the author discusses the case for systematic genetic screening of newborns and children at-risk of developing or carrying mutations for Duchenne Muscular Dystrophy (DMD). Belgium remains the only country to conduct systematic newborn screening and follow-up testing for DMD. Germany, Wales and Canada have abandoned DMD routine genetic testing and the US has never implemented newborn screening. The US Discretionary Advisory Committee on Heritable Disorders in Newborns and Children (DACHDNC) recommends screening for 57 disorders, among which DMD does not feature. The author argues that past criteria for excluding DMD from routine screening, namely high rates of false positives and lack of treatment, no longer apply to the disease. She also highlights that growing progress in DMD genetic diagnosis and potential treatments should be considered. While ten years ago, no medical benefit resulted from newborn screening for DMD, today’s personalised therapeutic approaches show promise in slowing disease progression and, in some cases, reversing the underlying causes of DMD. Two drugs in late stage clinical development, Ataluren (PTC Therapeutics) and Drisapersen (Prosensa) demonstrate efficacy to increase dystrophin production - a key protein in muscle function - in DMD patients affected by several DMD gene mutations. The author therefore urges newborn screening committees to address the value of routine testing, enabling early disease management.

21/07/2014 - FDA grants Fast Track designation to Akashi Therapeutics' HT-100 for treatment of DMD

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to Akashi Therapeutics' most advanced product candidate, HT-100 (delayed-release halofuginone), an orally available, small molecule drug candidate intended to reduce fibrosis and inflammation and promote healthy muscle regeneration in boys with DMD. Fast track designation is granted by the FDA to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Akashi is currently treating patients with DMD in a phase 1b/2a multi-center clinical program to evaluate HT-100 safety and tolerability and assess trends in a range of exploratory biomarkers and efficacy endpoints. There were no serious or clinically significant adverse events in the first 17 DMD patients to receive HT-100 for up to 92 days at doses ranging from 0.3 to 1.2 milligrams per day. The preliminary data on the 12 boys who received repeated doses of HT-100 indicate that the drug is having the desired effects on muscle tissue with respect to fibrosis.

21/07/2014 - ReveraGen DMD drug moves forward to phase 1 clinical trial

ReveraGen BioPharma is moving ahead with a phase 1 trial of an experimental drug in development, VBP15, to treat Duchenne muscular dystrophy (DMD). The drug, will be evaluated for safety in healthy people in this phase 1 study. VBP15 is an experimental compound intended to replicate the benefits of corticosteroid drugs like prednisone and deflazacort, which are widely used to treat DMD, but to eliminate their unwanted side effects. VBP15 is an oral drug that has shown efficacy in animal models of Duchenne muscular dystrophy through both anti-inflammatory and membrane stabilization properties. VBP15 shares some beneficial aspects of the glucocorticoid drug prednisone, but with fewer significant side effects and improved efficacy in pre-clinical trials. In studies, VBP15 reduced inflammation and stabilize cell membranes, both of which are important to treating DMD. There are no approved drugs for DMD, although daily prednisone or deflazacort are often used off label. The significant side effect profiles associated with these drugs, including stunting of growth, mood changes, bone fragility, and weight gain detract significantly from patient quality of life. Finding alternatives to glucocorticoids in DMD is an important priority and pending regulatory review and approval, clinical trials of these drugs will be an important milestone. If VBP15 is safe and well tolerated in healthy volunteers, the next step is likely to be a trial of the drug in people with DMD.

21/07/2014 - Melusin chaperone overexpression delays the onset of Emery-Dreifuss cardiomyopathy

Familial cardiomyopathies are caused by genetic mutations that induce accumulation of misfolded proteins with consequent cardiomyocyte death and maladaptive cardiac remodelling. Molecular chaperones are a family of proteins devoted to prevent accumulation of misfolded proteins by promoting either their refolding or degradation via the ubiquitin-proteasome or the autophagosome systems and can thus represent a potential mean to treat familial cardiomyopathies. Melusin is a muscle specific chaperone protein whose overexpression effectively prevents maladaptive cardiac remodeling and heart failure both in pressure overload and myocardial infarct mouse models. In this study the authors used in vivo gene delivery with cardiotropic adeno associated virus 9 vector to induce melusin expression in the heart of mice carrying H222P Lamin A mutation mimicking human Emery-Dreifuss familial cardiomyopathy. Mutant male mice develop spontaneous dilated cardiomyopathy from 4 months of age and die within 10-12 months of age. Homozygous mutant mice were injected with AAV9-Melusin (I.V. injection of 1012 viral particles/mouse) either at 1 month of age before development of the cardiomyopathy or at 4 months when cardiomyopathy was already present to test for both preventive and therapeutic activity. Cardiac function was monitored by echocardiography for the following months. While untreated mice progressively developed left ventricle dilation and reduced contractility (FS%), mice injected with AAV9-Melusin retained physiological level of contractility and were protected toward LV dilation. Ten months after the treatment, 40% of mutant mice died, while 100% of melusin-treated mice were alive. A second group of mutant male mice was injected with AAV9-melusin at 4 months of age when the cardiomyopathy was already detectable. Interestingly melusin prevented the deterioration of contractility in the following 6 months and significantly reduced mortality. These data indicate that melusin chaperone overexpression can effectively delay the onset of Emery-Dreifuss cardiomyopathy as well as arrest the progression of the already established pathology.

21/07/2014 - The burden of Duchenne muscular dystrophy: An international, cross-sectional study

The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in Europe-Assessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and $54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and $120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and $71,900. This study shows that DMD is associated with a substantial economic burden. The results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. The description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies.

21/07/2014 - Early decreasing ovarian function in women with myotonic dystrophy

Myotonic dystrophy (DM) is the most common form of muscular dystrophy in adults. There are conflicting reports about its effect on female fertility. This study investigated ovarian reserve and IVF-preimplantation genetic diagnosis (PGD) outcome in women with DM1. A total of 21 women undergoing PGD for DM1 were compared with 21 age- and body mass index-matched women undergoing PGD for other diseases. Ovarian reserve markers, response to stimulation, embryo quality and clinical pregnancy and live birth rates were compared. Day-3 FSH concentration was higher, while anti-Müllerian hormone (AMH) concentration and antral follicle count (AFC) were lower in the DM1 group (median, range: 6.9 (1.8-11.3) versus 5.7 (1.5-10.7)IU/l; 0.9 (0.17-5.96) versus 2.68 (0.5-9.1)ng/ml; and 13 (0-63) versus 23 (8-40) follicles, respectively, all P<0.05). Total FSH dose was higher (5200 versus 2250IU, P=0.004), while the numbers of oocytes retrieved (10 versus 16, P<0.04) and metaphase-II oocytes (9 versus 12, P<0.03) were lower in the DM1 group. The number of cycles with top-quality embryos and the clinical pregnancy rate were lower in the DM1 group. In conclusion, there is evidence of diminished ovarian reserve and less favourable IVF-PGD outcome in women with DM1. There is evidence of subfertility in males affected with the disease but conflicting reports about the effect of the disease on female fertility. The authors recommend advising these women about the possibility of early decreasing ovarian function in order to prevent any delay in reproductive planning.

21/07/2014 - The exosomal pathway plays a central role in neurodegenerative diseases

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here the authors show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

21/07/2014 - Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

Sporadic inclusion body myositis (sIBM) is the commonest idiopathic inflammatory muscle disease in people over 50 years old. It is characterized by slowly progressive muscle weakness and atrophy, with typical pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. The cause(s) of sIBM are still unknown, but are considered complex, with the contribution of multiple factors such as environmental triggers, ageing and genetic susceptibility. This review summarizes the current understanding of the genetic contributions to sIBM and provides some insights for future research in this mysterious disease with the advantage of the rapid development of advanced genetic technology. An international sIBM genetic study is ongoing and whole-exome sequencing will be applied in a large cohort of sIBM patients with the aim of unravelling important genetic risk factors for sIBM.

21/07/2014 - Evaluation and construction of diagnostic criteria for inclusion body myositis

The objective of this study was to use patient data to evaluate and construct diagnostic criteria for inclusion body myositis (IBM), a progressive disease of skeletal muscle. The literature was reviewed to identify all previously proposed IBM diagnostic criteria. These criteria were applied through medical records review to 200 patients diagnosed as having IBM and 171 patients diagnosed as having a muscle disease other than IBM by neuromuscular specialists at 2 institutions, and to a validating set of 66 additional patients with IBM from 2 other institutions. Machine learning techniques were used for unbiased construction of diagnostic criteria. Twenty-four previously proposed IBM diagnostic categories were identified. Twelve categories all performed with high (≥97%) specificity but varied substantially in their sensitivities (11%-84%). The best performing category was European Neuromuscular Centre 2013 probable (sensitivity of 84%). Specialized pathologic features and newly introduced strength criteria (comparative knee extension/hip flexion strength) performed poorly. Unbiased data-directed analysis of 20 features in 371 patients resulted in construction of higher-performing data-derived diagnostic criteria (90% sensitivity and 96% specificity). Published expert consensus-derived IBM diagnostic categories have uniformly high specificity but wide-ranging sensitivities. High-performing IBM diagnostic category criteria can be developed directly from principled unbiased analysis of patient data. This study provides Class II evidence that published expert consensus-derived IBM diagnostic categories accurately distinguish IBM from other muscle disease with high specificity but wide-ranging sensitivities.

21/07/2014 - Antititin antibody in early- and late-onset myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against neuromuscular junction proteins, 85% of patients have antibodies against acetylcholine receptor (AChR-MG). Antititin antibodies are present in a subset of patients with MG. This study aimed to determine the value of antititin antibodies as severity markers and thymoma predictors in early- and late-onset MG. Two-hundred and ninety-five consecutive MG patients (188 F and 107 M) aged 12-89 years (mean 50y) were included. 164 patients had early-onset (EOMG, ≤50 years of age), 131 had late-onset MG (LOMG). Twenty-six patients had thymoma. Symptoms, severity graded with MGFA scale, thymus histology, medications, and treatment results were analyzed. Antititin antibodies were present in 27% (81) of all patients: 54% of thymoma MG, 0.6% of non-thymomatous EOMG, and 55% of LOMG, with proportion of titin-positive patients increasing linearly from 40% in the 6th to 88% in the 9th decade of life. Titin-positive patients had more bulbar symptoms (P = 0.003). Severity of MG, need for immunosuppression, myasthenic crisis risk or treatment results were not related to its presence. Antititin antibodies had 56% sensitivity, 99% specificity, 90% positive predictive value (PPV), and 95% negative predictive value (NPV) for thymoma diagnosis in EOMG, and 50% sensitivity, 75% specificity, 71% PPV and 55% NPV in LOMG. Antititin antibodies have high PPV and NPV for thymoma in EOMG. In MG without thymoma, antititin antibodies can be considered as markers of LOMG, but not of a severe course in our MG cohort.

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