Progressive Muscle Disease Research Articles

Sarcopenia (literature review)

Today, when it comes to geriatric syndromes, scientists pay an extraordinary amount of attention to sarcopenia, due to its significant medical and social consequences of the condition. It has been established that in the presence of sarcopenia the risk of falls and fractures increases, daily physical activity decreases. It is associated with pathologies of the cardiovascular system and respiratory organs, and cognitive impairment; quality of life is made worse, patients with sarcopenia need extraneous help. The prevalence of sarcopenia varies significantly (5-70%) depending on age, gender and ethnicity. In 2009, the European Working Group on Sarcopenia in Older People (EWGSOP) was set up to actively develop definitions and diagnostic criteria for sarcopenia. In 2010, a first consensus was published on the definition and diagnosis of sarcopenia, in 2019, the consensus was updated. According to the latest revision of EWGSOP consensus, sarcopenia is a progressive and generalized skeletal muscle disease that is associated with an increased risk of falls, fractures, impaired physical activity and mortality. The review of the EWGSOP consensus is driven by the significant increase of the number of sarcopenia studies in the world, and the emergence of new data on the epidemiology, mechanisms of development, diagnosis, prevention and treatment of the condition. To date, sarcopenia is considered a disorder. In 2016, the diagnosis of sarcopenia was formally included in the supplemented 10th International Classification of Diseases under the code M 62.84. This article presents data on the epidemiology of sarcopenia, describes the mechanisms of development, outlines the latest recommendations for the diagnosis of sarcopenia according to the 2019 EWGSOP consensus, as well as methods for the prevention and treatment of the disease. Key words: sarcopenia, muscle, age. For citation: Povoroznyuk VV, Dzerovych NI. Sarcopenia (LITERATURE REVIEW). Journal of the National Academy of Medical Sciences of Ukraine. 2019;25(3):321–31

Dysphagia diagnosis with questionnaire, tongue strength measurement, and FEES in patients with childhood-onset muscular dystrophy

IntroductionDysphagia in progressive muscle diseases is primarily due to muscle weakness. Objective of our study is to investigate the prevalence and phenotypes of dysphagia in patients with childhood onset muscular dystrophy (MD) with the use of a validated questionnaire, the measurement of tongue strength and Flexible Endoscopic Evaluation of Swallowing (FEES). MethodsProspective observational longitudinal study of dysphagia in a cohort of 58 patients attending the Pediatric Department Center for Neuromuscular Diseases. Control participants were 56 age and sex matched healthy volunteers. Dysphagia was evaluated with the Eating Assessment Tool-10 (EAT-10), and the measurement of Maximal Isometric Tongue Pressure (MITP) and tongue endurance (Iowa Oral Performance Instrument-IOPI). Dysphagic patients were submitted to FEES. Recorded data included demographic and anthropometric characteristics, type of MD, feeding status, and spirometry. ResultsOur patients' cohort consisted of 41 children, 11 adolescents, and 6 adults. Based on EAT-10, 20.7% of the patients were dysphagic: 14.63% of children, 27.3% of adolescents and 50% of adults. The main complain was solid food dysphagia. Spirometry parameters mean values for children and adolescent patients corresponded to lower than the fifth percentile. Means of FVC and FEV1 expressed as % predicted for adult patients were 27.8 (SD:25.05) and 28.8 (SD:28.44) respectively. Reduced tongue strength was measured to children aged 9-10, adolescent and adult MD patients. The main FEES findings were pharyngeal residue, spillage of food before the swallow, and supraglottal penetration. DiscussionThis is the first study to use a validated questionnaire to evaluate dysphagia in childhood onset MD and report dyphagia prevalence at different patients' age. This is the first study reporting MITP in children and adults with generalised MD. Tongue pressures are reduced well before clinical signs of dysphagia are present. ConclusionScreening of potentially dysphagic MD patients can be based on a validated questionnaire. Patients with an EAT-10 score suggestive of dysphagia at regular follow-up can have the MITP measured and in the case of reduced values a thorough dysphagia evaluation with FEES is indicated.

Bayesian model of disease progression in GNE myopathy.

One Sentence Summary: A Bayesian repeated measures model based on quantitative muscle strength data from a prospective Natural History Study was developed to determine disease progression and design clinical trials for GNE myopathy, a rare and slowly progressive muscle disease. GNE myopathy is a rare muscle disease characterized by slowly progressive weakness and atrophy of skeletal muscles. To address the significant challenges of defining the natural history and designing clinical trials for GNE myopathy, we developed a Bayesian latent variable repeated measures model to determine disease progression. The model is based on longitudinal quantitative muscle strength data collected as part of a prospective Natural History Study. The GNE Myopathy Progression Model provides an understanding of disease progression that would have otherwise required a natural history of unfeasible duration. "Disease age," the model-generated measure of disease progression, highly correlates with a variety of clinical, functional and patient-reported outcomes. With the incorporation of a treatment effect parameter to the GNE Disease Progression Model, we describe a novel GNE Myopathy Disease Modification Analysis that significantly increases power and reduces the number of subjects required to test the effectiveness of novel therapies when compared to more traditional analysis methods. The GNE Myopathy Disease Progression Model and Disease Modification Analysis can be applied to muscle diseases with prospectively collected muscle strength data, and a variety of rare and slowly progressive diseases.

NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY: P.385Physician-Level muscle disease classifier for computer-aided diagnostics with neural networks

Even in the current era of molecular biology, muscle pathology still plays a central role in diagnosing muscle disease. Among these diseases, muscular dystrophy (MD) is a group of progressive hereditary muscle diseases for which no curative therapy is available, and immune-mediated necrotizing myopathy (IMNM) is a subclass of myositis that can be treated by immune therapy. Whereas MD and IMNM are both pathologically characterized by the presence of necrotic and regenerating fibers and often look similar. Therefore, the differentiation of these conditions is a hot topic in myology. To develop and evaluate an algorithm for computer-aided muscle histopathological diagnosis that uses deep learning. We chose two disease categories, MD and IMNM, and aimed to distinguish between these conditions. We prepared 11-layer convolutional neural networks and 1977 (MD: 885, IMNM: 1092) H&E-stained muscle section images classified in real diagnosis. Of these, 190 (MD: 78, IMNM: 112) images were used as a test set and the others (MD: 807, IMNM: 980) for training. After training our model with the training dataset, we evaluated its classification performance. For comparison, seven physicians also classified the same test set. After training of the model, the AUC, the area under the ROC (Receiver operating characteristic) curve, of our model was 0.94. In terms of accuracy, the classifier achieved better results, 88% on average, than seven physicians specializing in muscle disease among whom the best accuracy was 78%, indicating that our model outperforms physicians at classifying the two muscle diseases on H&E images. There are a number of limitations in this study. For example, we used only H&E images and the classification (diagnosis) was made between only two disease conditions. Nevertheless, our results suggest the deep neural network model can make pathological diagnosis better than physicians at least under certain conditions.

Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance.

Sporadic late-onset nemaline myopathy (SLONM) with monoclonal gammopathy of undetermined significance (MGUS) is a rare subacute progressive muscle disease. The prognosis is poor due to severe respiratory insufficiency. Recently, however, autologous stem-cell transplantation following high-dose melphalan has been shown to be effective unless there is delay before the treatment. Therefore, early recognition of the disease is important. This review gives an overview of recent advances in SLONM-MGUS, which could help to understand clinical and pathological features and treatment. Efficacy of autologous stem-cell transplantation following high-dose melphalan has been demonstrated in a long-term observation study. Subsequently, reports from other groups also have supported it. Furthermore, efficacy of chemotherapy toward plasma cell dyscrasia without stem-cell transplantation have been reported as well. A few case reports have suggested the presence of cardiac involvement related to SLONM-MGUS. SLONM-MGUS is now considered as a treatable disease. Antiplasma cell dyscrasia therapy is a promising therapeutic option. Meanwhile, the pathomechanic link between muscle degeneration and monoclonal gammopathy remains unclear and further investigations are warranted.

P.189 - Incidence and prevalence of inclusion body myositis in western Sweden

The slowly progressive muscle disease inclusion body myositis (IBM) causing muscle weakness and swallowing difficulties is the most common acquired myopathy in the elderly. To obtain more information of comorbidity, biomarkers and genetic background we aimed to investigate epidemiological aspects of IBM in a population based study. The region Västra Götaland in western Sweden includes approximately 1.5 million inhabitants (data from SCB, Statistics Sweden). Nearly all muscle biopsies performed to diagnose muscle disease in the region have since 1985 been analyzed at the Department of Pathology and Genetics at the Sahlgrenska University Hospital, Gothenburg. Patients were identified by screening all muscle histology reports from 1996 to 2016 for diagnosis myositis or myopathy. An additional approach was to identify all patients with diagnosis IBM at the Neuromuscular Centre at Sahlgrenska University Hospital. All patients living in the region Västra Götaland were included if they fulfilled the ENMC research criteria for clinico-pathologically defined IBM from 2011. The date of the first biopsy fulfilling the ENMC criteria was used as date of diagnosis. A total of 84 patients fulfilled the inclusion criteria. The point prevalence of IBM December 31st 2015 was 27 (95% CI 20–37) per million inhabitants. The incidence rate during the 20-year period varied from 0 (95% CI 0–2.5) to 5.4 (95% CI 2.3–10.1) per million inhabitants and year. Both prevalence and incidence are probably underestimated in our study due to exclusion of patients not fulfilling the strict 2011 ENMC criteria for clinico-pathologically defined IBM. Although inclusion criteria may vary in different studies, the prevalence is similar to a previous study from Norway (33 per million) and higher than a study from the Netherlands (4.9 per million) using the ENMC criteria from 2011 and 1997 respectively. Our well-defined patient cohort will be the basis for further epidemiological studies.

BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

BackgroundFacioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD.MethodsWe screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures.ResultsOur screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively.ConclusionsThese data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets.

Improving Reproducibility of Phenotypic Assessments in the DyW Mouse Model of Laminin-α2 Related Congenital Muscular Dystrophy.

Laminin-α2 related Congenital Muscular Dystrophy (LAMA2-CMD) is a progressive muscle disease caused by partial or complete deficiency of laminin-211, a skeletal muscle extracellular matrix protein. In the last decade, basic science research has queried underlying disease mechanisms in existing LAMA2-CMD murine models and identified possible clinical targets and pharmacological interventions. Experimental rigor in preclinical studies is critical to efficiently and accurately quantify both negative and positive results, degree of efficiency of potential therapeutics and determine whether to move a compound forward for additional preclinical testing. In this review, we compare published available data measured to assess three common parameters in the widely used mouse model DyW, that mimics LAMA2-CMD, we quantify variability and analyse its possible sources. Finally, on the basis of this analysis, we suggest standard set of assessments and the use of available standardized protocols, to reduce variability of outcomes in the future and to improve the value of preclinical research.

Pathomechanisms of anti-cytosolic 5'-nucleotidase 1A autoantibodies in sporadic inclusion body myositis.

Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5'-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis. We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies. Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A-positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the autoantibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A-positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A-positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration. Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. Ann Neurol 2017;81:512-525.

Respiratory failure because of neuromuscular disease.

Understanding the mechanisms and abnormalities of respiratory function in neuromuscular disease is critical to supporting the patient and maintaining ventilation in the face of acute or chronic progressive impairment. Retrospective clinical studies reviewing the care of patients with Guillain-Barré syndrome and myasthenia have shown a disturbingly high mortality following step-down from intensive care. This implies high dependency and rehabilitation management is failing despite evidence that delayed improvement can occur with long-term care. A variety of mechanisms of phrenic nerve impairment have been recognized with newer investigation techniques, including EMG and ultrasound. Specific treatment for progressive neuromuscular and muscle disease has been increasingly possible particularly for the treatment of myasthenia, metabolic myopathies, and Duchenne muscular dystrophy. For those conditions without specific treatment, it has been increasingly possible to support ventilation in the domiciliary setting with newer techniques of noninvasive ventilation and better airway clearance. There remained several areas of vigorous debates, including the role for tracheostomy care and the place of respiratory muscle training and phrenic nerve/diaphragm pacing. Recent studies and systematic reviews have defined criteria for anticipating, recognizing, and managing ventilatory failure because of acute neuromuscular disease. The care of patients requiring long-term noninvasive ventilatory support for chronic disorders has also evolved. This has resulted in significantly improved survival for patients requiring domiciliary ventilatory support.

Kinesio taping application in a pediatric patient with spinal muscular atrophy

Kinesio taping is one of the elastic bandage methods which has been quite popular in the last 20 years and has been applied in various musculoskeletal conditions. Although the mechanism of action is not clear, many theories have been suggested so far. In this case report, we aimed to present the results of kinesiotape application for back pain of the patient with spinal muscular atrophy which is one of the progressive muscular disorders. It was performed for three times with four days interval. Fascial technique B (Space technique) was applied. Reduce of pain was also observed during the subsequent applications. The application of kinesio taping could be beneficial on reducing the pain in patients with progressive muscle diseases.

FLNC myofibrillar myopathy results from impaired autophagy and protein insufficiency.

Myofibrillar myopathy is a progressive muscle disease characterized by the disintegration of muscle fibers and formation of protein aggregates. Causative mutations have been identified in nine genes encoding Z-disk proteins, including the actin binding protein filamin C (FLNC). To investigate the mechanism of disease in FLNCW2710X myopathy we overexpressed fluorescently tagged FLNC or FLNCW2710X in zebrafish. Expression of FLNCW2710X causes formation of protein aggregates but surprisingly, our studies reveal that the mutant protein localizes correctly to the Z-disk and is capable of rescuing the fiber disintegration phenotype that results from FLNC knockdown. This demonstrates that the functions necessary for muscle integrity are not impaired, and suggests that it is the formation of protein aggregates and subsequent sequestration of FLNC away from the Z-disk that results in myofibrillar disintegration. Similar to those found in patients, the aggregates in FLNCW2710X expressing fish contain the co-chaperone BAG3. FLNC is a target of the BAG3-mediated chaperone assisted selective autophagy (CASA) pathway and therefore we investigated its role, and the role of autophagy in general, in clearing protein aggregates. We reveal that despite BAG3 recruitment to the aggregates they are not degraded via CASA. Additionally, recruitment of BAG3 is sufficient to block alternative autophagy pathways which would otherwise clear the aggregates. This blockage can be relieved by reducing BAG3 levels or by stimulating autophagy. This study therefore identifies both BAG3 reduction and autophagy promotion as potential therapies for FLNCW2710X myofibrillar myopathy, and identifies protein insufficiency due to sequestration, compounded by impaired autophagy, as the cause.

Interventions for dysphagia in long-term, progressive muscle disease.

Normal swallowing function is divided into oral, pharyngeal, and oesophageal phases. The anatomy and physiology of the oral cavity facilitates an oral preparatory phase of swallowing, in which food and liquid are pushed towards the pharynx by the tongue. During pharyngeal and oesophageal phases of swallowing, food and liquid are moved from the pharynx to the stomach via the oesophagus. Our understanding of swallowing function in health and disease has informed our understanding of how muscle weakness can disrupt swallowing in people with muscle disease. As a common complication of long-term, progressive muscle disease, there is a clear need to evaluate the current interventions for managing swallowing difficulties (dysphagia). This is an update of a review first published in 2004. To assess the effects of interventions for dysphagia in people with long-term, progressive muscle disease. On 11 January 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, LILACS, and CINAHL. We checked references in the identified trials for additional randomised and quasi-randomised controlled trials. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform on 12 January 2016 for ongoing or completed but unpublished clinical trials. We included randomised and quasi-randomised controlled trials that assessed the effect of interventions for managing dysphagia in adults and children with long-term, progressive muscle disease, compared to other interventions, placebo, no intervention, or standard care. Quasi-randomised controlled trials are trials that used a quasi-random method of allocation, such as date of birth, alternation, or case record number. Review authors previously excluded trials involving people with muscle conditions of a known inflammatory or toxic aetiology. In this review update, we decided to include trials of people with sporadic inclusion body myositis (IBM) on the basis that it presents as a long-term, progressive muscle disease with uncertain degenerative and inflammatory aetiology and is typically refractory to treatment. We applied standard Cochrane methodological procedures. There were no randomised controlled trials (RCTs) that reported results in terms of the review's primary outcome of interest, weight gain or maintenance. However, we identified one RCT that assessed the effect of intravenous immunoglobulin on swallowing function in people with IBM. The trial authors did not specify the number of study participants who had dysphagia. There was also incomplete reporting of findings from videofluoroscopic investigations, which was one of the review's secondary outcome measures. The study did report reductions in the time taken to swallow, as measured using ultrasound. No serious adverse events occurred during the study, although data for the follow-up period were lacking. It was also unclear whether the non-serious adverse events reported occurred in the treatment group or the placebo group. We assessed this study as having a high risk of bias and uncertain confidence intervals for the review outcomes, which limited the overall quality of the evidence. Using GRADE criteria, we downgraded the quality of the evidence from this RCT to 'low' for efficacy in treating dysphagia, due to limitations in study design and implementation, and indirectness in terms of the population and outcome measures. Similarly, we assessed the quality of the evidence for adverse events as 'low'. From our search for RCTs, we identified two other non-randomised studies, which reported the effects of long-term intravenous immunoglobulin therapy in adults with IBM and lip-strengthening exercises in children with myotonic dystrophy type 1. Headaches affected two participants treated with long-term intravenous immunoglobulin therapy, who received a tailored dose reduction; there were no adverse events associated with lip-strengthening exercises. Both non-randomised studies identified improved outcomes for some participants following the intervention, but neither study specified the number of participants with dysphagia or demonstrated any group-level treatment effect for swallowing function using the outcomes prespecified in this review. There is insufficient and low-quality RCT evidence to determine the effect of interventions for dysphagia in long-term, progressive muscle disease. Clinically relevant effects of intravenous immunoglobulin for dysphagia in inclusion body myositis can neither be confirmed or excluded using the evidence presented in this review. Standardised, validated, and reliable outcome measures are needed to assess dysphagia and any possible treatment effect. Clinically meaningful outcomes for dysphagia may require a shift in focus from measures of impairment to disability associated with oral feeding difficulties.

Pediatric palliative care: Comprehensive support for children

Palliative Care (PC), is the set of actions and tools that seek relief from symptoms and suffering of patients and their families to diseases that threaten their lives. This support includes different types of resources covering the clinical, socio.economic, emotional, psychological and spiritual aspects. Due to increasing life expectancy of humans and the fact that chronic diseases account for 60% of premature death, mainly due to cardiovascular diseases, neurological and malignant tumors; has been the global need to create, implement, and enhance knowledge and PC local programs. In pediatrics, there are four main reasons why a child can and should receive pediatric palliative care.(PPC): Cancer, Cystic fibrosis, Metabolic or Mitochondrial and/or Progressive Muscle Diseases and Neurological Disorders. In this article we analyze synthetically the definition, types and basic definitions on the CPP matter. Also, we share the local experience about the first pediatric palliative care program focus in oncologic patients on the Dominican Republic. To review the basics and history of palliative care. To establish the goals and definition of pediatric palliative care, symptom management, terminal illness and integral support. To describe the local pediatric palliative care in oncology unit at Dr.Robert Reid Cabral Children's Hospital in Dominican Republic as the first PPC local program in the country for children with cancer.

Diastolic dysfunction precedes hypoxia-induced mortality in dystrophic mice.

Duchenne muscular dystrophy (DMD) is a progressive striated muscle disease that is characterized by skeletal muscle weakness with progressive respiratory and cardiac failure. Together respiratory and cardiac disease account for the majority of mortality in the DMD patient population. However, little is known regarding the effects of respiratory dysfunction on the dystrophic heart. The studies described here examine the effects of acute hypoxia on cardiac function. These studies demonstrate, for the first time, that a mouse model of DMD displays significant mortality following acute exposure to hypoxia. This mortality is characterized by a steady decline in systolic function. Retrospective analysis reveals that significant decreases in diastolic dysfunction, especially in the right ventricle, precede the decline in systolic pressure. The initial hemodynamic response to acute hypoxia in the mouse is similar to that observed in larger species, with significant increases in right ventricular afterload and decreases in left ventricular preload being observed. Significant increases in heart rate and contractility suggest hypoxia-induced activation of the sympathetic nervous system. These studies provide evidence that while hypoxia presents significant hemodynamic challenges to the dystrophic right ventricle, global cardiac dysfunction precedes hypoxia-induced mortality in the dystrophic heart. These findings are clinically relevant as the respiratory insufficiency evident in patients with DMD results in significant bouts of hypoxia. The results of these studies indicate that hypoxia may contribute to the acceleration of the heart disease in DMD patients. Importantly, hypoxia can be avoided through the use of ventilatory support.

Homozygous Desmocollin-2 Mutations and Arrhythmogenic Cardiomyopathy

Dominant mutations in desmocollin-2 (DSC2) gene cause arrhythmogenic cardiomyopathy (ACM), a progressive heart muscle disease characterized by ventricular tachyarrhythmias, heart failure, and risk of juvenile sudden death. Recessive mutations are rare and are associated with a cardiac or cardiocutaneous phenotype. Here, we evaluated the impact of a homozygous founder DSC2 mutation on clinical expression of ACM. An exon-by-exon analysis of the DSC2 coding region was performed in 94 ACM index patients. The c.536A>G (p.D179G) mutation was identified in 5 patients (5.3%), 4 of which resulted to be homozygous carriers. The 5 subjects shared a conserved haplotype, strongly indicating a common founder. Genetic and clinical investigation of probands' families revealed that p.D179G homozygous carriers displayed severe forms of biventricular cardiomyopathy without hair or skin abnormalities. The only heterozygous proband, who carried an additional variant of unknown significance in αT-catenin gene, showed a mild form of ACM without left ventricular involvement. All heterozygous family members were clinically asymptomatic. In conclusion, this is the first homozygous founder mutation in DSC2 gene identified among Italian ACM probands. Our findings provide further evidence of the occurrence of recessive DSC2 mutations in patients with ACM predominantly presenting with biventricular forms of the disease.

Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy

Duchenne muscular dystrophy (DMD) is a progressive muscle disease with severe cardiac complications. It is believed that cellular oxidative stress and augmented Ca2+ signaling drives the development of cardiac pathology. Some mitochondrial and metabolic dysfunctions have also been reported. Here we investigate cellular mechanisms responsible for impaired mitochondrial metabolism in dystrophic cardiomyopathy at early stages of the disease. We employed electrophysiological and imaging techniques to study mitochondrial structure and function in cardiomyocytes from mdx mice, an animal model of DMD. Here we show that mitochondrial matrix was progressively oxidized in myocytes isolated from mdx mice. Moreover, an abrupt increase in workload resulted in significantly more pronounced oxidation of mitochondria in dystrophic cells. Electron micrographs revealed a gradually increased number of damaged mitochondria in mdx myocytes. Degradation in mitochondrial structure was correlated with progressive increase in mitochondrial Ca2+ sequestration and mitochondrial depolarization, despite a substantial and persistent elevation in resting cytosolic sodium levels. Treatment of mdx cells with cyclosporine A, an inhibitor of mitochondrial permeability transition pore (mPTP), shifted both resting and workload-dependent mitochondrial redox state to the levels recorded in control myocytes. It also significantly reduced workload dependent depolarization of mitochondrial membrane in dystrophic cardiomyocytes. Overall, our studies highlight age dependent deterioration of mitochondrial function in dystrophic cardiomyocytes, which seems to be associated with excessive opening of mPTP due to oxidative stress and cellular Ca2+ overload.

Motor replacement surgery via tendon transfer in radial nerve palsy

Restoration of active extension of wrist, thumb and digits by muscle-tendon transposition. Radial nerve palsy due to peripheral nerve injury. Peripheral nerve disease. Muscle or tendon injury. Restoration of wrist extension in high radial nerve palsy. Reversible distal radial nerve palsy, absence of suitable donor muscles, spasticity, limited range of motion of affected joints, extensive scarring and inappropriate soft tissue conditions, unjustifiable loss of function at donor site. Reinnervated donor muscles, progressive muscle disease, insufficient patient compliance. Dissection of the flexor carpi ulnaris, palmaris longus and pronator teres tendon insertion. Transposition of the tendons. Interweaving of tendons of the pronator teres and extensor carpi radialis brevis muscles, the extensor digitorum communis and flexor carpi ulnaris muscles, as well as the extensor pollicis longus and palmaris longus muscles using the Pulvertaft technique. 3Weeks immobilization in forearm splint. Additional immobilization for 2weeks at night. Subsequently, intensive physical and occupational therapy for another 4-6weeks is required, starting 3weeks postoperatively. The procedure was carried out in 12patients over the past 14years. We treated proximal radial nerve palsy in nine cases. In accordance with the current medical literature, we consider the described motor replacement surgery a reliable procedure.

Current concepts in dystrophinopathies.

Dystrophinopathies comprise a group of hereditary muscle disorders characterized by progressive wasting and weakness of skeletal muscle, as a result of degeneration of muscle fibers, and can be distinguished by the mode of transmission, age at onset and pattern of muscle weakness. The range of phenotypes associated with the region Xp21 has been expanding since identification of the gene in 1987. The mild end of the spectrum includes the phenotype of the muscle cramps with myoglobinuria and isolated quadriceps myopathy, while at the severe end, there are progressive muscle diseases that are classified as Duchenne / Becker muscular dystrophy (DMD/BMD).

Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency.

Mutations in the co-chaperone Bcl2-associated athanogene 3 (BAG3) can cause myofibrillar myopathy (MFM), a childhood-onset progressive muscle disease, characterized by the formation of protein aggregates and myofibrillar disintegration. In contrast to other MFM-causing proteins, BAG3 has no direct structural role, but regulates autophagy and the degradation of misfolded proteins. To investigate the mechanism of disease in BAG3-related MFM, we expressed wild-type BAG3 or the dominant MFM-causing BAG3 (BAG3(P209L)) in zebrafish. Expression of the mutant protein results in the formation of aggregates that contain wild-type BAG3. Through the stimulation and inhibition of autophagy, we tested the prevailing hypothesis that impaired autophagic function is responsible for the formation of protein aggregates. Contrary to the existing theory, our studies reveal that inhibition of autophagy is not sufficient to induce protein aggregation. Expression of the mutant protein, however, did not induce myofibrillar disintegration and we therefore examined the effect of knocking down Bag3 function. Loss of Bag3 resulted in myofibrillar disintegration, but not in the formation of protein aggregates. Remarkably, BAG3(P209L) is able to rescue the myofibrillar disintegration phenotype, further demonstrating that its function is not impaired. Together, our knockdown and overexpression experiments identify a mechanism whereby BAG3(P209L) aggregates form, gradually reducing the pool of available BAG3, which eventually results in BAG3 insufficiency and myofibrillar disintegration. This mechanism is consistent with the childhood onset and progressive nature of MFM and suggests that reducing aggregation through enhanced degradation or inhibition of nucleation would be an effective therapy for this disease.