This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic... Show moreThis international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. Endof-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by the Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs. Show less
Background: In Becker muscular dystrophy evidence for neurocognitive and behavioral comorbidity is evolving. More insight into the extend of these problems is of great importance for early... Show moreBackground: In Becker muscular dystrophy evidence for neurocognitive and behavioral comorbidity is evolving. More insight into the extend of these problems is of great importance for early detection and remediation in clinical practice.Objective: In this study we aimed to describe the neurocognitive and behavioral features of a Dutch adult cohort of BMD patients, and to evaluate correlations to motor function outcomes.Methods: 28 adult BMD patients were included. Intelligence, executive functioning, verbal memory and reaction times were assessed cross-sectionally. Additionally, patients completed questionnaires on behavioral and emotional symptoms, psychosocial and executive functions. Results were compared to normative data and correlated with disease severity as measured by the 10-meter run/walk test and Performance of the Upper Limb version 1.2.Results: 15 patients (53.6%) had a high educational level despite frequent grade repeating (48.3%) during primary or secondary school. Neuropsychological testing revealed that intellectual abilities, verbal memory, processing speed and executive functioning were statistically significant below average, but still within normal range. Regarding outcomes of the behavioral questionnaires, no significant differences were reported compared to the norm population. No relevant correlations with disease severity were found.Conclusions: This cohort of adult BMD patients exhibits minor cognitive impairments and no significant behavioral problems. The lower outcomes on processing speed and verbal memory, combined with the relatively high prevalence of grade repeating during primary and secondary school, implies that these minor impairments played a role in childhood. However, the on average high educational levels suggests that they grow out of their cognitive impairments with ageing. Show less
Background: Outcome measures for non-ambulant Duchenne muscular dystrophy (DMD) patients are limited, with only the Performance of the Upper Limb (PUL) approved as endpoint for clinical trials... Show moreBackground: Outcome measures for non-ambulant Duchenne muscular dystrophy (DMD) patients are limited, with only the Performance of the Upper Limb (PUL) approved as endpoint for clinical trials.Objective: We assessed four outcome measures based on devices developed for the gaming industry, aiming to overcome disadvantages of observer-dependency and motivation.Methods: Twenty-two non-ambulant DMD patients (range 8.6-24.1 years) and 14 healthy controls (HC; range 9.5-25.4 years) were studied at baseline and 16 patients at 12 months using Leap Motion to quantify wrist/hand active range of motion (aROM) and a Kinect sensor for reached volume with Ability Captured Through Interactive Video Evaluation (ACTIVE), Functional Workspace (FWS) summed distance to seven upper extremity body points, and trunk compensation (KinectTC). PUL 2.0 was performed in patients only. A stepwise approach assessed quality control, construct validity, reliability, concurrent validity, longitudinal change and patient perception.Results: Leap Motion aROM distinguished patients and HCs for supination, radial deviation and wrist flexion (rangep = 0.006 to <0.001). Reliability was low and the manufacturer's hand model did not match the sensor's depth images. ACTIVE differed between patients and HCs (p < 0.001), correlated with PUL (rho = 0.76), and decreased over time (p = 0.030) with a standardized response mean (SRM) of -0.61. It was appraised as fun on a 10-point numeric rating scale (median 9/10). PUL decreased over time (p < 0.001) with an SRM of -1.28, and was appraised as fun (median 7/10). FWS summed distance distinguished patients and HCs (p < 0.001), but reliability in patients was insufficient. KinectTC differed between patients and HCs (p < 0.01), but correlated insufficiently with PUL (rho = -0.69).Conclusions: Only ACTIVE qualified as potential outcome measure in non-ambulant DMD patients, although the SRM was below the commonly used threshold of 0.8. Lack of insight in technological constraints due to intellectual property and software updates made the technology behind these outcome measures a kind of black box that could jeopardize long-term use in clinical development. Show less
Kyba, M.; Bloch, R.J.; Dumonceaux, J.; Harper, S.Q.; Maarel, S.M. van der; Sverdrup, F.M.; ... ; Chen, Y.W. 2020
Muscular dystrophies (MDs) encompass a wide variety of inherited disorders that are characterized by loss of muscle tissue associated with a progressive reduction in muscle function. With a cure... Show moreMuscular dystrophies (MDs) encompass a wide variety of inherited disorders that are characterized by loss of muscle tissue associated with a progressive reduction in muscle function. With a cure lacking for MDs, preclinical developments of therapeutic approaches depend on well-characterized animal models that recapitulate the specific pathology in patients. The mouse is the most widely and extensively used model for MDs, and it has played a key role in our understanding of the molecular mechanisms underlying MD pathogenesis. This has enabled the development of therapeutic strategies. Owing to advancements in genetic engineering, a wide variety of mouse models are available for the majority of MDs. Here, we summarize the characteristics of the most commonly used mouse models for a subset of highly studied MDs, collated into a table. Together with references to key publications describing these models, this brief but detailed overview would be useful for those interested in, or working with, mouse models of MD. Show less
Putten, M. van; Hmeljak, J.; Aartsma-Rus, A.; Dowling, J.J. 2020
Neuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment... Show moreNeuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment exists for any of the NMDs. For multiple disorders, however, therapeutic strategies are currently being tested in clinical settings, and the first successful treatments have now entered clinical practice (e.g. spinraza for spinal muscular atrophy). Successful clinical translation depends on the quality and translatability of preclinical findings and on the predictive value of the experimental models used in their initial development. This Special Issue of Disease Models & Mechanisms has a particular focus on translational research for NMDs. The collection includes original research focusing on advances in the development of novel in vitro and in vivo models, broader understanding of disease pathology and progression, and approaches to modify the disease course in these models. We also present a series of special articles and reviews that highlight our understanding of cellular mechanisms, biomarkers to tract disease pathology, the diversity of mouse models for NMDs, the importance of high-quality preclinical studies and data validation, and the pitfalls of successfully moving a potential therapeutic strategy to the clinic. In this Editorial, we summarize the highlights of these articles and place their findings in the broader context of the NMD research field. Show less
In African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this... Show moreIn African neurological practice, muscle disorders are either underdiagnosed or underrepresented. This may in part be due to the large burden of other more common neurological disorders. In this report we describe the first Tanzanian patient with genetically confirmed Becker muscular dystrophy. His phenotype and genotype were compatible with elsewhere in the world. Remarkably, this patient reported his progressive weakness of the legs with difficulty in walking only after a fall. We demonstrate that muscular dystrophies occur in sub-Saharan Africa. Neurologists must however be aware that patients are likely to delay seeking medical care for muscle disorders. (C) 2019 Elsevier B.V. All rights reserved. Show less
The muscular dystrophies are a heterogeneous collection of inherited and progressive myogenic disorders sharing similar clinical “dystrophic” characteristics. Many therapies are currently... Show moreThe muscular dystrophies are a heterogeneous collection of inherited and progressive myogenic disorders sharing similar clinical “dystrophic” characteristics. Many therapies are currently being tested in clinical trials and several of them achieved marketing authorisation. Additionally, many promising treatments are currently being tested in preclinical animal models. At a pathological level, patients show chronic inflammation and degeneration of muscle fibers, which eventually are replaced by adipose and fibrotic tissue leading to loss of muscle tissue and function. Targeting pathways involved in regulation of muscle regeneration and fibrosis can improve muscle quality and function. This would be beneficial for many patients with neuromuscular disorders, which share similar pathology. There is a great demand to accelerate the translation of potential new treatments from the bench to the clinic. Therefore, natural history studies and reliable outcome measures are required for preclinical mouse models improving study design and comparison between studies. To address the lack of a therapy targeting muscle pathology, the thesis focuses on evaluating therapeutic potential of antisense oligonucleotides inhibition of TGF-β and myostatin type I receptors and elucidating their function in muscles. Additionally, this thesis contains a natural history dataset that can be useful to design preclinical studies in dystrophic mouse models. Show less
In this thesis research is presented about the progressive muscle diseases Duchenne and Becker muscular dystrophy, two hereditary muscle diseases caused by a mutation in the gene coding for... Show moreIn this thesis research is presented about the progressive muscle diseases Duchenne and Becker muscular dystrophy, two hereditary muscle diseases caused by a mutation in the gene coding for dystrophin, a protein involved in muscle membrane stability. The first part describes the disease course of both diseases. It evaluates the effect of developments in care of Duchenne patients, improving age at wheelchair dependence and survival. Data are presented about the relatively mild disease course of selected Becker patients with a mutation that would be the result of exon skipping in a Duchenne patient, illustrating the possible result of this therapeutic approach. The second part of this thesis focusses on research into factors involved in disease variability. Data are presented regarding the role of dystrophin quantity in disease severity in Becker patients, showing no linear relationship. Expression of several dystrophin associated proteins is shown not to influence disease course either. Contrarily, a single nucleotide polymorphism in the LTBP4 gene involved in fibrosis and muscle regeneration is shown to influence disease severity. Lastly, a disease severity scale for Becker patients is presented in this thesis, enabling a better comparison of individual patients for the purpose of scientific research. Show less
Skeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of... Show moreSkeletal and cardiac muscle disorders are associated with substantial morbidity and mortality. Despite many improvements in the medical and surgical management of these disorders, development of effective treatments has proven to be challenging. This is because of the limited suitability of existing experimental models for acquiring a thorough understanding of the mechanisms underlying skeletal and cardiac muscle diseases and the lack of efficiency and specificity of many of the currently available therapeutic interventions. Therefore, the aim of this thesis was to establish and use dedicated cellular models in combination with genetic interventions to study the biology of skeletal and cardiac muscles in healthy and diseased states and thereby identify potential targets for future therapeutic interventions. The experiments described in this thesis indeed emphasized the importance of cellular models for (i) elucidating the mechanisms underlying skeletal and cardiac muscle diseases and (ii) identification of novel therapeutic targets. This thesis also underlined the usefulness of viral vector-mediated gene transfer technology for development of biological assays and the evaluation of therapeutic targets. In conclusion, application of in vitro models in combination with genetic interventions can improve our understanding of skeletal and cardiac muscle diseases and aid development of new therapies for these disorders. Show less
Molecular confirmation of a clinical diagnosis of an inherited disease or of congenital malformations is of paramount importance for patients and their families. It is the conclusion of the... Show moreMolecular confirmation of a clinical diagnosis of an inherited disease or of congenital malformations is of paramount importance for patients and their families. It is the conclusion of the differential diagnostic process, and provides information on the prognosis, in some cases on the therapeutic options, and on the recurrence risk. Currently, targeted sequencing of gene (s) of interest is the preferred approach for searching for small pathogenic mutations. The work presented in this thesis describes the application of new techniques for detecting small variations (mutations) in genomic DNA that underlie various disorders. These techniques include High Resolution Melting Curve Analysis (HR-MCA) followed by Sanger sequencing, targeted, X-exome and whole exome capture followed by Next Generation Sequencing (NGS). We have optimized, tested and applied the different new molecular techniques mentioned above to 1) faci litate the detection of disease causing mutations in several disorders with suspected Mendelian inheritance, 2) to speed up the identification of disease genes, 3) to provide a systematic tool for classifying previously intractable genetic diseases Show less
Dystrophinopathies include the well known Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). This thesis is a collection of several clinical and genetic studies on... Show moreDystrophinopathies include the well known Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). This thesis is a collection of several clinical and genetic studies on dystrophinopathies with implications for genetic counselling of patients and their families and for future therapy (e.g. personalized medicine) of patients suffering from this group of chronic progressive muscle diseases. The following recommendations are made: - Testing for dystrophinopathies in newborn boys on a voluntary basis should start as soon as possible in the Netherlands. This will reduce the chance of the birth of subsequent affected boys in the family and will also help in early introduction of possible therapy when this becomes available. - Parents should be given the choice of having their daughters tested prenatally, if foetal DNA is available. They should also be encouraged to have their daughters tested, even before adulthood. This will not only considerably reduce the incidence of DMD but will also ease the burden for the parents who have to inform their daughter of their future risks. - Genetic counsellors should have a more active approach to cascade screening and informing the patients and their families of their risks and possibilities. Show less
Limb Girdle Muscular Dystrophy (LGMD) is a rare progressive heterogeneous disorder that can be caused by mutations in at least 21 different genes. These genes are often widely expressed and encode... Show moreLimb Girdle Muscular Dystrophy (LGMD) is a rare progressive heterogeneous disorder that can be caused by mutations in at least 21 different genes. These genes are often widely expressed and encode proteins with highly differing functions. And yet mutations in all of them give rise to a similar clinical presentation: adult onset muscle weakness, with muscles of the pelvic and shoulder girdle as predominantly affected muscle groups. This thesis explores a potential molecular mechanism that unifies the different genetic defects, which individually can cause a limb girdle muscular dystrophy, with a focus on LGMD2A and 2B. Show less
The muscular dystrophies are a group of neuromuscular disorders characterized by progres_sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular... Show moreThe muscular dystrophies are a group of neuromuscular disorders characterized by progres_sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are not yet clear. Furthermore, the muscular dystrophies differ in clinical presentation and severity. The processes responsible for this di_vergence are largely unknown as well. In this thesis, gene expression profiling has been applied to study the molecular and cellular mechanisms and subsequent biological processes that play a role in muscular dystrophy. To characterize the processes associated with regeneration, we have compared gene expression levels in hindlimb muscle tissue of mdx and control mice in a temporal study. Additionally, we have determined the gene expression profiles of dif_ferentiating human myoblasts in vitro, since regeneration processes recapitulate myogenesis. We also set out to compare gene expression levels of different mouse models for muscular dystrophy to find common and distinct molecular mechanisms that underlie different forms of muscular dystrophy. Accordingly, we first had to determine the effects of genetic background variation between inbred mouse strains, and to study the feasibility of alternative experimental designs. Show less
The purpose of this study is to discuss several aspects of facioscapulohumeral disease, also called "autosomal dominant facioscapulohumeral muscular dystrophy" or "Landouzy-Dejerine type of... Show moreThe purpose of this study is to discuss several aspects of facioscapulohumeral disease, also called "autosomal dominant facioscapulohumeral muscular dystrophy" or "Landouzy-Dejerine type of muscular dystrophy" or "Landouzy-Dejerine' s disease" . We consider this disorder well defined and recognizable, justifying the term facioscapulohumeral disease, abbreviated FSHD. Show less
