Search

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, most cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified 10 bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) predisposing individuals to recurrent rhabdomyolysis. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in sarcoplasmic reticulum function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in sarcoplasmic reticulum Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the sarcoplasmic reticulum and/or a decrease in Ca2+ sarcoplasmic reticulum storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease. Cabrera-Serrano et al. show that biallelic loss-of-function variants in the gene encoding obscurin (OBSCN) predispose individuals to recurrent and severe episodes of rhabdomyolysis, typically with onset in the teenage years.

Our aim was to identify clinical outcomes, serological features and possible prognostic indicators of paediatric myasthenia gravis (MG). We collected 74 MG patients with disease onset before the age of 16 years (73% pre-pubertal onset defined as ≤10 years), seen regularly at two UK specialist centres, over a period of 11 years. The cohort was multi-ethnic, with a high number of non-Caucasians (52%). Ocular presentation was seen in 38 (51%) and only 8 (21%) of these generalised. Fifty-two (70%) patients had antibodies to the acetylcholine receptor (AChR) measured by radioimmunoprecipitation, 10 (14%) had antibodies only to clustered AChRs detected by a cell based assay, 3 (4%) had muscle-specific kinase and one (1%) low-density lipoprotein receptor-related protein 4 antibody. Only 8 (11%) had no detectable antibodies. Seventeen patients attained drug free remission (Kaplan Meyer survival curve estimates 25% by 7 years). Several factors were associated with a higher likelihood of free remission: onset age ≤10 years, Asian and Caucasian races, lack of AChR antibodies on RIA, and normal repetitive nerve stimulation at diagnosis. However, in a multifactorial regression analysis, the antibody status was the only significant predictor for drug free remission, with 60% of patients with antibodies only to clustered AChR achieving this outcome. Complete drug free remission is not uncommon in paediatric MG and several factors appear to influence this outcome with antibody status being the most important. These factors can be easily evaluated at diagnosis, and may help to determine whose patients are likely to require more intensive treatments.

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, the majority of cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified ten bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) co-segregating with disease. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in SR function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in SR Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the SR and/or a decrease in Ca2+ SR storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.

Aim: To investigate the in vivo skeletal muscle metabolism in patients with β-enolase deficiency (GSDXIII) during exercise, and the effect of glucose infusion. Methods: Three patients with GSDXIII and 10 healthy controls performed a nonischemic handgrip test as well as an incremental cycle ergometer test measuring maximal oxidative consumption (VO2max) and a 1-hour submaximal cycle test at an intensity of 65% to 75% of VO2max. The patients repeated the submaximal exercise after 2 days, where they received a 10% iv-glucose supplementation. Results: Patients had lower VO2max than healthy controls, and two of three patients had to stop prematurely during the intended 1-hour submaximal exercise test. During nonischemic forearm test, all patients were able to produce lactate in normal amounts. Glucose infusion had no effect on patients' exercise capacity. Conclusions: Patients with GSDXIII experience exercise intolerance and episodes of myoglobinuria, even to the point of needing renal dialysis, but still retain an almost normal anaerobic metabolic response to submaximal intensity exercise. In accordance with this, glucose supplementation did not improve exercise capacity. The findings show that GSDXIII, although causing episodic rhabdomyolysis, is one of the mildest metabolic myopathies affecting glycolysis.

ObjectiveTo describe decline in muscle strength and physical function in patients with sporadic inclusion body myositis (IBM).MethodsManual muscle testing (MMT), quantitative muscle testing (QMT) and disability scoring using the IBM Functional Rating Scale (IBMFRS) were undertaken for 181 patients for up to 7.3 years. The relationship between MMT, QMT and IBMFRS composite scores and time from onset were examined using linear mixed effects models adjusted for gender and age of disease onset. Adaptive LASSO regression analysis was used to identify muscle groups that best predicted the time elapsed from onset. Cox proportional hazards regression was used to evaluate time to use of a mobility aid.ResultsMultilevel modelling of change in percentage MMT, QMT and IBMFRS score over time yielded an average decline of 3.7% (95% CI 3.1% to 4.3%), 3.8% (95% CI 2.7% to 4.9%) and 6.3% (95% CI 5.5% to 7.2%) per year, respectively. The decline, however, was not linear, with steeper decline in the initial years. Older age of onset was associated with a more rapid IBMFRS decline (p=0.007), but did not influence the rate of MMT/QMT decline. Combination of selected muscle groups allowed for generation of single measures of patient progress (MMT and QMT factors). Median (IQR) time to using a mobility aid was 5.4 (3.6–9.2) years, significantly affected by greater age of onset (HR 1.06, 95% CI 1.04 to 1.09, pConclusionThis prospective observational study represents the largest IBM cohort to date. Measures of patient progress evaluated in this study accurately predict disease progression in a reliable and useful way to be used in trial design.

This chapter looks at how two fundamentally different pathological processes are associated with disease at the neuromuscular junction: acquired disorders in which autoantibodies are directed against nerve or muscle receptor or ion channels; rare inherited conditions in which the defect may be pre- or postsynaptic. The acquired neuromuscular junction disorders are associated with antibodies directed against one of the ion channels. The fact that there are three autoimmune disorders known to affect such a small region may be explained by the neuromuscular junction, unlike the peripheral nerve, not being contained within the blood–nerve barrier, which stops just short of the nerve terminal, and thus being potentially exposed to circulating humoral attack. The inherited disorders may affect presynaptic processes (acetylcholine resynthesis, packaging, or release), acetylcholinesterase binding, or postsynaptic function (acetylcholine receptor numbers or localization). Pathogenic mechanisms are considered in more detail when discussing individual disorders.

Myotonia is defined at an electrical level as repetitive discharge of the muscle fibre membrane after initial activation, which occurs due to dysfunction of the membrane’s ion channels, most commonly the chloride channel, less commonly the sodium channel. This manifests clinically as stiffness of the muscle and delayed relaxation after voluntary contraction (e.g. difficulty relaxing the grip after clenching the fingers, and stiffness in the thigh muscles and difficulty walking on first moving after rest). Disabling myotonia may respond to carbamazepine, phenytoin or, often most effectively, mexiletine, although supplies are now limited. This chapter takes a closer look at the condition, its symptoms, presentations, diagnosis, and treatment.

Disturbances of the biochemical or ionic balance of muscle resulting in impaired muscle function can be caused by a disparate group of conditions, including primary inherited disorders affecting enzymes or ion channels, and secondary disorders in which metabolic or endocrine disequilibrium disturbs normal function. This chapter explores the primary metabolic myopathies, mostly autosomal recessive disorders in which lack of activity of a specific enzyme impairs adenosine triphosphate generation. Clinical presentation is with exercised-induced symptoms, but there are fundamental differences in manifestations depending upon whether the enzyme defect affects glycogen/glucose metabolism or fatty acid metabolism, reflecting the very different contributions that these pathways make to energy production depending on the nature of the exercise.

Introduction The ability to distinguish between normal thymus, thymic hyperplasia, and thymoma should aid clinical management and decision making in patients with myasthenia gravis (MG). We sought to determine the accuracy of routine imaging in predicting thymic pathology. Methods We retrospectively analyzed records of patients with MG from the Oxford Myasthenia Centre registry who had undergone thymectomy. Each patient received 1 radiological diagnosis and 1 histological diagnosis. Results We included 106 patients. Radiological and histological diagnoses agreed in 73 (68.9%) patients. Sensitivity and specificity, respectively, were calculated for each radiological diagnosis as follows: thymoma 90% and 95.5%, hyperplasia 17.6% and 98.6%, and normal 96.9% and 60.8%. Discussion Routine chest computed tomography and MRI can effectively identify thymoma. However, they are not reliable tools to differentiate between thymic hyperplasia and normal thymus in patients with MG. Muscle Nerve, 2018.

A 23-year-old woman had presented initially to a podiatrist complaining of poorly fitting shoes during her adolescence. After extensive neurological review, she was diagnosed with ataxia with oculomotor apraxia type 2. This is a progressive autosomal recessive ataxia associated with cerebellar atrophy, peripheral neuropathy and an elevated serum α-fetoprotein. Within Europe, it is the most frequent autosomal recessive ataxia after Friedreich’s ataxia and is due to mutations in the senataxin (SETX) gene. The age of onset is approximately 15 years.The diagnosis of oculomotor apraxia type 2 is often challenging. We provide a framework for assessing a young ataxic patient with or without oculomotor apraxia and review clues that will aid diagnosis. The prognosis, level of disability, cancer and immunosuppression risk all markedly differ between the conditions. Patients and their families need the correct diagnosis for genetic counselling, management and long-term surveillance with appropriate subspecialty services.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction for which many therapies were developed before the era of evidence-based medicine. Despite the basic principles of treatment being well known, patients continue to receive suboptimal treatment. A myasthenia gravis guidelines group was therefore established under the aegis of the Association of British Neurologists. These guidelines attempt to steer a path between evidence-based practice where available and established best practice where evidence is unavailable. It is not possible to consider all the potential decisions in managing MG without resorting to opinion rather than evidence. Where there is insufficient evidence or a choice of options, the guidelines invite the clinician to seek the opinion of a myasthenia expert. The guidelines support clinicians in using the right treatments in the right order and in optimizing the use of well-known therapeutic agents. Clinical practice can be audited against these guidelines.

ObjectiveTo determine interrater variability in diagnosing individual muscle biopsy abnormalities and diagnosis.MethodsWe developed a scoring tool to analyze consensus in muscle biopsy reading of an ad hoc workgroup of international experts. Twenty-four samples from patients with suspected idiopathic inflammatory myopathy (IIM) were randomly selected, providing sections that were stained with standard histologic and immunohistochemical methods. Sections were made available on an online platform, and experts were queried about myopathologic features within 4 pathologic domains: muscle fibers, inflammation, connective tissue, and vasculature. A short clinical presentation of cases was included, and experts were asked to give a tentative diagnosis of polymyositis, dermatomyositis, inclusion-body myositis, antisynthetase syndrome–related myositis, immune-mediated necrotizing myopathy, nonspecific myositis, or other disease. Fleiss κ values, scoring interrater variability, showed the highest agreement within the muscle fiber and connective tissue domains.ResultsDespite overall low κ values, moderate agreement was achieved for tentative diagnosis, supporting the idea of using holistic muscle biopsy interpretation rather than adding up individual features.ConclusionThe assessment of individual pathologic features needs to be standardized and harmonized and should be measured for sensitivity and specificity for subgroup classification. Standardizing the process of diagnostic muscle biopsy reading would allow identification of more homogeneous patient cohorts for upcoming treatment trials.

Glycogen storage disease type XIII (GSDXIII) is a very rare inherited metabolic myopathy characterized by autosomal‐recessive mutations in the ENO3 gene resulting in muscle β‐enolase deficiency, an enzymatic defect of the distal part of glycolysis. Enzyme kinetic studies of two patients presenting with exertion intolerance and recurrent rhabdomyolysis are reported. Next generation sequencing confirmed patient 1 was homozygous for p.E187K in ENO3, while patient 2 was homozygous for p.C357Y. ENO3 variants pathogenicity was confirmed by functional studies in skeletal muscle. p.E187K caused extremely low total enolase activity. p.C357Y was associated with a higher level of residual activity but kinetic studies showed a lower maximum work rate (V max). This study illustrates that GSDXIII may be caused by either null mutations leading to β‐enolase deficiency or by mutations that alter the enzyme's kinetic profile. This study highlights the importance of carrying out functional studies as part of the diagnostic process following the identification of variants with next generation sequencing.

Summary Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a “Global FSHD registry”. We suggest that the registry’s ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally. Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8132-1) contains supplementary material, which is available to authorized users.

Background: There is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years. Objective: Based on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians’ views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients. Methods: Thirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated and presented in the second questionnaire to seek elaboration and identify consensus. Results: All 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population. Conclusions: In the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies.

BackgroundSporadic inclusion body myositis (IBM) is the most common age-related acquired myopathy. Our aim was to longitudinally evaluate clinical, quantitative and functional characteristics of the disease to develop statistical models of progression that can be used in clinical trials.MethodsIn a prospective cohort study, we recruited 205 patients with a diagnosis of IBM across three centres (London, Oxford and Newcastle).Patients underwent bilateral manual muscle testing (MRC scale), quantitative muscle testing and disability scoring (IBM Functional Rating Scale) at each follow up visit. The time at which a patient first required a mobility aid was recorded.Linear multilevel models were fitted to investigate the progression of these scores over time. Cox proportional hazards regression was used to model time to use of a mobility aid.ResultsIn the preliminary analyses we have generated reliable multilevel models of disease progression using those muscle groups that are worst affected by the disease over time. We have also modelled the progression of IBMFRS over time. These models can be used to predict/monitor disease progression.ConclusionThis study will be the largest prospective observational study in IBM to date and will reveal useful outcome measures that can be used in clinical trials.

The ability to distinguish between normal thymus, thymic hyperplasia, and thymoma should aid clinical management and decision making in patients with myasthenia gravis (MG). We sought to determine the accuracy of routine imaging in predicting thymic pathology.We retrospectively analyzed records of patients with MG from the Oxford Myasthenia Centre registry who had undergone thymectomy. Each patient received 1 radiological diagnosis and 1 histological diagnosis.We included 106 patients. Radiological and histological diagnoses agreed in 73 (68.9%) patients. Sensitivity and specificity, respectively, were calculated for each radiological diagnosis as follows: thymoma 90% and 95.5%, hyperplasia 17.6% and 98.6%, and normal 96.9% and 60.8%.Routine chest computed tomography and MRI can effectively identify thymoma. However, they are not reliable tools to differentiate between thymic hyperplasia and normal thymus in patients with MG. Muscle Nerve, 2018.

Mitophagy is a cellular mechanism for the recycling of mitochondrial fragments. This process is able to improve mitochondrial DNA (mtDNA) quality in heteroplasmic mtDNA disease, in which mutant mtDNA co-exists with normal mtDNA. In disorders where the load of mutant mtDNA determines disease severity it is likely to be an important determinant of disease progression. Measuring mitophagy is technically demanding. We used pharmacological modulators of autophagy to validate two techniques for quantifying mitophagy. First we used the IN Cell 1000 analyzer to quantify mitochondrial co-localisation with LC3-II positive autophagosomes. Unlike conventional fluorescence and electron microscopy, this high-throughput system is sufficiently sensitive to detect transient low frequency autophagosomes. Secondly, because mitophagy preferentially removes pathogenic heteroplasmic mtDNA mutants, we developed a heteroplasmy assay based on loss of m.3243A > G mtDNA, during culture conditions requiring oxidative metabolism (“energetic stress”). The effects of the pharmacological modulators on these two measures were consistent, confirming that the high throughput imaging output (autophagosomes co-localising with mitochondria) reflects mitochondrial quality control. To further validate these methods, we performed a more detailed study using metformin, the most commonly prescribed antidiabetic drug that is still sometimes used in Maternally Inherited Diabetes and Deafness (MIDD). This confirmed our initial findings and revealed that metformin inhibits mitophagy at clinically relevant concentrations, suggesting that it may have novel therapeutic uses.

Myasthenia gravis is an autoimmune disease of the neuromuscular junction for which many therapies were developed before the era of evidence based medicine. The basic principles of treatment are well known, however, patients continue to receive suboptimal treatment as a result of which a myasthenia gravis guidelines group was established under the aegis of The Association of British Neurologists. These guidelines attempt to steer a path between evidence-based practice where available, and established best practice where evidence is unavailable. Where there is insufficient evidence or a choice of options, the guidelines invite the clinician to seek the opinion of a myasthenia expert. The guidelines support clinicians not just in using the right treatments in the right order, but in optimising the use of well-known therapeutic agents. Clinical practice can be audited against these guidelines.

Rarely, inflammation can be present in genetic myopathies, such as dysferlinopathies, facioscapulohumeral muscular dystrophy and GNE-myopathy (hereditary inclusion body myopathy). This may lead to erroneous initial diagnosis and unnecessary therapy which bear serious side effects. We report on an unusual case of mutations in the TTN gene presenting with inflammatory infiltrates in the muscle biopsy. Only after intensive immune-modulating therapies failed, a genetic myopathy was considered. Exome sequencing and search for mutated muscle protein-encoding genes disclosed compound heterozygous mutations in TTN: K26320T and A6135G. The parents carry one each of the mutations. Titinopathy could be considered also in patients presenting with inflammatory infiltrates resistant to therapy.

Introduction Earlier small case series and clinical observations reported on chronic pain playing an important role in facioscapulohumeral dystrophy (FSHD). The aim of this study was to determine the characteristics and impact of pain on quality of life (QoL) in patients with FSHD. Methods We analyzed patient reported outcome measures collected through the U.K. FSHD Patient Registry. Results Of 398 patients, 88.6% reported pain at the time of study. The most frequent locations were shoulders and lower back. A total of 203 participants reported chronic pain, 30.4% of them as severe. The overall disease impact on QoL was significantly higher in patients with early onset and long disease duration. Chronic pain had a negative impact on all Individualised Neuromuscular Quality of Life Questionnaire domains and overall disease score. Discussion Our study shows that pain in FSHD type 1 (FSHD1) is frequent and strongly impacts on QoL, similar to other chronic, painful disorders. Management of pain should be considered when treating FSHD1 patients. Muscle Nerve 57: 380–387, 2018

Multisystem proteinopathy (MSP) involves disturbances of stress granule (SG) dynamics and autophagic protein degradation that underlie the pathogenesis of a spectrum of degenerative diseases that affect muscle, brain, and bone. Specifically, identical mutations in the autophagic adaptor SQSTM1 can cause varied penetrance of 4 distinct phenotypes: amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Paget's disease of the bone, and distal myopathy. It has been hypothesized that clinical pleiotropy relates to additional genetic determinants, but thus far, evidence has been lacking. Here, we provide evidence that a TIA1 (p.N357S) variant dictates a myodegenerative phenotype when inherited, along with a pathogenic SQSTM1 mutation. Experimentally, the TIA1-N357S variant significantly enhances liquid-liquid-phase separation in vitro and impairs SG dynamics in living cells. Depletion of SQSTM1 or the introduction of a mutant version of SQSTM1 similarly impairs SG dynamics. TIA1-N357S-persistent SGs have increased association with SQSTM1, accumulation of ubiquitin conjugates, and additional aggregated proteins. Synergistic expression of the TIA1-N357S variant and a SQSTM1-A390X mutation in myoblasts leads to impaired SG clearance and myotoxicity relative to control myoblasts. These findings demonstrate a pathogenic connection between SG homeostasis and ubiquitin-mediated autophagic degradation that drives the penetrance of an MSP phenotype.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction for which many therapies were developed before the era of evidence-based medicine. Despite the basic principles of treatment being well known, patients continue to receive suboptimal treatment. A myasthenia gravis guidelines group was therefore established under the aegis of the Association of British Neurologists. These guidelines attempt to steer a path between evidence-based practice where available and established best practice where evidence is unavailable. It is not possible to consider all the potential decisions in managing MG without resorting to opinion rather than evidence. Where there is insufficient evidence or a choice of options, the guidelines invite the clinician to seek the opinion of a myasthenia expert. The guidelines support clinicians in using the right treatments in the right order and in optimizing the use of well-known therapeutic agents. Clinical practice can be audited against these guidelines.

ObjectivesAutoantibodies directed against cytosolic 5′-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5′-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis.Materials and methodsData from various European inclusion body myositis registries were pooled. Anticytosolic 5′-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression.ResultsData from 311 patients were available for analysis; 102 (33%) had anticytosolic 5′-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients.InterpretationDifferences were observed in clinical and histopathological features between anticytosolic 5′-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5′-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy worldwide with complex, multi-systemic, and progressively worsening symptoms. There is currently no treatment for this inherited disorder and research can be challenging due to the rarity and variability of the disease. The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information. For this cross-sectional “snapshot” analysis, 556 patients with a confirmed diagnosis of DM1 registered between May 2012 and July 2016 were included. An almost even distribution was seen between genders and a broad range of ages was present from 8 months to 78 years, with the largest proportion between 30 and 59 years. The two most frequent symptoms were fatigue and myotonia, reported by 79 and 78% of patients, respectively. The severity of myotonia correlated with the severity of fatigue as well as mobility impairment, and dysphagia occurred mostly in patients also reporting myotonia. Men reported significantly more frequent severe myotonia, whereas severe fatigue was more frequently reported by women. Cardiac abnormalities were diagnosed in 48% of patients and more than one-third of them needed a cardiac implant. Fifteen percent of patients used a non-invasive ventilation and cataracts were removed in 26% of patients, 65% of which before the age of 50 years. The registry’s primary aim was to facilitate and accelerate clinical research. However, these data also allow us to formulate questions for hypothesis-driven research that may lead to improvements in care and treatment. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8483-2) contains supplementary material, which is available to authorized users.

PURPOSE OF REVIEW: Myotonic dystrophies type 1 and type 2 are progressive multisystem genetic disorders with clinical and genetic features in common. Myotonic dystrophy type 1 is the most prevalent muscular dystrophy in adults and has a wide phenotypic spectrum. The average age of death in myotonic dystrophy type 1 is in the fifth decade. In comparison, myotonic dystrophy type 2 tends to cause a milder phenotype with later onset of symptoms and is less common than myotonic dystrophy type 1. Historically, patients with myotonic dystrophy type 1 have not received the medical and social input they need to maximize their quality and quantity of life. This review describes the improved understanding in the molecular and clinical features of myotonic dystrophy type 1 as well as the screening of clinical complications and their management. We will also discuss new potential genetic treatments. RECENT FINDINGS: An active approach to screening and management of myotonic dystrophies type 1 and type 2 requires a multidisciplinary medical, rehabilitative and social team. This process will probably improve morbidity and mortality for patients. Genetic treatments have been successfully used in in-vitro and animal models to reverse the physiological, histopathological and transcriptomic features. SUMMARY: Molecular therapeutics for myotonic dystrophy will probably bridge the translational gap between bench and bedside in the near future. There will still be a requirement for clinical screening of patients with myotonic dystrophy with proactive and systematic management of complications.

Objective. To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods. We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results. Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10(-8) ) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion. Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. � 2013 American College of Rheumatology.

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases. © 2013 WILEY PERIODICALS, INC.

A national U.K. workshop to discuss practical clinical management issues related to pregnancy in women with myasthenia gravis was held in May 2011. The purpose was to develop recommendations to guide general neurologists and obstetricians and facilitate best practice before, during and after pregnancy. The main conclusions were (1) planning should be instituted well in advance of any potential pregnancy to allow time for myasthenic status and drug optimisation; (2) multidisciplinary liaison through the involvement of relevant specialists should occur throughout pregnancy, during delivery and in the neonatal period; (3) provided that their myasthenia is under good control before pregnancy, the majority of women can be reassured that it will remain stable throughout pregnancy and the postpartum months; (4) spontaneous vaginal delivery should be the aim and actively encouraged; (5) those with severe myasthenic weakness need careful, multidisciplinary management with prompt access to specialist advice and facilities; (6) newborn babies born to myasthenic mothers are at risk of transient myasthenic weakness, even if the mother's myasthenia is well-controlled, and should have rapid access to neonatal high-dependency support.

Rhabdomyolysis is often due to a combination of environmental trigger(s) and genetic predisposition; however, the underlying genetic cause remains elusive in many cases. Mutations in CAV3 lead to various neuromuscular phenotypes with partial overlap, including limb girdle muscular dystrophy type 1C (LGMD1C), rippling muscle disease, distal myopathy and isolated hyperCKemia. Here we present a series of eight patients from seven families presenting with exercise intolerance and rhabdomyolysis caused by mutations in CAV3 diagnosed by next generation sequencing (NGS) (n = 6). Symptoms included myalgia (n = 7), exercise intolerance (n = 7) and episodes of rhabdomyolysis (n = 2). Percussion-induced rapid muscle contractions (PIRCs) were seen in five out of six patients examined. A previously reported heterozygous mutation in CAV3 (p.T78M) and three novel variants (p.V14I, p.F41S, p.F54V) were identified. Caveolin-3 immunolabeling in muscle was normal in 3/4 patients; however, immunoblotting showed more than 50% reduction of caveolin-3 in five patients compared with controls. This case series demonstrates that exercise intolerance, myalgia and rhabdomyolysis may be caused by CAV3 mutations and broadens the phenotypic spectrum of caveolinopathies. In our series, immunoblotting was a more sensitive method to detect reduced caveolin-3 levels than immunohistochemistry in skeletal muscle. Patients presenting with muscle pain, exercise intolerance and rhabdomyolysis should be routinely tested for PIRCs as this may be an important clinical clue for caveolinopathies, even in the absence of other "typical" features. The use of NGS may expand current knowledge concerning inherited diseases, and unexpected/atypical phenotypes may be attributed to well-known human disease genes.

Muscle disorders (myopathies) are rare in all age groups. They may be inherited or acquired. Inherited disorders presenting for the first time in middle age and later include myotonic dystrophy, oculopharyngeal muscular dystrophy and mitochondrial disorders, particularly chronic progressive external ophthalmoplegia. Acquired disorders are more common and most are amenable to therapy, an important exception being inclusion body myositis, which is also the most common myopathy presenting over the age of 50 years. The idiopathic inflammatory myopathies, dermatomyositis and polymyositis, respond to immunosuppressant drug therapy. Dermatomyositis may be a paraneoplastic condition and surveillance for cancer is essential. Clinical assessment alone will frequently suggest the correct diagnosis but confirmation may require muscle biopsy or DNA analysis. Drug-induced myopathy is under-recognized but particularly important in the older population because of multiple drug therapy and the explosion in the use of statins. © 2012 John Wiley and Sons, Ltd.

Primary muscle disorders (myopathies) are rare, even within a neurology clinic. It has been estimated that there are about 70,000 people in the UK (population ∼62 million) with a peripheral neuromuscular disorder, with about one-half of them having a myopathy. A fundamental distinction is between acquired and inherited myopathies. Currently, a majority of the former will respond to removal of the cause or specific treatment, such as immunosuppression, whereas despite the hopes of 'genetic engineering' the majority of the latter have no specific treatment, although appropriate interventions can greatly improve both morbidity and mortality. For the latter group, genetic counselling issues are of fundamental importance. All of these diseases are best managed by a multidisciplinary team led by a clinician with a specific interest in neuromuscular disease. Many individual myopathies are extremely rare and will not be seen by most neurologists during their careers. The tyro cannot be expected necessarily to identify these rarities, but should have the generic skills to be able to recognize the broad nature of the problem and to refer on as appropriate. However, it would be indefensible to miss a treatable disorder such as myositis, and they should certainly be aware of the major clinical features and management issues of the more common disorders, notably myotonic dystrophy and those with multisystemic manifestations such as the mitochondrial cytopathies. © 2012 Elsevier Ltd. All rights reserved.

Antibodies to muscle-specific kinase (MuSK) are found in a variable proportion of patients with myasthenia without typical acetylcholine receptor (AChR) antibodies, but their characteristics and pathogenic mechanisms are not fully understood. We discuss the incidence and pathogenicity of MuSK antibodies and how clinical studies, animal models, and cultured cell lines can be used to elucidate their pathogenic mechanisms. Patients without either AChR or MuSK antibodies (seronegative myasthenia) appear to present another disease subtype that is highly similar to that of typical myasthenia gravis. We demonstrate a new method that detects AChR antibodies in these patients and show that these low-affinity AChR antibodies are predominantly IgG1 and can activate complement C3b deposition. Similarly MuSK antibodies, although mainly IgG4, are partially IgG1 and can activate C3b deposition. Overall, these results suggest that complement-activation may be an important pathogenic mechanism even in patients without conventional AChR antibodies.

Myopathy is a convenient shorthand term meaning muscle disease or dysfunction. In other words, the myopathies are those conditions in which the patient's symptoms and signs can be attributed to a pathological process affecting either the structure of muscle fibres or their associated interstitial tissues, or to disturbance of the biochemical or electrophysiological function of those fibres. Myopathies are rare in all age ranges. They may be inherited or acquired. Onset of inherited myopathies in elderly people, not surprisingly, is uncommon, but some of these diseases are asymptomatic, or cause such minor symptoms that their significance is not appreciated by the patient, and thus they may not be recognized until late on in life. Their recognition may have implications for other, younger, family members. Many of the acquired myopathies afflicting older people are treatable, but the commonest, inclusion body myositis, is not, and incorrect diagnosis and inappropriate use of steroids may compound morbidity.

Cardiac abnormalities, cardiomyopathy and skeletal muscle weakness have been described in female carriers of the Xp21 (Duchenne and Becker) muscular dystrophies (J Neurol 1975;209(4):279-285; Br Med J 1969;2:418-420; J AmMed Assoc 1996;275(17):1335-1338; Neurology 1980;30(5):497-501; Neuromusc Disord 1999;9:347-351; Arch Neurol 1989;46:673-675). We have screened volunteers from our Xp21 genetics register and found the prevalence of previously unrecognized, clinically relevant, abnormalities in this group to be less than previously reported. We studied 91 women (56 carriers and 35 controls), aged between 18 and 69 years, from our local population known to the Oxford Regional Genetics Register. Our study included controls, with the investigators being blind to the subject's genetic status. The prevalence of previously unrecognised cardiac abnormalities on echocardiogram and ECG was 18% (10/56). Seven percent (4/56) of carriers had cardiomyopathy, defined by significant LV dilatation and decreased shortening fraction. In most cases, subjects with abnormal cardiac findings were asymptomatic. Echocardiography was more frequently abnormal than electrocardiography, but in many subjects the measurements of left ventricular dimensions were only just outside the normal ranges. The prevalence of skeletal muscle weakness was 12% (7/56). It was usually recognized by the individual, although not previously volunteered, but was mild and did not substantially affect activities of daily living.

BACKGROUND: McArdle disease is a rare metabolic myopathy caused by a complete absence of the enzyme muscle glycogen phosphorylase. Affected people experience symptoms of fatigue and cramping within minutes of exercise and are at risk for acute muscle injury (rhabdomyolysis) and acute renal failure. If the first few minutes of exercise are paced, a 'second wind' will occur enabling exercise to continue. This is due to mobilisation and utilisation of alternative fuel substrates. Aerobic training appears to improve work capacity by increasing cardiovascular fitness. OBJECTIVES: To assess the effects of aerobic training in people with McArdle disease. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register (11 January 2011), CENTRAL (2010, Issue 4), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011). SELECTION CRITERIA: All randomised and quasi-randomised controlled studies of aerobic exercise training in people of all ages with McArdle disease. DATA COLLECTION AND ANALYSIS: Two authors identified possible studies for inclusion and assessed their methodological quality. Had more than one study of sufficient methodological quality been identified we would have undertaken a meta-analysis. MAIN RESULTS: There were no randomised or quasi-randomised controlled trials of aerobic training in people with McArdle disease. However, three open studies using small numbers of participants provided some evidence that aerobic training improves fitness without adverse events in people with McArdle disease. AUTHORS' CONCLUSIONS: Evidence from non-randomised studies using small numbers of patients suggest that it would be safe and worthwhile for larger controlled trials of aerobic training to be undertaken in people with McArdle disease.

We report a sibship in which the syndrome of congenital arthrogryposis occurred in two male and two female neonates, three of whom died. The mother was asymptomatic at the time of the first pregnancy and the subsequent development of muscle weakness was later confirmed to be due to myasthenia gravis. The literature on this association is briefly reviewed and the extremely high risk of recurrence of this complication in subsequent pregnancies is addressed.

Aims The study aimed to determine the opinions of individuals with neurological conditions on factors facilitating their physical activity participation. Methods Four condition-specific focus groups (muscular dystrophy, multiple sclerosis, motor neurone disease and Parkinson's disease) were run with a total of 24 people. Themes that emerged were used to create an eight-item self-completed questionnaire, which explored barriers to participation, preferred activities and support networks. A cross-sectional survey was then conducted using this questionnaire with individuals with a range of neurological conditions. Findings Three themes categories emerged from the focus groups: ‘opinions of physical activity’, ‘barriers to physical activity’, and ‘factors that would encourage increased physical activity involvement’. Of the 115 distributed questionnaires, 80 (70%) responses were received. Swimming, stretching and walking were the three most popular activities. The most common barriers were embarrassment, perceived lack of condition-specific knowledge of the fitness professionals about neurological disease and the impact of that on exercise advice. Facilitators were use of specific groupbased exercise sessions and the presence of specifically trained staff. Conclusions People with neurological conditions enjoy participating in physical activity but reported several barriers that prevent their participation in exercise. Respondents identified barriers and facilitators in functional, psychological and environmental domains. It is important that healthcare professionals and fitness professionals identify and remove these barriers to promote greater participation in exercise among people with neurological conditions.

BioMarin Europe feels that our letter on the costs of orphan drugs such as amifampridine (Firdapse) for Lambert Eaton myasthenic syndrome (LEMS) and the safety of existing unlicensed treatments, such as 3,4-diaminopyridine base (3,4-DAP), contained inaccuracies.1 2 The Department of Health has confirmed that the additional cost of amifampridine in England is £9 768 668 (€11 400 035; $15 294 803) (excluding …