Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies.

Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.

Myasthenia gravis: Association of British Neurologists' management guidelines.

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.

Two recurrent mutations are associated with GNE myopathy in the North of Britain.

OBJECTIVE: GNE myopathy is a rare recessive myopathy associated with inclusion bodies on muscle biopsy. The clinical phenotype is associated with distal muscle weakness with quadriceps sparing. Most of the current information on GNE myopathy has been obtained through studies of Jewish and Japanese patient cohorts carrying founder mutations in the GNE gene. However, little is known about GNE myopathy in Europe where the prevalence is thought to be very low. METHODS: Patients were referred through the National Specialist Commissioning Team service for limb-girdle muscular dystrophies at Newcastle (UK). All patients harbouring mutations in the GNE gene were recruited for our study. Detailed clinical and genetic data as well as muscle MRIs and muscle biopsies were reviewed. RESULTS: We identified 26 patients harbouring mutations in the GNE gene. Two previously reported mutations (c.1985C>T, p.Ala662Val and c.1225G>T, p.Asp409Tyr) were prevalent in the Scottish, Northern Irish and Northern English populations; with 90% of these patients carrying at least one of the two mutations. Clinically, we confirmed the homogenous pattern of selective quadriceps sparing but noted additional features like asymmetry of weakness at disease onset. CONCLUSIONS: GNE myopathy is an important diagnosis to consider in patients presenting with distal leg muscle weakness. We report, for the first time, two common mutations in the north of Britain and highlight the broader spectrum of clinical phenotypes. We also propose that the prevalence of GNE myopathy may be underestimated due to the frequent absence of rimmed vacuoles in the muscle biopsy.

Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.

OBJECTIVE: Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement. METHODS: We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology. RESULTS: We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450. CONCLUSIONS: Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

The modified rankin scale to assess disability in myasthenia gravis: Comparing with other tools.

INTRODUCTION: We explored the modified Rankin scale (mRS) as a tool to quantitate disability in myasthenia gravis (MG). Our aim was to correlate patients' perception of their disability with that of the care provider and determine its relationship with other MG-related scores. METHODS: We evaluated 107 MG patients at 2 neurological centers. Patients were assessed over the telephone before and after clinic visits using the 15-item Myasthenia Gravis Quality-of-Life index (MG-QOL15) and mRS. At the clinic, patients were assessed using the MG-QOL15, MG Composite (MGC), and mRS. RESULTS: The MG-QOL15 correlated with the MGC, mRS, and assessors' scores of patients. Assessors' perception of disease burden was in line with that of the patients' scoring. MG-QOL15 scores obtained over the telephone were consistent with those obtained in the clinic. Scores were generally higher in patients receiving steroids at >5 mg/day and in those receiving or seeking benefits. CONCLUSION: The MG-QOL15 and mRS are useful for estimating disability in MG.

Real-World Data on Access to Standards of Care for People With Spinal Muscular Atrophy in the UK.

Spinal Muscular Atrophy (SMA) is characterized by muscle atrophy and weakness and has an incidence of 1:11. 000 live births which projects an estimated population in the UK of 650-1,300 affected patients. Standards of Care (SoC) were updated in 2017 and they have been widely adopted as a reference for implementation of care in SMA across the globe. The effectiveness of implementation and adherence to these standards across different countries is unclear. The aim of this study is to describe the experience of individuals with SMA regarding their care in the UK. An online anonymised survey was sent out via patient organizations, the UK SMA Patient Registry, professional networks, and social media to reach across the UK. The survey captured demographic profile, professionals involved in a patient's care, Interventions and access to mobility aids and home adaptations. Participants responded about their access to services and to rate how important each professional and intervention was for their health and wellbeing. One hundred and twenty-eight responses were collected with a median age of 34 years (1-81). Seventy-three percent of participants were adults and 60% men. Overall good access to neurologist (>90%) but limited to nurse specialist (48%) and physiotherapist (57%). Good access to respiratory support was reported but limited for interventions for positioning and bracing and exercise. This survey highlights that access to certain professionals for people with SMA is limited in the UK. Striking differences were noted between pediatric and adult populations. Limited access to care were regularly reported, with half of the study population consistently not accessing full multidisciplinary care. Access to interventions for contracture management were recorded to have significant limitations. Mobility aids and home adaptations are widely available and were also reported as the most valued interventions. Access to nutritional support or speech and language therapy appears only to be available for a small proportion of the participants. Access to respiratory care was good especially in severe forms of SMA. We found pockets of good practice in the UK that align with the SoC. However, access is not equal for adults and children and access to certain professionals is significantly limited.

The Oculobulbar Facial Respiratory score is a tool to assess bulbar function in myasthenia gravis patients.

The Oculobulbar Facial Respiratory (OBFR) score is a tool that objectively measures bulbar function in myasthenia gravis (MG). In this study, we analyzed the relation between the OBFR and the MG Activities of Daily Living (MG-ADL) score, and also with the more recently described MG Composite and 15-item MG Quality-of-Life (MG-QOL15) scales. We recruited 42 patients from two centers and assessed them on two occasions, approximately 6 months apart, using the OBFR, MG Composite, MG-ADL, and MG-QOL15 scales. The 'modified' OBFR score was derived from the original OBFR score. The OBFR score correlated significantly with the MG Composite, MG-ADL, and MG-QOL15 scores for both assessments, and with the sum of the bulbar items for all three scores. It also correlated strongly with the individual bulbar-related items of all three scores. The 'modified' OBFR score also correlated significantly with all the aforementioned scores. This study confirmed construct validity of the OBFR and 'modified' OBFR scores.

A novel MT-CO2 variant causing cerebellar ataxia and neuropathy: The role of muscle biopsy in diagnosis and defining pathogenicity.

Pathogenic variants in mitochondrial DNA (mtDNA) are associated with significant clinical heterogeneity with neuromuscular involvement commonly reported. Non-syndromic presentations of mtDNA disease continue to pose a diagnostic challenge and with genomic testing still necessitating a muscle biopsy in many cases. Here we describe an adult patient who presented with progressive ataxia, neuropathy and exercise intolerance in whom the application of numerous Mendelian gene panels had failed to make a genetic diagnosis. Muscle biopsy revealed characteristic mitochondrial pathology (cytochrome c oxidase deficient, ragged-red fibers) prompting a thorough investigation of the mitochondrial genome. Two heteroplasmic MT-CO2 gene variants (NC_012920.1: m.7887G>A and m.8250G>A) were identified, necessitating single fiber segregation and familial studies - including the biopsy of the patient's clinically-unaffected mother - to demonstrate pathogenicity of the novel m.7887G>A p.(Gly101Asp) variant and establishing this as the cause of the mitochondrial biochemical defects and clinical presentation. In the era of high throughput whole exome and genome sequencing, muscle biopsy remains a key investigation in the diagnosis of patients with non-syndromic presentations of adult-onset mitochondrial disease and fully defining the pathogenicity of novel mtDNA variants.

Ptosis Surgery in Patients with Myasthenia Gravis: A Useful Adjunct to Medical Therapy.

INTRODUCTION: Medical management can have limitations in improving ptosis in patients with myasthenia gravis (MG). We present our experience of ptosis surgery in MG. MATERIALS AND METHODS: Clinical records of all patients with MG undergoing ptosis surgery from September 2007 to November 2013 in a single center were retrospectively reviewed. Change in upper marginal reflex distance (uMRD) was the main outcome measure. RESULTS: Sixteen external levator advancement (ELA) procedures were performed on 11 MG patients. Fourteen of 16 procedures had pre- and postoperative uMRD documented. Thirteen of 14 procedures had improved lid height; mean increase in uMRD was 2.4 mm (P=0.0005651). Two patients required secondary lid elevation. Postoperative complications included more noticeable diplopia (n=1) and exposure keratopathy (n=1). CONCLUSION: Ptosis surgery is a useful adjunct to medical therapy to improve lid height in MG patients with ptosis. Risks of diplopia and exposure keratopathy should be discussed with the patient pre-operatively.

A Physical and Psychological Approach to Managing Fatigue in Myasthenia Gravis: A Pilot Study.

BackgroundFatigue in myasthenia gravis (MG) is common and difficult to manage. Unlike myasthenic weakness it is not amenable to drug therapies.ObjectiveOur primary aim was to investigate whether a combination of physical and psychological therapy would help address symptoms of fatigue in MG patients, who have stable disease but residual problematic fatigue. Our secondary aim was to quantitate fatigue by applying different scores and to ascertain which would be most relevant to apply in MG.MethodsWe recruited 10 MG patients with stable disease and who suffer from fatigue. Nine of these 10 patients participated in a 10-week program that involved physical and psychological intervention. We quantified their fatigue using the modified fatigue impact scale (MFIS), the visual analogue fatigue scale (VAFS) and the fatigue severity scale (FSS) at the start of the study, at various intervals during the program and 3 months later.ResultsDuring the program, there was a small improvement in the physical and psychosocial subscale of the MFIS. There was a significant improvement (p < 0.01) in the VAFS at the end of the program. No clear improvement was noted in FSS. Three months later, all fatigue scores declined to baseline but 50% of patients had made some life-style changes.ConclusionsThis is a small pilot study, which utilized a combined approach with physical and psychological therapy, and showed some benefit in improving fatigue in patients with MG. The improvement was small and unsustained. Because of the small patient cohort, one cannot derive any firm conclusions and a larger study is required to investigate this further.

The Association of British Neurologists' myasthenia gravis guidelines.

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.

Quantitative EMG of facial muscles in myasthenia patients with MuSK antibodies.

OBJECTIVE: Our aim was to study the pathophysiological process leading to facial muscle atrophy in 13 patients with MuSK antibody positive myasthenia gravis (MuSK-MG), and to compare with findings from 12 acetylcholine receptor antibody positive myasthenia patients (AChR-MG), selected because they suffered from the same degree of disease severity and required similar treatment. METHODS: Motor unit action potential (MUAP) and interference pattern analysis from orbicularis oculi (O oculi) and orbicularis oris (O oris) muscles were studied using a concentric needle electrode, and compared with findings in 20 normal subjects, 6 patients receiving botulinum toxin injections (representing a neurogenic model) and 6 patients with a muscle dystrophy (representing a myopathic model). The techniques and control data have been reported previously. RESULTS: The mean MUAP durations for O oculi and O oris were significantly reduced (p<0.001) in both MG cohorts when compared with healthy subjects, and were similar to those in the myopathic control group. They were significantly different from those obtained from the neurogenic control group (p<0.001 for both O oculi and O oris). The MUAP findings in O oculi occurred independently from neuromuscular blocking on single fibre EMG (SFEMG) in the same muscle. On turns amplitude analysis (TAA), 50% of MuSK-MG patients and 42% of AChR-MG patients had a pattern in O oculi which was similar to that in the myopathic control group, and 62% of MuSK-MG patients and 50% of AChR-MG patients had a pattern in O oris that was also similar to that in the myopathic control group. The TAA findings for O oculi and O oris in both MG cohorts were different from those obtained from the neurogenic control group. CONCLUSIONS: Facial muscle atrophy in MuSK-MG patients is not neurogenic and the pathophysiological changes are akin to a myopathic process. The selected AChR-MG patients also show evidence of a similar pathophysiological process in the facial muscles albeit to a lesser degree. SIGNIFICANCE: We propose that muscle atrophy in MuSK-MG is a myopathic process consisting of either muscle fibre shrinkage or loss of muscle fibres from motor units. The duration of disease and long-term steroid treatment may be further contributory factors.

A retrospective study of acetylcholine receptor antibody positive ocular myasthenia in the West of Scotland.

Ocular myasthenia is the milder end of the myasthenia gravis spectrum but treatment can be challenging especially in older patients. We retrospectively studied all patients on our database with ocular myasthenia (OMG), positive for acetylcholine receptor (AChR) antibodies. We identified 93 patients (64 men and 29 women). The mean age at disease onset was 63y, median 68y. Most (72%) experienced ptosis with diplopia; 19% experienced ptosis alone, while 7.5% complained of diplopia without ptosis. As expected, pyridostigmine was commenced early at diagnosis in the majority (69%) and 20% were still receiving pyridostigmine at final review. Immunosuppression was prescribed in 50%. Seven patients had ptosis repair surgery; 20 patients used prisms at some stage. >75% had several comorbidities. Our OMG cohort is an older population with several comorbidities. Final outcomes in those who received immunosuppression were similar to those who had not.

Correction: Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1: A multicentre cohort follow-up study.

[This corrects the article DOI: 10.1371/journal.pone.0174166.].

Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1: A multicentre cohort follow-up study.

OBJECTIVE: High sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1). METHODS: 117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months. RESULTS: Fifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level < 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score. CONCLUSIONS: Plasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting.

Clinical Features, Molecular Heterogeneity, and Prognostic Implications in YARS2-Related Mitochondrial Myopathy.

Importance: YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. Objectives: To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. Design, Setting, and Participants: An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. Main Outcome and Measures: The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Results: Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes. Conclusions and Relevance: The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.

Turns amplitude analysis of the orbicularis oculi and oris muscles.

OBJECTIVE: The aim of the study was to determine whether 'clouds' from turns amplitude analysis obtained from the orbicularis oculi and oris muscles without force monitoring can be used to differentiate pathological processes affecting the face. METHODS: The interference pattern from orbicularis oculi and orbicularis oris was studied using a concentric needle electrode. Data-points from 20 normal subjects were plotted on a logarithmic scale of mean amplitude between turns versus turns/second, from which linear regression analysis defined the 95% confidence intervals. This enabled us to draw the boundaries of the normal cloud on a linear plot. Data-points from the interference pattern in two pathological cohorts, of 6 patients receiving botulinum toxin injections (representing a neurogenic model), and 6 patients with a muscle dystrophy (representing a myopathic model) were plotted against the normal cloud. These findings were compared and correlated with the mean durations obtained on motor unit action potential analysis from these same two facial muscles. RESULTS: The majority of patients receiving botulinum toxin injections into their facial muscles showed a pattern of high amplitude with low turns/s, or low amplitude with a low-to-normal range of turns/s in both facial muscles. These findings were associated with high-duration motor unit action potentials in most cases. In the myopathic group of patients 66% showed a pattern of low amplitude with low-to-normal range of turns/s in O oculi and O oris. This correlated with short-duration motor unit action potentials in both facial muscles. CONCLUSIONS: We have demonstrated that turns amplitude analysis without force monitoring can be used to study the interference pattern from facial muscles and can be applied to differentiate primary neurogenic from myopathic pathological processes. SIGNIFICANCE: Turns amplitude analysis without force monitoring in the facial muscles can be used as an effective and practical method of interference pattern analysis to complement findings from conventional motor unit action potential analysis.

Correlating extent of neuromuscular instability with acetylcholine receptor antibodies.

In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylcholine receptor (AChR) antibody titers with single-fiber EMG studies to explore whether a relationship exists between these parameters. We found that the AChR antibody titers correlated significantly with the mean of the mean consecutive difference of orbicularis oculi (OO, P<0.0001) and extensor digitorum communis (EDC, P<0.0001). The correlation was found to be stronger in OO. The antibody titers also correlated with the percentage of potential pairs with increased jitter in both muscles and, again, the correlation was more significant in OO (P<0.0001) than in EDC (P=0.001). We speculate that this relationship is stronger in OO than in the limb muscles, because the architectural and immunological differences in the motor unit render OO more vulnerable and sensitive to disturbances in neuromuscular transmission.