M. Parton

Workshop reportInclusion body myositis: MRC Centre for Neuromuscular Diseases, IBM workshop, London, 13 June 2008

This first MRC workshop on inclusion body myositis assembled 29 clinicians and scientists. The workshop sought to establish a platform upon which an organised international network of neuromuscular specialists could consider a range of important unresolved issues in relation to IBM. The aims of the workshop were as follows: to review current practice regarding clinical and histopathological diagnostic criteria, to assess recent advances in relation to aetiology and basic science with potential for translation into clinical trials, to review current evidence for IBM treatments and lessons applicable to future trial design, to review genetic advances in IBM and to consider an IBM disease-specific prospective database in an electronic network.

Cytosolic 5′-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis

Objectives Autoantibodies 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 methods Data 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. Results Data 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. Interpretation Differences 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.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Alternating hemiplegia of childhood is rare and usually results from mutations in cardiac- and brain-expressed ATP1A3. In an ECG study of 52 cases, Jaffer et al. reveal dynamic cardiac repolarisation or conduction abnormalities in over 50%. Abnormalities are more common in those ≥16 years, and suggest impaired cardiac repolarisation reserve.

Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis

Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). Sequestosome 1 (SQSTM1) and valosin-containing protein (VCP) are 2 key genes associated with several neurodegenerative disorders but have yet to be thoroughly investigated in sIBM. A candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest. We identified 6 rare missense variants in the SQSTM1 and VCP in 7 sIBM patients (4.0%). Two variants, the SQSTM1 p.G194R and the VCP p.R159C, were significantly overrepresented in this sIBM cohort compared with controls. Five of these variants had been previously reported in patients with degenerative diseases. The messenger RNA levels of major histocompatibility complex genes were upregulated, this elevation being more pronounced in SQSTM1 patient group. We report for the first time potentially pathogenic SQSTM1 variants and expand the spectrum of VCP variants in sIBM. These data suggest that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.

Frequency and circumstances of falls in people with Inclusion Body Myositis: a questionnaire survey to explore falls management and physiotherapy provision

OBJECTIVES To survey the incidence and circumstances of falls for people with inclusion body myositis (IBM) in the UK, and to investigate the provision of physiotherapy and falls management. DESIGN Postal questionnaire survey. SETTING Participants completed questionnaires at home. PARTICIPANTS Ninety-four people diagnosed with IBM were screened against the inclusion criteria. Seventy-two potential participants were sent a questionnaire, and 62 were completed and returned. Invited participants were sent an adapted Falls Event Questionnaire pertaining to falls, perceived causes of falls and the provision of physiotherapy. Questionnaires were returned anonymously. MAIN OUTCOME MEASURES The proportions of respondents who reported a fall or a near fall, along with the frequencies of falls and near falls were calculated. Descriptive data of falls were collected pertaining to location and cause. Data analysis was performed to investigate provision of physiotherapy services. RESULTS The response rate was 86% [62/72, mean (standard deviation) age 68 (8) years]. Falls were reported by 98% (61/62) of respondents, with 60% (37/62) falling frequently. In this study, age was not found to be an indicator of falls risk or frequency. Twenty-one percent (13/62) of respondents had not seen a physiotherapist in relation to their IBM symptoms, and of those that had, 31% (15/49) had not seen a physiotherapist until more than 12 months after IBM was diagnosed. Only 18% (11/61) of fallers reported that they had received falls management input. CONCLUSIONS Falls are a common occurrence for people with IBM, independent of age and years since symptoms first presented, and are poorly addressed by appropriate physiotherapy management. National falls guidelines are not being followed, and referral rates to physiotherapy need to improve.

Mutational spectrum and phenotypic variability of VCP-related neurological disease in the UK

Hereditary inclusion body myopathy (IBM) with Pagets disease of the bone (PDB) and frontotemporal dementia (FTD) (IBMPFD) is a rare autosomal dominant disorder due to mutations in the valosin-containing protein gene ( VCP ).1 Pathogenic VCP variants have also been associated with amyotrophic lateral sclerosis2 and other phenotypes including dilated cardiomyopathy and Parkinsons disease. We describe phenotypic and genetic findings of 42 individuals from 21 families with VCP mutations. As our service is the reference laboratory for the UK, we calculated the UKs point prevalence based on the 2011 Census as the number of cases per population. In total, 42 individuals were identified, 23 men and 19 women from 21 kinships (see online supplementary tables S1A, B). Based on our data, the expected point prevalence of IBMPFD in the UK is 0.066/100 000 population. Eighteen unrelated patients harbour a previously described mutation. In addition, three patients from two families harbour two novel variants (c.604G>T, p.G202W in exon 6 and c.1316C>G, p.A439G in exon 11) that are predicted to be pathogenic by in silico analysis (Alamut interpretation software V.2.4) and segregate with disease. Three previously described mutations were identified in exon 5 of the VCP gene. The mutation p.R155H (c.464G>A) was found in 11 families. The mutation p.R191Q (c.572G>A) was found in three unrelated patients, p.R155C (c.463C>T) in two families, and p.R93C (c.277C>T) in two unrelated patients (see online supplementary material genetic analysis and mutation analysis). The mean age of disease onset was …

Ongoing Developments in Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM.

EMERGENCY NEUROMUSCULAR ADMISSIONS ARE AVOIDABLE: A REGIONAL AUDIT OF UNPLANNED HOSPITAL ADMISSIONS OF NEUROMUSCULAR PATIENTS 2009–2011: FINAL RESULTS AND RECOMMENDATIONS

Introduction Neuromuscular diseases (NMD) require long–term multi–disciplinary care. In 2010–11 there were 5.3 million emergency admissions of which 213,000 related to neurological disorders. 13% of these (∼28,000) were secondary to NMD. With each admission costing ∼£3000 per day, it is estimated that this leads to costs of £81 m nationally (£28 m in four specialised commissioning groups [SCG]: London, East of England, South–East Coast and South–Central). Fundamentally, avoidable admissions have an adverse effect on quality of life. Studies have shown that strengthening links between specialist and primary care, integration of health and psychosocial care and hospital at home interventions are associated with lower emergency admission rates. The aims were to: 1. Determine the proportion of avoidable emergency admissions directly attributable to NMD 2. Determine what proportion of patients are known to specialist neuromuscular services and compare characteristics of such admissions against centres without a specialist service 3. Identify reasons for emergency admissions and preventable measures. Methodology A retrospective case note audit was conducted across 12 trusts in four SCG regions. Emergency admissions in patients with NMD were identified by SCG IT teams using secondary user services data and ICD–10 codes for neuromuscular and metabolic disorders between January 2009 and June 2011. In the absence of national clinical standards of care for NMD, consensus criteria to identify avoidable admissions were developed by an expert panel (Table 1). Data analysis was undertaken independently by London SCG. Results There were 576 unplanned admissions for 395 patients. Of 395 patients, 65% had a pre–existing NMD and 25% of these were known to specialist NMD services. Of 576 separate admissions, 65% were at hospitals with a specialist service and 74% of these admissions were in patients with a pre–existing NMD. Overall, 37.5% of unplanned admissions were avoidable and 5% potentially avoidable. Further analysis showed that of the admissions directly attributable to NMD, 63% were avoidable and 5.7% potentially avoidable. There was no difference in preventability of admissions between hospitals with and without specialist NMD services (p=0.79). The main measures that may have prevented an avoidable admission were: On–going disease monitoring, access to specialist services (nurse specialist, therapists, equipment and cardiorespiratory care), and implementation of an emergency plan. 20% of patients known to NMD services had a documented emergency plan. 58% of inpatients were reviewed by a neurologist. Conclusions Over one–third of emergency admissions were avoidable, majority occurring in patients with pre–existing NMDs. Only a quarter of neuromuscular patients are known to a specialist and 20% have an emergency plan in place. Key recommendations were developed for the national working specification after consultation with the All Party Parliamentary Group for Muscular Dystrophy to reduce fragmentation of care. These are: 1. Monitoring of patients and access to neuromuscular services between appointments 2. Specialist NMD centres to lead coordination of care across sub–specialties 3. Strengthen links with social services and local hospitals to enable advice 4. All patients with a known NMD should have a documented referral to the neurology team during admission and an emergency plan on discharge.

A case of necrotizing myopathy with proximal weakness and cardiomyopathy

A male amateur body builder presented at age 23 years with a 2-year history indicative of progressive proximal limb weakness. His initial symptom was a rash which was nonpruritic and he described as “ring” lesions on his trunk which spontaneously resolved after 6 months. Following resolution of

097 Valosin Containing Protein (VCP) and Myofibrillar Myopathies (MFM) genes' mutations are not associated with sporadic Inclusion Body Myositis (sIBM)

Background Inclusion body myopathy with dementia and Paget disease of bone (IBMPFD) and myofibrillar myopathies (MFM) are genetically determined myopathies that can mimic sporadic Inclusion Body Myositis (sIBM), especially if the disease phenotype is incomplete (eg, skeletal muscle involvement only), if there is no family history (either because a mutation arises in the germ line or because the disease in the parents was unrecognised) and if the histological features overlap with those of sIBM. It is therefore possible that some sIBM cases may be caused by undetected mutations in the IBMPFD and MFM causative genes. Objective To investigate the association of sIBM with mutations in the IBMPFD and MFM causative genes. Methods Twenty-nine patients with sIBM (meeting diagnostic criteria for definite or probable sIBM according to Griggs) were screened for mutations in the following genes: valosin containing protein (VCP), Desmin (DES), Myotilin (MYOT) and Crystallin alpha-B (CRYAB). Results No pathogenic mutations in the VCP, DES, MYOT and CRYAB genes were detected in this group of sIBM patients. Conclusion This study provides evidence that common mutations in the VCP, DES, MYOT and CRYAB genes are not associated with the development of sIBM. Our results support current clinical practice in patients with sIBM, which are not usually screened for mutations in these genes, unless there the history or biopsy findings suggest a genetically determined myopathy.