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An 84-year-old lady with slowly progressive limb and axial muscle weakness with onset in her teens was referred for genetic investigations. Targeted next generation sequencing (NGS) revealed a homozygous mutation GYG1 in exon5:c.487delG:p.D163fs, confirming the diagnosis of Polyglucosan Body Myopathy 2 (PGBM2). Retrospective review of muscle pathology revealed a florid vacuolar myopathy with histochemical and ultrastructural features consistent with a polyglucosan storage myopathy. No cardiac symptoms were reported. Our case is consistent with the core phenotype of GYG1-related PGBM2 apart from an early onset of weakness without cardiac symptoms. The presence of α-amylase resistant PAS-positive material in skeletal muscle biopsy of patients with slowly progressive limb girdle muscle weakness should prompt the search for GYG1 mutations. This case highlights the combined role of muscle pathology and NGS in the molecular resolution of patients with undiagnosed neuromuscular conditions.

Mutations in calpain-3 cause limb girdle muscular dystrophy 2A. Biopsy pathology is typically dystrophic, sometimes characterized by frequent lobulated fibres. More recently calpain mutations have been shown in association with eosinophilic myositis, suggesting that calpain mutations may render muscle susceptible to inflammatory change. We present the case of a 33-year old female with mild proximal muscle weakness and high CK levels (6698 IU/L at presentation). Muscle biopsy showed clusters of fibre necrosis associated with very dense macrophage infiltrates and small numbers of lymphocytes, raising the possibility of an inflammatory myopathy. No eosinophils were observed. Immunosuppressive treatment was started without clinical improvement. MRI demonstrated bilateral fatty replacement in posterior thigh and calf muscles. Western blot results prompted Sanger sequencing of the calpain-3 gene revealing compound heterozygous mutations c.643_663del and c.1746-20C>G. Our case widens the myopathological spectrum of calpainopathies to include focal macrophage rich inflammatory change.

Report on the EUROMAC McArdle Exercise Testing Workshop, Madrid, Spain, 11–12 July 2014 Ros Quinlivan *, Alejandro Lucia , Renata S. Scalco , Alfredo Santalla , Jatin Pattni , Richard Godfrey , Ramon Marti d on behalf of the Workshop Participants a MRC Centre for Neuromuscular Diseases, University College London, London WC1N 3BG, UK b Universidad Europea de Madrid, 28670 Madrid, Spain c Department of Sport Health and Exercise Sciences, Brunel University, Uxbridge UB8 3PH, UK d Vall D’Hebron Research Institute and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Catalonia, Spain Received 12 May 2015

Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment.

McArdle disease is a rare condition and often people have had symptoms for many years before the diagnosis is made. There is no specific treatment for the condition but early diagnosis and appropriate management may improve exercise tolerance and prevent acute rhabdomyolysis. Here we present a patient with McArdle disease where an acute episode of neck muscle contracture causing nuchal rigidity was misdiagnosed as meningitis. The patient went onto develop an acute allergic reaction to systemic penicillin with potential life-threatening complications. The patient’s neck contracture was induced by dental extraction during which she was required to hold her mouth open and neck rigid for a prolonged time. This case illustrates that contracture in McArdle disease does not necessarily follow ’exercise’ and highlights the need for careful management during procedures.

Recurrent rhabdomyolysis complicates a number of inherited muscle and metabolic disorders and represents a serious, potentially life-threatening condition which frequently requires critical care. Identification of the underlying genetic cause has traditionally relied upon detailed history and examination findings which subsequently guide the investigative work-up. However, in many cases the causative molecular defect remains undetermined. This study aims to investigate whether utilising next-generation sequencing (NGS) technology early in the diagnostic pathway might offer a rapid, cost-effective tool for the diagnosis of patients with recurrent attacks of rhabdomyolysis when a genetic aetiology is suspected. We have designed a “rhabdomyolysis gene panel” comprised of 48 genes known or predicted to cause rhabdomyolysis using NGS technology. Over 200 patients have been recruited. In addition, array CGH and whole exome sequencing may be used. A pilot study of 53 patients with a panel of sequenced 35 rhabdomyolysis genes using an amplicon based sequencing panel on an Illumina MiSeq was performed. 52 of the first 53 first evaluated patients have a variant in at least 1 gene. 49 patients have heterozygous variants in at least two different genes. We identified 15 cases out of 52 with probable pathogenic mutations using this approach. The pilot study showed that the rhabdomyolysis genetic panel is a potentially useful way to identify genetic alterations in patients with rhabdomyolysis. The high number of symptomatic patients with mutations identified in more than one gene associated with rhabdomyolysis suggests that gene–gene interaction(s) may play an important role. We are currently preparing a new extended panel of 48 genes.

The European Union has funded the development of a new disease registry for McArdle disease and other rare glyco (geno) lytic disorders presenting with exercise intolerance. The aim of the project is to identify as many patients as possible across all European countries and to collect important natural history and epidemiological data. Clinicians working in the European Union (EU) and patients with McArdle disease or other rare glyco (geno) lytic disorders presenting with exercise intolerance from the EU are able to participate in this project. Registration is via a secure web platform accessed through the EUROMAC website http://euromacregistry.eu/ . Both patients and doctors will need to supply epidemiological and clinical information. Data will be anonymised to ensure participants’ protection. We hope to create the largest international cohort of people with such rare conditions. Data on epidemiology and natural history will be generated, supporting knowledge about these rare disorders. We hope to increase awareness of these disorders and the website will signpost patients and clinicians to diagnostic and clinical centres of excellence across Europe. We plan to develop standards of care which will be posted on the website and we hope that the registry will be the gateway to future large scale multi-centre clinial trials. The EUROMAC is an international registry for patients with McArdle disease and other rare glyco (geno) lytic disorders presenting with exercise intolerance and it is open to all EU residents. Further information is presented online in the EUROMAC website http://euromacregistry.eu/ . We seek to recruit as many European partners as possible and welcome collaborators and volunteers both from health services and patient support organisations.

4,055 JCR (2014) Q1, posicion 27 de 192 (Clinical Neurology), posicion 61 de 252 (Neurosciences)