R. Scalco

Rhabdomyolysis: a genetic perspective

Rhabdomyolysis (RM) is a clinical emergency characterized by fulminant skeletal muscle damage and release of intracellular muscle components into the blood stream leading to myoglobinuria and, in severe cases, acute renal failure. Apart from trauma, a wide range of causes have been reported including drug abuse and infections. Underlying genetic disorders are also a cause of RM and can often pose a diagnostic challenge, considering their marked heterogeneity and comparative rarity.In this paper we review the range of rare genetic defects known to be associated with RM. Each gene has been reviewed for the following: clinical phenotype, typical triggers for RM and recommended diagnostic approach. The purpose of this review is to highlight the most important features associated with specific genetic defects in order to aid the diagnosis of patients presenting with hereditary causes of recurrent RM.Abstract in PortugueseA rabdomiólise (RM) é um evento agudo e grave, caracterizado por danos do músculo esquelético com a liberação, em grande quantidade, de componentes intracelulares para a corrente sanguínea. Uma vasta gama de causas tem sido relatada, incluindo trauma, abuso de drogas e infecções. Doenças hereditárias também podem causar RM, mas muitas vezes representam um desafio diagnóstico, considerando a sua heterogeneidade e raridade. Por fim, diversas doenças neuromusculares costumam estar associadas com níveis de CK cronicamente elevados, dificultando a identificação correta dos episódios de RM.Nesse artigo, revisamos os diversos defeitos genéticos associados à RM. Cada gene foi revisado abrangendo os seguintes: fenótipo clínico, gatilhos para RM e abordagem diagnóstica. O objetivo desta revisão é destacar as características mais importantes associados a defeitos genéticos específicos, a fim de auxiliar o diagnóstico de pacientes com causas hereditárias de RM recorrente.

Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy?

Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed.

Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy

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.

Emotionally-intense situations can result in rhabdomyolysis in McArdle disease.

Despite the majority of patients with McArdle disease reporting symptoms including fatigue, cramps and episodes of myoglobinuria from early childhood, diagnosis is often delayed by several decades. Additionally, many individuals with rhabdomyolysis remain undiagnosed. The occurrence of symptoms during exercise, particularly isometric muscle contraction such as heavy lifting, is well known in McArdle disease. However, isometric muscle contraction that occurs with emotion is not recognised as exercise and may be missed as a trigger for rhabdomyolysis, potentially leading to a delay in diagnosis. Three patients are presented here, all with symptoms from childhood including episodes of rhabdomyolysis induced by tense emotional situations without physical exertion; two patients reported recurrent episodes while watching rather than playing football. The remaining patient developed rhabdomyolysis during a heated argument. These patients’ histories emphasise the risk from sustained isometric muscle contraction that occurs in emotive situations for patients with McArdle disease.

Atypical periodic paralysis and myalgia: A novel RYR1 phenotype

Objective To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations. Methods Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed. Results Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. RYR1 analysis confirmed likely pathogenic variants in all 3 cases. Conclusions RYR1 mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.

McArdle Disease Misdiagnosed as Meningitis

Patient: Female, 44 Final Diagnosis: McArdle disease Symptoms: Exercise intolerance • muscle contracture • myalgia • myoglobinuria • recurrent rhabdomyolysis Medication: — Clinical Procedure: — Specialty: Neurology Objective: Rare disease Background: McArdle disease is a glycogen storage disorder mainly characterized by exercise intolerance. Prolonged muscle contracture is also a feature of this condition and may lead to rhabdomyolysis (RM), which is a serious event characterized by acute skeletal muscle damage. Case Report: A 44-year-old female patient presented with an acute contracture of the posterior neck muscles, causing severe nuchal rigidity. The contracture was induced during a dental extraction as she held her mouth open for a prolonged period, with her neck in a rigid position. She presented with severe pain in her ear and head, as well as fever, vomiting, and confusion. Based on her symptoms, she was initially misdiagnosed with bacterial meningitis and experienced an acute allergic reaction to the systemic penicillin she was subsequently administered. Lumbar puncture results were normal. High serum creatine kinase (CK) levels, recurrent exercise-related muscle symptoms, and a previous history of recurrent myoglobinuria raised the suspicion of an underlying neuromuscular condition. McArdle disease was confirmed by muscle biopsy and a genetic test, which revealed that the patient was homozygous for the R50X mutation in the PYGM gene. Conclusions: This case illustrates that even seemingly innocuous movements, if rapid isotonic or prolonged isometric in nature, can elicit a muscle contracture in McArdle disease patients. Here, we highlight the need for careful management in this patient population even during routine healthcare procedures. The allergic reaction to antibiotics emphasises that misdiagnoses may result in iatrogenic harm.

Report on the EUROMAC McArdle Exercise Testing Workshop, Madrid, Spain, 11–12 July 2014

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

G.P.22

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.

Calpainopathy with macrophage-rich, regional inflammatory infiltrates

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.

Dantrolene as a possible prophylactic treatment for RYR1-related rhabdomyolysis

Rhabdomyolysis (RM) may result from gene-environment interactions (1). Mutations in RYR1 lead to various neuromuscular phenotypes including malignant hyperthermia susceptibility and RM (2, 3). Preventive measures specifically aimed at RYR1-related RM mainly consist of avoidance of known triggers such as exercising in hot environments and untreated pyrexia. We report use of oral dantrolene as a prophylactic treatment for RYR1- related RM in three severely affected patients (patient consent was obtained for case report publication) (Table 1).