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Item does not contain fulltext, BACKGROUND: Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility. OBJECTIVE: To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients. METHODS: We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders. RESULTS: A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy. CONCLUSIONS: Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and incr

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Item does not contain fulltext, Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside

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Contains fulltext : 282760.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 282657.pdf (Publisher’s version ) (Open Access), Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between the prevalence of risk genotypes and actual MH incidence remains unexplained. We investigated the role of pre-operative exercise and pyrexia as potential MH modifying factors. We included cases from 5 MH referral centers with 1) clinical features suggestive of MH, 2) confirmation of MH susceptibility on Contracture Testing (IVCT or CHCT) and/or RYR1 genetic testing, and a history of 3) strenuous exercise within 72 h and/or pyrexia >37.5 °C prior to the triggering anesthetic. Characteristics of MH-triggering agents, surgery and succinylcholine use were collected. We identified 41 cases with general anesthesias resulting in an MH event (GA+MH, n = 41) within 72 h of strenuous exercise and/or pyrexia. We also identified previous general anesthesias without MH events (GA-MH, n = 51) in the index cases and their MH susceptible relatives. Apart from pre-operative exercise and/or pyrexia, trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with GA+MH events. These observations suggest a link between pre-operative exercise, pyrexia and MH.

Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between the prevalence of risk genotypes and actual MH incidence remains unexplained. We investigated the role of pre-operative exercise and pyrexia as potential MH modifying factors. We included cases from 5 MH referral centers with 1) clinical features suggestive of MH, 2) confirmation of MH susceptibility on Contracture Testing (IVCT or CHCT) and/or RYR1 genetic testing, and a history of 3) strenuous exercise within 72 h and/or pyrexia >37.5 °C prior to the triggering anesthetic. Characteristics of MH-triggering agents, surgery and succinylcholine use were collected. We identified 41 cases with general anesthesias resulting in an MH event (GA+MH, n = 41) within 72 h of strenuous exercise and/or pyrexia. We also identified previous general anesthesias without MH events (GA-MH, n = 51) in the index cases and their MH susceptible relatives. Apart from pre-operative exercise and/or pyrexia, trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with GA+MH events. These observations suggest a link between pre-operative exercise, pyrexia and MH.

Contains fulltext : 238097.pdf (Publisher’s version ) (Open Access), INTRODUCTION: Malignant hyperthermia (MH) and exertional rhabdomyolysis (ERM) have long been considered episodic phenotypes occurring in response to external triggers in otherwise healthy individuals with variants in RYR1. However, recent studies have demonstrated a clinical and histopathological continuum between patients with RYR1-related congenital myopathies and those with ERM or MH susceptibility. Furthermore, animal studies have shown non-neuromuscular features such as a mild bleeding disorder and an immunological gain-of-function associated with MH/ERM related RYR1 variants raising important questions for further research. Awareness of the neuromuscular disease spectrum and potential multisystem involvement in RYR1-related MH and ERM is essential to optimize the diagnostic work-up, improve counselling and and future treatment strategies for patients affected by these conditions. This study will examine in detail the nature and severity of continuous disease manifestations and their effect on daily life in patients with RYR1-related MH and ERM. METHODS: The study protocol consists of four parts; an online questionnaire study, a clinical observational study, muscle imaging, and specific immunological studies. Patients with RYR1-related MH susceptibility and ERM will be included. The imaging, immunological and clinical studies will have a cross-sectional design, while the questionnaire study will be performed three times during a year to assess disease impact, daily living activities, fatigue and pain. The imaging study consists of muscle ultrasound and whole-body magnetic resonance imaging studies. For the immunological studies, peripheral mononuclear blood cells will be isolated for in vitro stimulation with toll-like receptor ligands, to examine the role of the immune system in the pathophysiology of RYR1-related MH and ERM. DISCUSSION: This study will increase knowledge of the full spectrum of neuromuscular and multisystem features of RYR1-related MH and ERM

Contains fulltext : 218262.pdf (publisher's version ) (Open Access), Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequenc

Contains fulltext : 206096.pdf (publisher's version ) (Closed access)

1 april 2017, Item does not contain fulltext, The physiological process by which Ca2+ is released from the sarcoplasmic reticulum is called excitation-contraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca2+channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca2+ release channel of the sarcoplasmic reticulum. The released Ca2+ binds to troponin C, enabling contractile thick-thin filament interactions. The Ca2+ is subsequently transported back into the sarcoplasmic reticulum by specialized Ca2+ pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca2+ channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca2+ pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca2+ homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca2+ regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca2+ regulation or excitation-contraction coupling. The principal chal

Item does not contain fulltext, Malignant hyperthermia is a potentially fatal hypermetabolic disorder triggered by halogenated anesthetics and the myorelaxant succinylcholine in genetically predisposed individuals. About 50% of susceptible individuals carry dominant, gain-of-function mutations in RYR1 [which encodes ryanodine receptor type 1 (RyR1)], though they have normal muscle function and no overt clinical symptoms. RyR1 is predominantly found in skeletal muscle but also at lower amounts in immune and smooth muscle cells, suggesting that RYR1 mutations may have a wider range of effects than previously suspected. Mild bleeding abnormalities have been described in patients with malignant hyperthermia carrying gain-of-function RYR1 mutations. We sought to determine the frequency and molecular basis for this symptom. We found that some patients with specific RYR1 mutations had abnormally high bleeding scores, whereas their healthy relatives did not. Knock-in mice with the malignant hyperthermia susceptibility RYR1 mutation Y522S (MHS RYR1Y522S) had longer bleeding times than their wild-type littermates. Primary vascular smooth muscle cells from RYR1Y522S knock-in mice exhibited a higher frequency of subplasmalemmal Ca(2+) sparks, leading to a more negative resting membrane potential. The bleeding defect of RYR1Y522S mice and of one patient was reversed by treatment with the RYR1 antagonist dantrolene, and Ca(2+) sparks in primary vascular smooth muscle cells from the MHS RYR1Y522S mice were blocked by ryanodine or dantrolene. Thus, RYR1 mutations may lead to prolonged bleeding by altering vascular smooth muscle cell function. The reversibility of the bleeding phenotype emphasizes the potential therapeutic value of dantrolene in the treatment of such bleeding disorders.

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Item does not contain fulltext, Congenital myopathies are genetically and clinically heterogeneous conditions causing severe muscle weakness, and mutations in the ryanodine receptor gene (RYR1) represent the most frequent cause of these conditions. A common feature of diseases caused by recessive RYR1 mutations is a decrease of ryanodine receptor 1 protein content in muscle. The aim of the present investigation was to gain mechanistic insight into the causes of this reduced ryanodine receptor 1. We found that muscle biopsies of patients with recessive RYR1 mutations exhibit decreased expression of muscle-specific microRNAs, increased DNA methylation and increased expression of class II histone deacetylases. Transgenic mouse muscle fibres over-expressing HDAC-4/HDAC-5 exhibited decreased expression of RYR1 and of muscle-specific miRNAs, whereas acute knock-down of RYR1 in mouse muscle fibres by siRNA caused up-regulation of HDAC-4/HDAC-5. Intriguingly, increased class II HDAC expression and decreased ryanodine receptor protein and miRNAs expression were also observed in muscles of patients with nemaline myopathy, another congenital neuromuscular disorder. Our results indicate that a common pathophysiological pathway caused by epigenetic changes is activated in some forms of congenital neuromuscular disorders.

Item does not contain fulltext, BACKGROUND AND PURPOSE: Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. METHODS: A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012). RESULTS: The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. CONCLUSIONS: This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.

Item does not contain fulltext, Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Agrin is the major factor mediating the neuronal regulation of postsynaptic structures at the vertebrate neuromuscular junction, but the details of how it orchestrates this unique three-dimensional structure remain unknown. Here, we show that agrin induces the formation of the dense network of microtubules in the subsynaptic cytoplasm and that this, in turn, regulates acetylcholine receptor insertion into the postsynaptic membrane. Agrin acted in part by locally activating phosphatidylinositol 3-kinase and inactivating GSK3?, which led to the local capturing of dynamic microtubules at agrin-induced acetylcholine receptor (AChR) clusters, mediated to a large extent by the microtubule plus-end tracking proteins CLASP2 and CLIP-170. Indeed, in the absence of CLASP2, microtubule plus ends at the subsynaptic muscle membrane, the density of synaptic AChRs, the size of AChR clusters, and the numbers of subsynaptic muscle nuclei with their selective gene expression programs were all reduced. Thus, the cascade linking agrin to CLASP2-mediated microtubule capturing at the synaptic membrane is essential for the maintenance of a normal neuromuscular phenotype.

A grin is the major factor mediating the neuronal regulation of postsynaptic structures at the vertebrate neuromuscular junction, but the details of how it orchestrates this unique three-dimensional structure remain unknown. Here, we show that agrin induces the formation of the dense network of microtubules in the subsynaptic cytoplasm and that this, in turn, regulates acetylcholine receptor insertion into the postsynaptic membrane. Agrin acted in part by locally activating phosphatidylinositol 3-kinase and inactivating GSK3., which led to the local capturing of dynamic microtubules at agrin-induced acetylcholine receptor ( AChR) clusters, mediated to a large extent by the microtubule plus-end tracking proteins CLASP2 and CLIP-170. Indeed, in the absence of CLASP2, microtubule plus ends at the subsynaptic muscle membrane, the density of synaptic AChRs, the size of AChR clusters, and the numbers of subsynaptic muscle nuclei with their selective gene expression programs were all reduced. Thus, the cascade linking agrin to CLASP2-mediated microtubule capturing at the synaptic membrane is essential for the maintenance of a normal neuromuscular phenotype.

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18F-FDG. Copper-64 (64Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability