Diagnosis and treatment of postoperative malignant hyperthermia in a pediatric patient with congenital myopathy due to RyR1 gene mutations / 中华麻醉学杂志

A 14-year-old male pediatric patient was admitted to the hospital mainly because of neck and back deformity, with limited activity for 7 yr, dysphagia and short of breath for more than 10 months.He was diagnosed with cervical lordosis deformity, RyR1 gene-related myopathy, high possibility of multi-minicore disease and being susceptible to malignant hyperthermia.Posterior cervical orthopedic internal fixation surgery was successfully performed under total intravenous anesthesia with propofol.The vital signs were stable during anesthesia and operation which lasted for 10 h. The patient was admitted to intensive care unit after the uneventful operation.When emerging from general anesthesia, the patient suddenly presented with symptoms of muscular fasciculation in the head, face, trunk and limbs, along with elevated body temperature as high as 39.4℃, severe acidosis and hypercapnia, meanwhile, the blood creatine kinase, blood myoglobin and urinary myoglobin gradually increased.The patient was diagnosed with malignant hyperthermia based on the clinical grading scale score of 63.Dantrolene sodium was infused intravenously, combined with multiple treatments such as physical cooling, correction of acidosis and electrolyte disturbance, alkalization of urine, intermittent hemofiltration and plasma exchange.The arrhythmia and delirium were treated symptomatically.The pediatric patient was fully recovered and discharged with good outcomes.

Ryanodine receptor 2 mutation: Not only catecholaminergic polymorphic ventricular tachycardia but also epileptiform discharges in electroencephalogram

@#Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias, and RyR2 mutations have been shown in the aetiology of catecholaminergic polymorphic ventricular tachycardia. We report the case of a patient with catecholaminergic polymorphic ventricular tachycardia resulting from a RYR2 mutation who had not only typical electroencephalogram changes, but also epileptiform discharges in electroencephalogram. We believe the changes were closely related to the RYR2 mutation.

Mechanism of calcium leak and its relationship with atrial fibrillation: Research progress / 第二军医大学学报

Calcium as a ubiquitous messenger participates in the pathophysiology progresses of various cells. Synchronized calcium signaling transduction is related to normal cardiac myocyte excitation-contraction coupling and beating rhythm. Calcium homeostasis abnormality in atrial myocyte is an important influencing mechanism of atrial fibrillation (AF), and it is mostly resulted from calcium leak caused by destabilization of sarcoplasmic reticulum calcium release channel ryanodine receptor 2 (RyR2). Calcium leaks, including calcium sparks and calcium waves, can trigger extra depolarization and even action potential, and cause AF on the basis of atrial pathology altering matrices. In this review, we summarized the manifestations and influencing factors of calcium leak, and its potential role in the development and progress of AF.

Association between prion infection and Ryanodine receptor 2 in scrapie-263 K infected hamster / 中华实验和临床病毒学杂志

Objective@#To classify the expression of RyR2 in the brain of prion infected hamsters.@*Methods@#Immunohistochemical assays was used to verify that the location of RyR2 in the brain slices of hamster. Assays of the brain samples of intracranial inoculation of scrapie infected hamster (agent 263 K) and normal hamster were tested to evaluate the RyR2 expression by Western Blotting. Immunofluorescent assays were used to verify the co-location between RyR2 and PrP protein.@*Results@#RyR2 mainly located in cortex and Purkinje cells with parts of which are distributed in thalamus, hippocampus and olfactory bulb. The expression of RyR2 significantly decreased in the 263 K infected hamster at terminal stage. The Immunofluorescence tests showed that RyR2 was colocalized with PrP protein.@*Conclusions@#The experimental data showed that RyR2 may play a crucial role in prion disease, which might be closely linked to the cognition impairment and neuron loss. The relation between RyR2 and prion disease still needs further research.

Involvement of ryanodine receptor in skeletal muscle fatigue / 体力科学

Ryanodine receptors (RyRs) are tetrameric Ca2+ release channels of sarcoplasmic reticulum (SR). This review attempts to detail the key mechanism of RyR channel gating and to discuss the hypothesis that skeletal muscle fatigue, defined as reduced force production, would result from functional changes in both individual RyR channel opening and coupling among RyR channels. Previous studies have shown that RyR channels in skeletal muscle open simultaneously, called coupled gating, because of physical interaction among channels. In this review, mechanisms underlying muscle fatigue are discussed with consideration of the coupling effect. Fatigue mechanisms are thought to be different between acute exercise and long-term exercise training. The impairments in individual channel opening and coupling between RyR channels can occur after acute exercise, leading to decreased SR Ca2+ release and force depression. On the contrary, during long-term exercise training, individual channel opening would be enhanced but coupling between channels would be impaired. If this were to continue for long periods, SR Ca2+ content would reduce, leading to less Ca2+ release and lower force production.

The change of ryanodine receptor 2 expression in rats with septic shock / 中国小儿急救医学

Objective To investigate the changes of myocardial systolic and diastolic function and the expression of ryanodine receport 2 (RyR2)during different degree of myocardial dysfunction in septic shock rats.Methods We used random number method to divide 250 to 300g male Wistar rats into septic shock group and the control group which were divided into 4 subgroups at different time intervals of 0h,2h,4h,6h with six rats in each subgroup.The rat model of septic shock was established by intravenous dosing of LPS.When mean arterial pressure reduced by 25% to 30% from the basic value,a model of septic shock was established.We monitored the mean arterial pressure through femoral arterial catheterization and the left ventricular end-diastolic pressure,maximum rate of left ventricular systolic pressure rise(+dp/dt max) and maximum rate of left ventricular diastolic pressure drop(-dp/dt max)through carotid arterial catheterization.The pathological changes of myocardial tissue were observed via the pathological sections.The changes of RyR2 expression and the phosphorylation of RyR2 were detected via immunohistochemistry.The change of RyR2 gene expression was detected via PCR.Results In septic shock group,myocardial structure disturbance was worsen,myocardial tissue was ruptured,and myocardial cells and nucleus was disrupted.Myocardial dysfunction was gradually aggravated with the extension of time.The immunohistochemical results showed that the expression of RyR2 protein in septic shock group was higher than that in the control group(P<0.01), while the expression at 0h in septic shock group was the highest.As the extension of shock time,the myocardial function of rats decreased,the expression of RyR2 gradually declined in protein level,but the phosphorylation of RyR2 rised.The PCR results showed that the mRNA expression of RyR2 in septic shock group was higher than that in the control group(P<0.01), while the mRNA expression in septic shock group at early stage was the highest.As the extension of shock time,the mRNA expression of RyR2 gradually declined.Conclusion As the Ca2+ channel in the heart,the expression of RyR2 and the phosphorylation of RyR2 might be highly associated with the severity level of myocardial dysfunction under septic shock.

The role of RyR2 phosphorylation in heart failure / 复旦学报（医学版）

Heart failure is mainly characterized by myocardial systolic dysfunction,which is based on excitement-contraction coupling on the cellular level,and calcium (Ca2+) signaling plays a very important role in this process.The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is the major Ca2+ source of required for cardiac muscle excitation contraction coupling.RyR2 phosphorylation is the basis of SR calcium release,and RyR2 phosphorylation is mainly controled by protein kinase A (PKA) and calcium/calmodulin dependent protein kinase Ⅱ (CaMK Ⅱ).Although widely research in this area,excessive activation of RyR2 phosphorylation involved in the pathogenesis of heart failure are still controversial,which is discussed in this review.

Multi-modality CT study about the impact of human urinary kallidinogenase (HUK) on collateral circulation and blood perfusion in patients with acute cerebral ischemia (ACI) / 中国神经精神疾病杂志

Objective To study the impact of human urinary kallidinogenase (HUK) on collateral circulation and blood perfusion in patients with acute cerebral ischemia (ACI) using multi-modality CT methods. Methods In a randomized controlled clinical trial, 75 patients diagnosed with ACI were enrolled and divided into experiment group (treated with HUK)and control group (untreated with HUK). All participants underwent computer technology perfusion (CTP) and computed tomographic angiography (CTA) examination before and fourteenth day after treatment. The CT cerebral perfusion imaging (CTP), CT cerebrovascular imaging (CTA) and National Institutes of Health Stroke Scale (NIHSS) score were analyzed in two groups. The NIHSS score, cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP) were compared between the two groups before and after 14 days therapy. Results ① After treatment, The two group showed increased CBF and CBV values and decreased MTT and TTP values. The CBF improvement was significantly better in the HUK-treated group than in the control group (t=2.470,P<0.05).②MTT and TTP were shorter in the HUK-treated group than in the control group (t=2.126, t=2.213, P<0.05).③ CTA maximum intensity projection (MIP) sequence revealed that the number of patients collateral vessels was significantly increased in the HUK-treated group than in the control group ( x2=4.265, P<0.05). ④The NIHSS score improvement was significantly better in the HUK-treated group after 14 days treatment than in the control group (t=4.330, P<0.05). Conclusion Human urinary kallidinogenase can improve blood perfusion and ameliorates neurological deficits. It is a safe and effective drug for treating ACI patients. The multi-modality CT methods are effective measure to assess blood perfusion and collateral circulation in patients with acute cerebral ischemia.

Ryanodine receptor phosphorylation in sepsis-induced cardiomyopathy / 国际儿科学杂志

Sepsis is a systemic inflammatory reaction caused by infection,which is a common complication after bum,serious trauma,major surgery,pathological obstetrics,toxication and cardiopulmonary resuscitation.Simultaneously,it's also an important cause which can lead to septic shock and multiple organ dysfunction syndrome.Heart is the target of multiple organ dysfunction caused by sepsis,leading to different degrees of cardiac dysfunction by sepsis and vice verse.Ryanodine receptor is macromolecule composed by complex protein structure,which is the major component of Ca2+ channels.It's the necessary factor to adjust muscle,cardiac rhythm and contraction.It is also involved in regulating sarcoplasmic reticulum to release Ca2+.This article is to give a review of ryanodine receptors in cardiac dysfunction caused by sepsis.

Impact of Valsartan on Sarcoplasmic Reticulum Ryanodine Receptor2 in Myocardiocyte of Heart Failure Rabbits / 中国循环杂志

Objective: To explore sarcoplasmic reticulum ryanodine receptor2 (RyR 2) expression and calcium releasing function in chronic heart failure (CHF) rabbits and to study the impact of long term valsartan treatment in relevant animals. Methods: HF model was established by volume overloading with pressure overloading in experimental rabbits. 27 rabbits were divided into 3 groups: Sham group, HF group and HF+valsartan group. n=9 in each group and the animals were treated for 7 weeks. Left ventricular structure, hemodynamic parameters, expression and functional changes of myocardiocyte sarcoplasmic reticulum RyR 2 were observed and compared among different groups. Results: Compared with Sham group, HF group had increased left ventricular mess index (LVMI), left ventricular end diastolic pressure (LVEDP) and decreased left ventricular shortening fraction, LVEF, all P<0.05. Compared with HF group, HF+valsartan group showed decreased LVMI, LVEDP and increased left ventricular shortening fraction, LVEF, all P<0.05. Sarcoplasmic reticulum RyR 2 expression and calcium releasing function were lower in HF group than Sham group, P<0.05; while they were both higher in HF+valsartan group than HF group, P<0.05. Conclusion: Long term application of valsartan could improve the cardiac function which might be related to increased myocardial sarcoplasmic reticulum RyR 2 expression and calcium releasing function in experimental CHF rabbits.

Research progress about the cause of diabetic cystopathy and the treatment of it by caffeine / 医学研究生学报

Diabetic cystopathy is one of the most common complications caused by diabetes in urinary system.There were no obvious clinical manifestations in the early stage of the disease.With the progress of the disease, various complicated lower urinary tract symptoms appeared gradually.All these clinical manifestations cause grate trouble in the health and the quality of life of patients.However, its pathogenesis is not clear, myogenic and neurogenic is the main theory of its pathogenesis.Some studies indicate that long-term consumption of caffeine can reduce the incidence of it, and this article will discuss the cause of this disease and the treatment of caffeine in order to guide clinical practice.

Cardioprotective effects of Qishen Granule () on sarcoplasmic reticulum Cahandling in heart failure rats / 中国结合医学杂志

<p><b>OBJECTIVE</b>To assess the effects of Qishen Granule (, QSG) on sarcoplasmic reticulum (SR) Cahandling in heart failure (HF) model of rats and to explore the underlying molecular mechanisms.</p><p><b>METHODS</b>HF rat models were induced by left anterior descending coronary artery ligation surgery and high-fat diet feeding. Rats were randomly divided into sham (n=10), model (n=10), QSG (n=12, 2.2 g/kg daily) and metoprolol groups (n=12, 10.5 mg/kg daily). The therapeutic effects of QSG were evaluated by echocardiography and blood lipid testing. Intracellular Caconcentration and sarco-endoplasmic reticulum ATPase 2a (SERCA2a) activity were detected by specifific assay kits. Expressions of the critical regulators in SR Cahandling were evaluated by Western blot and real-time quantitative polymerase chain reaction.</p><p><b>RESULTS</b>HF model of rats developed ventricular remodeling accompanied with calcium overload and defective Carelease-uptake cycling in cardiomyocytes. Treatment with QSG improved contractive function, attenuated ventricular remodeling and reduced the basal intracellular Calevel. QSG prevented defective Caleak by attenuating hyperphosphorylation of ryanodine receptor 2, inhibiting expression of protein kinase A and up-regulating transcriptional expression of protein phosphatase 1. QSG also restored Cauptake by up-regulating expression and activity of SERCA2a and promoting phosphorylation of phospholamban.</p><p><b>CONCLUSION</b>QSG restored SR Cacycling in HF rats and served as an ideal alternative drug for treating HF.</p>

Clinical, pathological, imaging and genetic analysis of two cases of central core disease with different inheritance modes / 中国神经精神疾病杂志

Objective To study the clinical, pathological, imaging features of two cases of central core disease (CCD) with different inheritance and to explore the similarities and differences between autosomal recessive CCD (AR-CCD) and autosomal dominant CCD (AD-CCD). Methods Clinical manifestations, family history, muscle MRI and muscle biopsy were collected. Targeted next generation sequencing (NGS) and sanger sequencing were applied for genetic analysis. Co-segregation analysis was further conducted in one family. Results Their common clinical manifestations included childhood early-onset proximal limbs muscle weakness and dystrophy accompanied with facial involvement. The MRI revealed extensive muscular dystrophy and fatty filtration in the both thighs, but not in rectus femoris. Pathology of skeletal muscle showed typical central cores in type Ⅰ muscle fibers and eccentric cores only in AR-CCD. Targeted NGS identified 3 missense mutations in RYR1, including one novel mutation. Conclusion The present study has described clinical and pathological features of two typical CCD patients with different inheritance, which may be associated with the different mutations in RYR1 gene. Targeted NGS apparently improves the genetic diagnosis of CCD.

Ryanodine receptor 1 and its potential gating mechanism: Recent progress / 第二军医大学学报

The ryanodine receptors (RyRs) are intracellular Ca2+ releasing channels on the sarcoplasmic reticulum membrane and play a pivotal role in theexcitation-contraction coupling of skeletal and cardiac muscles as well as other physiological processes. With the recent development of CryoEM and the improvement of data analysis technique, scientists from China, the United States and Germany have acquired high-quality RyR1 images at the total resolutions of 3. 8 Å (1 Å = 10-10 m), 4. 8 Å and 6. 1 Å, respectively, which have been published in the same issue of Nature in 2015. RyRls are homotetrameric complexes with a molecular mass of more than 2 200 000, mainly containing a cytoplasmic region composed of NTD, SPRY, P1, P2, B-sol and C-sol domains and a channel region composed of S1-S6, VSL and CTD domains. As the most common factor affecting the condition of RyRl, Ca2+ is able to bind the EF-hand subdomain in the cytoplasmic region, which further causes the conformational change and finally leads to the channel opening.

Research progress on the role of CaMKⅡin cardiovascular disease / 天津医药

Calcium/calmodulin-dependent protein kinaseⅡ (CaMKⅡ) has multiple functions, which made it play a central role in cardiovascular disease. Especially it activates numerous downstream targets in various signaling pathways that promotes vascular disease, heart failure, myocardial hypertrophy and arrhythmias. CaMKⅡcan impact calcium balance and increase calcium leak in myocardial cell via phosphorylating L type calcium channel, Ryanodine receptor (RyR 2) and phos?pholamban (PLN), and regulate ATP sensitive potassium current (IKATP) and late sodium current by affecting sodium channels and potassium channels. In addition, It can directly regulate transcription via activating the silk crack the original activated protein kinases (MAPKs) and acetylation enzyme (HDAC). These mechanisms have important roles in myocardial hypertro?phy, heart failure and arrhythmia. So we focus to demonstrating the structure and action mechanism of CaMKⅡto improve a new therapy of cardiovascular disease.

Mild Clinical Features and Histopathologically Atypical Cores in Two Korean Families with Central Core Disease Harboring RYR1 Mutations at the C-Terminal Region

BACKGROUND: Central core disease (CCD) is a congenital myopathy characterized by distinctive cores in muscle fibers. Mutations in the gene encoding ryanodine receptor 1 (RYR1) have been identified in most CCD patients. CASE REPORT: Two unrelated patients presented with slowly progressive or nonprogressive proximal muscle weakness since childhood. Their family history revealed some members with the same clinical problem. Histological analysis of muscle biopsy samples revealed numerous peripheral cores in the muscle fibers. RYR1 sequence analysis disclosed a novel mutation in exon 101 (c.14590T>C) and confirmed a previously reported mutation in exon 102 (c.14678G>A). CONCLUSIONS: We report herein two families with CCD in whom missense mutations at the C-terminal of RYR1 were identified. Although it has been accepted that such mutations are usually associated with a severe clinical phenotype and clearly demarcated central cores, our patients exhibited a mild clinical phenotype without facial muscle involvement and skeletal deformities, and atypical cores in their muscle biopsy specimens.

Ryanodine Receptor-mediated Calcium Release Regulates Neuronal Excitability in Rat Spinal Substantia Gelatinosa Neurons

Nitric Oxide (NO) is an important signaling molecule in the nociceptive process. Our previous study suggested that high concentrations of sodium nitroprusside (SNP), a NO donor, induce a membrane hyperpolarization and outward current through large conductances calcium-activated potassium (BKca) channels in substantia gelatinosa (SG) neurons. In this study, patch clamp recording in spinal slices was used to investigate the sources of Ca2+ that induces Ca2+-activated potassium currents. Application of SNP induced a membrane hyperpolarization, which was significantly inhibited by hemoglobin and 2-(4-carboxyphenyl) -4,4,5,5- tetramethylimidazoline-1-oxyl-3-oxide potassium salt (c-PTIO), NO scavengers. SNP-induced hyperpolarization was decreased in the presence of charybdotoxin, a selective BKCa channel blocker. In addition, SNP-induced response was significantly blocked by pretreatment of thapsigargin which can remove Ca2+ in endoplasmic reticulum, and decreased by pretreatment of dentrolene, a ryanodine receptors (RyR) blocker. These data suggested that NO induces a membrane hyperpolarization through BKca channels, which are activated by intracellular Ca2+ increase via activation of RyR of Ca2+ stores.

Receptor de rianodina, fuga de calcio y arritmias / Ryanodine receptor, calcium leak and arrhythmias

La participación del canal de Ca2+/receptor de rianodina en el acoplamiento excitación-contracción cardiaco se conoce desde finales de los años ochenta, cuando en varios trabajos trascendentales se comunicó por primera vez su purificación y se encontró que correspondía a las estructuras conocidas como «pies¼ localizadas en las cisternas terminales del retículo sarcoplásmico. Adicionalmente a su papel como canal responsable del aumento global y transitorio de Ca2+ que activa a la maquinaria contráctil durante el ciclo cardiaco, el receptor de rianodina también libera Ca2+ durante la fase de relajación, dando lugar a la fuga de Ca2+ en la diástole que en condiciones fisiológicas regula el nivel de Ca2+ luminal, pero cuando se encuentra alterada participa en la generación de arritmias adquiridas o hereditarias. Recientemente, el esfuerzo de diversos grupos de investigación se ha enfocado en el desarrollo de herramientas farmacológicas para controlar la fuga diastólica de Ca2+ que se presenta alterada en algunas enfermedades cardiacas. En esta revisión nos enfocamos en describir la participación del receptor de rianodina cardiaco en la fuga diastólica de Ca2+ así como los diversos enfoques terapéuticos que se han implementado para controlar su actividad exacerbada en la diástole.

The participation of the ionic Ca2+ release channel/ryanodine receptor in cardiac excitation-contraction coupling is well known since the late '80s, when various seminal papers communicated its purification for the first time and its identity with the "foot" structures located at the terminal cisternae of the sarcoplasmic reticulum. In addition to its main role as the Ca2+ channel responsible for the transient Ca2+ increase that activates the contractile machinery of the cardiomyocytes, the ryanodine receptor releases Ca2+ during the relaxation phase of the cardiac cycle, giving rise to a diastolic Ca2+ leak. In normal physiological conditions, diastolic Ca2+ leak regulates the proper level of luminal Ca2+, but in pathological conditions it participates in the generation of both, acquired and hereditary arrhythmias. Very recently, several groups have focused their efforts into the development of pharmacological tools to control the altered diastolic Ca2+ leak via ryanodine receptors. In this review, we focus our interest on describing the participation of cardiac ryanodine receptor in the diastolic Ca2+ leak under physiological or pathological conditions and also on the therapeutic approaches to control its undesired exacerbated activity during diastole.

Effects of eugenol on resting tension of rat atria

In cardiac and skeletal muscle, eugenol (μM range) blocks excitation-contraction coupling. In skeletal muscle, however, larger doses of eugenol (mM range) induce calcium release from the sarcoplasmic reticulum. The effects of eugenol are therefore dependent on its concentration. In this study, we evaluated the effects of eugenol on the contractility of isolated, quiescent atrial trabeculae from male Wistar rats (250-300 g; n=131) and measured atrial ATP content. Eugenol (1, 3, 5, 7, and 10 mM) increased resting tension in a dose-dependent manner. Ryanodine [100 µM; a specific ryanodine receptor (RyR) blocker] and procaine (30 mM; a nonspecific RyR blocker) did not block the increased resting tension induced by eugenol regardless of whether extracellular calcium was present. The myosin-specific inhibitor 2,3-butanedione monoxime (BDM), however, reversed the increase in resting tension induced by eugenol. In Triton-skinned atrial trabeculae, in which all membranes were solubilized, eugenol did not change resting tension, maximum force produced, or the force vs pCa relationship (pCa=-log [Ca2+]). Given that eugenol reduced ATP concentration, the increase in resting tension observed in this study may have resulted from cooperative activation of cardiac thin filaments by strongly attached cross-bridges (rigor state).

Estudo clínico, histológico e molecular da miopatia centronuclear / A clinical, histological and molecular study of centronuclear myopathy

Introdução: A miopatia centronuclear é uma doença muscular congênita com apresentação clínica heterogênea, caracterizada histologicamente pela proeminência de fibras musculares com núcleos centralizados. Três formas são reconhecidas: neonatal grave, com herança ligada ao X e envolvimento do gene MTM1; autossômica dominante, com início geralmente tardio e curso mais leve, associada a mutações no gene DNM2; e autossômica recessiva, com gravidade intermediária entre as outras formas e envolvimento dos genes BIN1, RYR1 ou TTN. Apesar da identificação dos principais genes responsáveis pela doença, os métodos usuais de diagnóstico genético não encontram mutações em cerca da metade dos casos. Objetivo: O objetivo deste estudo foi a caracterização clínica, histológica e molecular de pacientes brasileiros portadores de miopatia centronuclear. Métodos: Laudos de dois bancos de biópsia muscular foram usados para identificar pacientes com diagnóstico de miopatia centronuclear nos últimos dez anos. As lâminas das biópsias foram revisadas e analisadas, e as famílias correspondentes convocadas para aplicação de protocolo clínico e coleta de sangue periférico para extração de DNA genômico. As famílias foram estudadas para os genes conhecidos por sequenciamento Sanger, MLPA, painel de genes implicados em doenças neuromusculares ou sequenciamento de exoma. Resultados: Foram convocados 24 pacientes provenientes de 21 famílias, em 16 das quais foi possível estabelecer o diagnóstico molecular. As 7 famílias com a forma neonatal grave constituíam um grupo homogêneo clínica e histologicamente, e mutações novas e conhecidas foram encontradas no gene MTM1 em 6 destas. Dois meninos deste grupo, com evolução estável, tiveram óbito súbito por choque hipovolêmico subsequente a rompimento de cisto hepático. O gene MTM1 também foi implicado em uma menina portadora manifestante, com quadro mais leve, na forma de uma macrodeleção em heterozigose, detectada por MPLA...

Introduction: Centronuclear myopathy is a heterogeneous congenital muscle disease, characterized by the prominence of centralized nuclei in muscle fibers. Three disease forms are recognized: a severe neonatal, X-linked form caused by mutations in the MTM1 gene; an autosomal dominant, late-onset milder form, associated to the DNM2 gene; and an autosomal recessive form, with intermediate severity, so far with the BIN1, RYR1 or TTN genes implicated. In spite of the identification of these genes, usual molecular diagnostic methods don't yield a molecular diagnosis in about half of cases. Objetives: The aim of this work was to study clinical, histological, and molecular aspects of centronuclear myopathy Brazilian patients. Methods: Reports taken from two muscle biopsy banks were used to identify centronuclear myopathy patients in the last ten years. Biopsy slides were reviewed and analyzed, and corresponding families recruited to apply a clinical protocol and to draw peripheral blood to extract genomic DNA. Families were studied for known genes via Sanger sequencing, MLPA, panel of genes implicated in neuromuscular diseases, or exome sequencing. Results: Twentyfour patients out of 21 families were recruited, and in 16 families molecular diagnosis was established. The 7 families with the severe neonatal form amounted to a clinically and histologically homogeneous group, and mutations, both known and novel, were found in the MTM1 gene in 6 of these. Two boys of this group, with a stable course, died suddenly of hypovolemic shock due to a hepatic cyst rupture. The MTM1 gene was also implicated in the case of a mild manifesting carrier girl with a heterozygous macrodeletion detected via MLPA...