Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T.

BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.

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.

Muscular MRI-based algorithm to differentiate inherited myopathies presenting with spinal rigidity.

OBJECTIVES: Inherited myopathies are major causes of muscle atrophy and are often characterized by rigid spine syndrome, a clinical feature designating patients with early spinal contractures. We aim to present a decision algorithm based on muscular whole body magnetic resonance imaging (mWB-MRI) as a unique tool to orientate the diagnosis of each inherited myopathy long before the genetically confirmed diagnosis. METHODS: This multicentre retrospective study enrolled 79 patients from referral centres in France, Brazil and Chile. The patients underwent 1.5-T or 3-T mWB-MRI. The protocol comprised STIR and T1 sequences in axial and coronal planes, from head to toe. All images were analyzed manually by multiple raters. Fatty muscle replacement was evaluated on mWB-MRI using both the Mercuri scale and statistical comparison based on the percentage of affected muscle. RESULTS: Between February 2005 and December 2015, 76 patients with genetically confirmed inherited myopathy were included. They were affected by Pompe disease or harbored mutations in RYR1, Collagen VI, LMNA, SEPN1, LAMA2 and MYH7 genes. Each myopathy had a specific pattern of affected muscles recognizable on mWB-MRI. This allowed us to create a novel decision algorithm for patients with rigid spine syndrome by segregating these signs. This algorithm was validated by five external evaluators on a cohort of seven patients with a diagnostic accuracy of 94.3% compared with the genetic diagnosis. CONCLUSION: We provide a novel decision algorithm based on muscle fat replacement graded on mWB-MRI that allows diagnosis and differentiation of inherited myopathies presenting with spinal rigidity. KEY POINTS: • Inherited myopathies are rare, diagnosis is challenging and genetic tests require specialized centres and often take years. • Inherited myopathies are often characterized by spinal rigidity. • Whole body magnetic resonance imaging is a unique tool to orientate the diagnosis of each inherited myopathy presenting with spinal rigidity. • Each inherited myopathy in this study has a specific pattern of affected muscles that orientate diagnosis. • A novel MRI-based algorithm, usable by every radiologist, can help the early diagnosis of these myopathies.

[Imaging of primary muscular diseases : What do neurologists expect from radiologists?] / Bildgebung primärer Muskelerkrankungen : Was erwartet der Neurologe vom Radiologen?

Imaging, in particular magnetic resonance imaging (MRI), has in recent years increasingly become a crucial tool for the diagnostics of inherited and acquired muscular diseases. The aim of imaging in neuromuscular disorders goes beyond the detection and quantification of degenerative muscular changes, such as fatty degeneration and includes recognition of very early signs of muscular pathologies presenting as muscular edema. Therefore, imaging is a valuable diagnostic method to support the clinical diagnosis and to narrow down the differential diagnoses, leading to specific additional diagnostic tests in order to establish the correct diagnosis. Although advances in MRI hardware and technology have led to a faster, more accurate and advanced image acquisition allowing whole body examination in a feasible fashion, the standardization of image acquisition and interpretation remains a challenge. The aim of this review article is to address the important and clinically relevant issues concerning the role of imaging of neuromuscular diseases in order to facilitate a good interdisciplinary management for the diagnostics and monitoring of neuromuscular diseases.

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...

Clinicopathological features of eight cases with tubular aggregate myopathy / 中华神经科杂志

Objective To investigate the clinicopathological features of tubular aggregate myopathy.Methods Eight patients as experimental group were diagnosed with tubular aggregate myopathy in Department of Neurology,People' s Liberation Army General Hospital,between March 2000 and March 2013.The data were retrospectively analyzed.Enzyme histochemical techniques and electron microscopy were taken to observe the muscle structures.Results The detection rate of tubular aggregate was 0.374％ (8/2 137).All of the 8 patients with tubular aggregate myopathy were male.Five patients presented with episodes of muscle weakness,while 3 patients presented chronic progressive muscle weakness.The main clinical features of all patients were muscle weakness.The creatine kinase level was mildly elevated in 4 patients,while it was normal in the other 4 patients.Electromyogram showed myogenic damage in 5 patients and normal in 3 patients.All of the 8 patients denied family history.By light microscopy,hematoxylin-eosin staining showed that tubular aggregates were multiple basophilic subsarcolemmal substance.Tubular aggregate stained red with modified Gomori trichrome stain,reacted intensely for nicotinamide adenine dinucleotidetetrazolium reductase,and remained unstained on oil red O,periodic acid Schiff,sudan black B,acid phosphatas,adenosine triphosphatase.By electron microscopy,tubular aggregates were densely packed tubules predominantly in the subsarcolemmal region.Conclusion Enzyme histochemical staining and electron microscopy show special features of tubular aggregate myopathy,are the critical techniques for the diagnosis of the disease.

Autosomal Dominant Centronuclear Myopathy with Unique Clinical Presentations

Centronuclear myopathies are clinically and genetically heterogenous diseases with common histological findings, namely, centrally located nuclei in muscle fibers with a predominance and hypotrophy of type 1 fibers. We describe two cases from one family with autosomal dominant centronuclear myopathy with unusual clinical features that had initially suggested distal myopathy. Clinically, the patients presented with muscle weakness and atrophy localized mainly to the posterior compartment of the distal lower extremities. Magnetic resonance imaging revealed predominant atrophy and fatty changes of bilateral gastrocnemius and soleus muscles. This report demonstrates the expanding clinical heterogeneity of autosomal dominant centronuclear myopathy.