Central Core Disease Research Articles

The Diagnostic Yield of Electromyography at Detecting Abnormalities on Muscle Biopsy: A Single Center Experience

ABSTRACT Historically, electromyography (EMG) is utilized early in the diagnostic evaluation of neuromuscular disorders, but its importance may be diminishing with more sophisticated genetic, imaging and immunohistochemistry investigations now available. In the present study, the diagnostic yield of EMG at predicting pathological abnormalities confirmed by muscle biopsy was determined at our neuroscience center. A retrospective study of consecutive cases reviewed at neuromuscular multidisciplinary meetings between 2007 and 2016 identified patients who had EMG and muscle biopsy as part of their diagnostic evaluation. EMG and biopsy findings were categorized as myopathic, neurogenic or normal. The diagnostic accuracy was determined by calculating the concordance between EMG and pathological findings. Of the 175 cases included in the analysis, there was definite concordance between EMG and muscle biopsy findings in 134 cases (76.6%). Abnormal EMG produced sensitivity of 87% and specificity of 65% for abnormal muscle biopsy. Seventeen patients had a normal EMG and an abnormal muscle biopsy, of which 6 had histopathological findings consistent with mitochondrial myopathy, central core myopathy or glycogen storage disorder. Conflicting EMG and muscle biopsy findings were observed in 10 cases. Inclusion body myositis, chronic neuromuscular disorders and dual pathologies were associated with discordant findings. This study demonstrates that EMG has accurate predictive value in diagnosing neuromuscular disorders at our neuroscience center. EMG retains a vital role, particularly in initial diagnostic evaluations of neuromuscular disorders.

Central Core Disease - A Disease That Is Easily Misdiagnosed as Duchenne Muscular Dystrophy

As a kind of congenital myopathy (CM), central core disease (CCD) is mainly characterized by low muscle tension, slow progressive or static proximal limb weakness. CM can be characterized by no symptoms to be unable to walk independently in the clinic, pathological changes can be manifested as only significant type 1 muscle fiber dominant type to typical central axial space structure, and there are also many genetic ways. Duchenne muscular dystrophy (DMD) is a common congenital myopathy, which is mainly manifested in the typical pathological changes of early progressive myasthenia and muscular dystrophy. Both CCD and DMD show similar clinical symptoms and their serum creatine kinase can be increased, which is often difficult to distinguish them through clinical characterization and laboratory examination. In this study, we report the clinical and genetic characteristics of two patients with progressive muscle weakness with elevated creatine kinase. They are the product of a first-cousin marriage and seek medical treatment due to asymptotic walking difficulties, muscle atrophy, joint contracture, scoliosis, and elevated creatine kinase levels. It was previously suspected as Duchenne muscular dystrophy. After that, the patient's DNA was sequenced by whole-exome sequencing (WES), and all coding regions were investigated. It was found that a new heterozygous missense mutation c.5092g > A in the RYR1 gene. Similar mutations have not been reported in the literature before. Bioinformatics software predicts that they have the possibility of pathogenesis, which is highly correlated with CCD. The purpose of this case is to report a new heterozygous mutation of the RYR1 gene, summarize the similarities and differences of clinical manifestations, genetic characteristics, and pathological changes of CCD and DMD, and provide a new idea for its differential diagnosis.

Malignant hyperthermia: a case report with good outcome.

Malignant hyperthermia: a case report with good outcome.

Congenital Myopathies: A Clinicopathological Study of 10 Cases in a Tertiary Care Hospital of North India.

ABSTRACTObjective:Congenital myopathies (CMs) are rare neuromuscular disorders. Through this article, authors want to present a clinicopathological study of 10 cases of CM.Materials and Methods:The study included patients with histopathologically confirmed CM attending the neurology services at the Institute of Human Behavior and Allied Sciences for 2 years. After collecting the demographic data, all patients were subjected to comprehensive workup including a detailed neurological examination and investigations, including muscle biopsy from representative involved muscle.Results:Ten patients diagnosed with CM. The most common CM type was congenital fiber-type disproportion (CFTD) seen in four cases followed by centronuclear myopathy in two cases and one each in desmin-related myopathy, central core disease, nemaline myopathy, CM with type II fiber hypoplasia. Clinically, they have variable features.Conclusion:This study from India highlights the importance of specific clinical features to look for when suspecting a CM coupled with specific features in histopathology. However, studies with longer duration are needed to find out the true prevalence and various spectra of CMs.

Dominant or recessive mutations in the RYR1 gene causing central core myopathy in Brazilian patients.

Central Core Disease (CCD) is an inherited neuromuscular disorder characterized by the presence of cores in muscle biopsy. CCD is caused by mutations in the RYR1 gene. This gene encodes the ryanodine receptor 1, which is an intracellular calcium release channel from the sarcoplasmic reticulum to the cytosol in response to depolarization of the plasma membrane. Mutations in this gene are also associated with susceptibility to Malignant Hyperthermia (MHS).In this study, we evaluated 20 families with clinical and histological characteristics of CCD to identify primary mutations in patients, for diagnosis and genetic counseling of the families.We identified variants in the RYR1 gene in 19/20 families. The molecular pathogenicity was confirmed in 16 of them. Most of these variants (22/23) are missense and unique in the families. Two variants were recurrent in two different families. We identified six families with biallelic mutations, five compound heterozygotes with no consanguinity, and one homozygous, with consanguineous parents, resulting in 30% of cases with possible autosomal recessive inheritance. We identified seven novel variants, four of them classified as pathogenic. In one family, we identified two mutations in exon 102, segregating in cis, suggesting an additive effect of two mutations in the same allele.This work highlights the importance of using Next-Generation Sequencing technology for the molecular diagnosis of genetic diseases when a very large gene is involved, associated to a broad distribution of the mutations along it. These data also influence the prevention through adequate genetic counseling for the families and cautions against malignant hyperthermia susceptibility.

Core myopathies - a short review.

Congenital myopathies represent a clinically and genetically heterogeneous group of early-onset neuromuscular diseases with characteristic, but not always specific, histopathological features, often presenting with stable and/or slowly progressive truncal and proximal weakness. It is often not possible to have a diagnosis on clinical ground alone. Additional extraocular, respiratory, distal involvement, scoliosis, and distal laxity may provide clues. The “core myopathies” collectively represent the most common form of congenital myopathies, and the name pathologically corresponds to histochemical appearance of focally reduced oxidative enzyme activity and myofibrillar changes on ultrastructural studies. Because of the clinical, pathological, and molecular overlaps, central core disease and multiminicore disease will be discussed together.

Evaluation of the Core Formation Process in Congenital Neuromuscular Disease With Uniform Type 1 Fiber and Central Core Disease.

Typical central core disease (CCD) is characterized pathologically by the presence of a core and is accompanied by type 1 fiber uniformity. Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is characterized pathologically by the presence of type 1 fiber uniformity but without the abnormal structural changes in muscle fibers. Interestingly, typical CCD and 40% of CNMDU1 cases are caused by the same mutations in RYR1, and thus CNMDU1 has been considered an early precursor to CCD. To better understand the nature of CNMDU1, we re-evaluated muscle biopsies from 16 patients with CNMDU1 using immunohistochemistry to RYR1, triadin and TOM20, and compared this to muscle biopsies from 36 typical CCD patients. In CCD, RYR1, and triadin were present in the core regions, while TOM20 was absent in the core regions. Interestingly, in 5 CNMDU1 cases with the RYR1 mutation, RYR1, and triadin were similarly present in core-like areas, while TOM20 was absent in the subsarcolemmal region. Furthermore, there was a correlation between the core position and the disease duration or progression-the older patients in more advanced stages had more centralized cores. Our results indicate that CNMDU1 due to RYR1 mutation is a de facto core myopathy.

In vivo RyR1 reduction in muscle triggers a core-like myopathy

Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.

CONGENITAL MYOPATHIES 1 – NEMALINE: P.25 Autosomal recessive congenital myopathy with splicing mutation (c.21522+3A>G) of NEB gene

Congenital myopathies are a heterogeneous group of hereditary primary muscle disorders that are present from birth, although their onset may be delayed until later in infancy or early childhood. The most common of these rare disorders are nemaline myopathy, central core disease, centronuclear (myotubular) myopathies, and congenital fiber type disproportion. Among them, nemaline myopathy, a rare congenital myopathy, is characterized by generalized muscle weakness, respiratory insufficiency, and the presence of rod structures on muscle biopsy, which is caused by mutations in at least 13 known genes.

CONGENITAL MYOPATHIES 2: P.103 Congenital neuromuscular disease with uniform type 1 fibers due to RYR1 mutation is a de facto core myopathy

Typical central core disease (CCD) is characterized pathologically by the presence of a ``core'' which is devoid of oxidative enzyme activity in the central region of myofibers, and is typically accompanied by a strong type 1 fiber predominance (> 99%), referred to as type 1 fiber uniformity. Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1) is characterized pathologically by the presence of essentially identical type 1 fiber uniformity but without the abnormal structural changes in muscle fibers.

Bi-allelic expression of the RyR1 p.A4329D mutation decreases muscle strength in slow-twitch muscles in mice

Mutations in the ryanodine receptor 1 (RYR1) gene are associated with several human congenital myopathies, including the dominantly inherited central core disease and exercise-induced rhabdomyolysis, and the more severe recessive phenotypes, including multiminicore disease, centronuclear myopathy, and congenital fiber type disproportion. Within the latter group, those carrying a hypomorphic mutation in one allele and a missense mutation in the other are the most severely affected. Because of nonsense-mediated decay, most hypomorphic alleles are not expressed, resulting in homozygous expression of the missense mutation allele. This should result in 50% reduced expression of the ryanodine receptor in skeletal muscle, but its observed content is even lower. To study in more detail the biochemistry and pathophysiology of recessive RYR1 myopathies, here we investigated a mouse model we recently generated by analyzing the effect of bi-allelic versus mono-allelic expression of the RyR1 p.A4329D mutation. Our results revealed that the expression of two alleles carrying the same mutation or of one allele with the mutation in combination with a hypomorphic allele does not result in functionally equal outcomes and impacts skeletal muscles differently. In particular, the bi-allelic RyR1 p.A4329D mutation caused a milder phenotype than its mono-allelic expression, leading to changes in the biochemical properties and physiological function only of slow-twitch muscles and largely sparing fast-twitch muscles. In summary, bi-allelic expression of the RyR1 p.A4329D mutation phenotypically differs from mono-allelic expression of this mutation in a compound heterozygous carrier.

New Compound Heterozygous Splice Site Mutations of the Skeletal Muscle Ryanodine Receptor (RYR1) Gene Manifest Fetal Akinesia: A Linkage with Congenital Myopathies

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been linked to malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. RYR1 is an intracellular calcium release channel and plays a crucial role in the sarcoplasmic reticulum and transverse tubule connection. Here, we report 2 fetuses from the same parents with compound heterozygous mutations in the RYR1 gene (c.10347+1G>A and c.10456-2Α>G) who presented with fetal akinesia and polyhydramnios at 27 and 19 weeks of gestation with intrauterine growth restriction in the third pregnancy. The prospective parents of the fetuses were heterozygous carriers for c.10456-2Α>G (mother) and c.10347+1G>A (father). Both mutations affect splice sites resulting in dysfunctional protein forms probably missing crucial domains of the C-terminus. Our findings reveal a new RYR1 splice site mutation (c.10456-2Α>G) that may be associated with the clinical features of myopathies, expanding the RYR1 spectrum related to these pathologies.

Impact of scoliosis surgery on pulmonary function in patients with muscular dystrophies and spinal muscular atrophy.

Scoliosis is a common complication of severe neuromuscular diseases. The aim of this study is to determine the impact of posterior spinal fusion on pulmonary function parameters in patients with severe neuromuscular disease at our medical center. Retrospective chart review of all patients with severe neuromuscular disease who had posterior spinal fusion between 2012 and 2017 at Texas Children's Hospital. Patients with growing rods, brain injury or malformation, and/or spina bifida were excluded. Pulmonary function measures before and after spinal surgery were determined. A total of 20 eligible patients were identified, 7 with Duchenne muscular dystrophy, 6 with spinal muscular atrophy, 3 with merosin deficient muscular dystrophy, 2 with Charcot-Marie-Tooth, 1 with central core disease, and 1 with dystroglycanopathy. The mean change in vital capacity from pre- to postspine surgery was a loss of 0.63 L for the spinal muscular atrophy patients, a loss of 0.36 L for the Duchenne muscular dystrophy patients, and a gain of 0.23 L for the merosin deficient patients. The difference between spinal muscular atrophy and merosin deficient patients was statistically significant (P = .02) CONCLUSION: In this single-center retrospective study, we found that after spine surgery for scoliosis, all patients with spinal muscular atrophy and most patients with Duchenne muscular dystrophy lost vital capacity, while the patients with merosin deficient muscular dystrophy gained vital capacity. These differences were not associated with differences is respiratory strength, body mass index, or surgical outcomes.

A Cryo-EM Based Study of An Equivalent N Terminal Domain Mutation in Skeletal and Cardiac Ryanodine Receptor (RyR)

Mutations in ryanodine receptors (RyRs), large intracellular Ca2+ channels on the sarcoplasmic reticulum, are linked to disorders such as malignant hyperthermia and central core disease in the case of skeletal RyR1 isoform and catecholaminergic polymorphic ventricular tachycardia (CPVT) in the case of cardiac RyR2 isoform. RyRs are complex molecular machines whose activity is under precise regulation of interdomain interactions between the various subdomains as well as external binding partners. We examined equivalent single point mutations in the N-terminal A (NTD-A) domain of skeletal and cardiac RyR isoforms using cryo-EM to study their effect on the channel conformation and shed light on the possible underlying mechanism of leakiness. We resolved the 3D structures of RyR1 R164C and RyR2 R176Q at 3.5 Å and 3.9 Å, respectively. 3D analysis suggests that mutation R164C results in a tilting of the rhomboid structure (composed of NTDs, SPRY1-3, P1, HD1 and HD2 domains) indicative of a “primed” state in the absence of any activator ligands (such as Ca2+ or caffeine) and could be a result of disruption of the NTD-A interaction with the neighboring central domain. The effects of mutation R176Q in RyR2 were milder, suggesting isoform-specific effects on channel conformation despite the mutation being a loss of positively charged residue, arginine, in both isoforms. Analysis of these and other long-range conformational changes provides insight into the leaky phenotype of RyR1 and RyR2 produced by mutations situated far away (>80 Å) from the pore. Supported by grants AHA 19POST34430178 (K.A.I) and AHA 14GRNT19660003, MDA352845, NIH R01 AR068431, and NIH U24GM116789 (M.S.).

Cored in the act: the use of models to understand core myopathies.

ABSTRACTThe core myopathies are a group of congenital myopathies with variable clinical expression – ranging from early-onset skeletal-muscle weakness to later-onset disease of variable severity – that are identified by characteristic ‘core-like’ lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (RYR1), whereas multi-minicore disease is linked to pathogenic variants of several genes, including selenoprotein N (SELENON), RYR1 and titin (TTN). Understanding the mechanisms that drive core development and muscle weakness remains challenging due to the diversity of the excitation-contraction coupling (ECC) proteins involved and the differential effects of mutations across proteins. Because of this, the use of representative models expressing a mature ECC apparatus is crucial. Animal models have facilitated the identification of disease progression mechanisms for some mutations and have provided evidence to help explain genotype-phenotype correlations. However, many unanswered questions remain about the common and divergent pathological mechanisms that drive disease progression, and these mechanisms need to be understood in order to identify therapeutic targets. Several new transgenic animals have been described recently, expanding the spectrum of core myopathy models, including mice with patient-specific mutations. Furthermore, recent developments in 3D tissue engineering are expected to enable the study of core myopathy disease progression and the effects of potential therapeutic interventions in the context of human cells. In this Review, we summarize the current landscape of core myopathy models, and assess the hurdles and opportunities of future modeling strategies.

Significance of Asymptomatic Hyper Creatine-Kinase Emia.

Whether asymptomatic hyper-CKemia (AHCE) should prompt a thorough work-up for muscle disease or not is controversially discussed. This review aims at summarizing and discussing recent findings concerning the cause, frequency, evolution, and work-up of conditions manifesting as AHCE and normal or abnormal electromyography (EMG) respectively muscle biopsy. Systematic PubMed search. There are numerous primary (hereditary) and acquired myopathies that manifest with permanent, recurrent, or temporary AHCE with/without myopathic EMG or muscle biopsy. AHCE particularly occurs at onset of these conditions, which include dystrophinopathies, myotilinopathies, calpainopathy, caveolinopathy, dysferlinopathy, central core disease, multicore disease, desminopathy, MD1, MD2, hypoPP, malignant hyperthermia susceptibility, Pompe disease, McArdle disease, myoadenylate deaminase-deficiency, CPT2-deficiency, mitochondrial disorders, or myopathy with tubular aggregates. Most likely, other primary myopathies manifest with AHCE as well, without having been reported. Patients with AHCE should be taken seriously and repeated CK determination must be conducted. If hyper-CKemia is persisting or recurrent, these patients should undergo an EMG and eventually muscle biopsy. If noninformative, genetic work-up by a panel or whole exome sequencing should be initiated, irrespective of the family history. Patients with AHCE should avoid excessive exercise, require sufficient hydration, require counseling with regard to the risk of malignant hyperthermia, and should inform anesthesiologists and surgeons about their condition before elective surgery. Recurrent AHCE should be taken seriously and managed with conventional work-up. If noninformative, genetic work-up should follow irrespective of the family history.

EP.132Central core myopathy in Chinese patients with Nav1.4 p.R675Q mutation

EP.132Central core myopathy in Chinese patients with Nav1.4 p.R675Q mutation

P.230Phenotype and pathological variability in RYR1-related myopathy with compound heterozygous variants in Japan

Mutations in RYR1 are often associated with central core disease, and are also the most common cause of other congenital myopathies (CMs) such as multi-minicore disease, CFTD (congenital fiber type disproportion) and centronuclear myopathy (CNM). There is an increasing interest in the clinical variability and pathologic overlap among these CMs due to RYR1 mutations. In addition, it has been reported that the compound heterozygous RYR1 mutations can cause more severe phenotype compared to the autosomal dominant cases. Here we report clinical and pathological features of the 3 patients with compound heterozygous variants in RYR1 who were seen and received muscle biopsy at NCNP. Case 1: a 2.5-year-old girl with generalized hypotonia, swallowing and respiratory problems since her birth. She had a markedly myopathic face with extraocular muscle involvement, and required tracheostomy and gastrostomy. She was diagnosed with CNM by muscle pathology. Case 2: a 10-month-old girl with hypotonia, reduced antigravity movements, and swallowing and respiratory problems since neonatal period. Nasogastric feeding and non-invasive ventilation were needed. She was diagnosed with CFTD by muscle pathology. Case 3: a 1-year-old girl with delayed motor milestones and generalized mild hypotonia, sparing facial and extraocular muscles. She was diagnosed with CNM by muscle pathology. The RYR1 variants found in these patients included nonsense mutation, splicing mutation and deletion, all of which were predicted to be pathogenic. Presence of a case with mild phenotype such as Case 3 indicates the broad clinical variability of congenital myopathy due to biallelic RYR1 mutations.

EP.129A probable new pathogenic variant in RYR1 gene? - 3 case reports

Congenital myopathies represent a group of diseases ascribed as pathogenic variants in over 20 genes. Of these, disorders related to RYR1 gene are the most frequent, identified in 90% of central core disease patients; however, several histological phenotypes including findings with no specific features have been described. We report here 3 relatives from the same pedigree segregating a variant in RYR1 gene. A 39-year-old female manifested with distal upper limb weakness which progressed to involve the distal lower limb, proximal upper limb, as well as the face. The symptoms presenting with childhood onset had a slow progression. Creatine kinase(CK) was normal with EMG findings supporting a myopathy. Spirometry showed a restrictive respiratory disturbance. Muscle biopsy showed no specific findings except a type 1 predominance. Her son, 6 years-old, has proximal muscle weakness and facial weakness. CK normal. His brother, 45 years-old, has the same symptom. CK normal. Spirometry showed a restrictive respiratory disturbance. A muscle biopsy was performed showing no specific findings. Her father had the same symptoms with onset during childhood. Clinical exome sequencing revealed a heterozygous probably pathogenic variant in RYR1 gene: c.12083C>T (p. Ser4028Leu). This variant was found in the literature in 2 cases. The first was a boy, 6 years-old with onset disease at 2 years old. Muscle biopsy showed no specific findings however. The autosomal dominant or de novo cases are considered less severe. The ClinVar database classifies this variant as uncertain significance (VUS), although Invitae database has already reported a family with 3 members affected who segregated the same variant (data not published) Considering the similarities between our family and the missense variants previously reported as pathogenic we support that this variant is better classified as probable pathogenic.

72. THE COUPLES’ CHOICES ON PREIMPLANTATION GENETIC TESTING FOR MONOGENIC AFTER GENETIC COUNSELING IN JAPAN

Introduction In Japan, preimplantation genetic testing for monogenic (PGT-M) can only be done under Japan Society of Obstetrics and Gynecology (JSOG) approval facility. Inside the approval facility, case has to get an approval from JSOG. Due to such strict condition, there are only 5 facilities that have experienced the PGT-M. Even to the genetic diseases that are subjects of PGT-M among other countries, it is not so in Japan and only limited to severe genetic diseases with onset at childhood. In this study, we will consider the issues of PGT-M in Japan from our genetic counseling and their subsequent decision by couples who wanted PGT-M at our clinic. Material & methods The subject is 31 couples who made reservation of consultation with our clinic for the purpose of PGT-M from August 2014. In order to obtain approval of PGT-M by JSOG, the couple need to receive genetic counseling not only at the PGT-M implementation facility but also at two different facilities. Results 21 couples out of 30 couples who received genetic counseling at our clinic wished to apply PGT-M to JSOG. A couple with a child with an Alpha-thalassemia X-linked mental retardation syndrome failed to undergo consultation for genetic counseling at our clinic because the condition of the child worsened. After genetic counseling at our clinic, seven couples did not want PGT-M. One couple with a child with congenital glycosylation disorder of glycosylation (type Ik) gave up PGT-M because it was difficult to attend our clinic with treatment of the affected child since it took more than 3 hours to our clinic. Four couples abandoned PGT-M because it takes a long time to approve. Also, in a couple with Myotonic dystrophy 1 male patient, the fact that they are not suited for PGT-M was not easily accepted and they had to be re-consulted by other facilities before they could accept the fact. The couple of congenital myopathy central core disease was selected for PGT-M because of adult onset disease. In other two couples, one couple applied for PGT-M at different facility, and the other has not yet been able to make the decision after genetic counseling. Conclusions Although there may be couples who want to take PGT-M, there are not enough facilities that have experienced the PGT-M in Japan. In addition, indication of PGT-M in Japan is severely limited to diseases in which symptoms that strongly disdain daily life are developed and the survival is dangerous before reaching adults. In the future, based on overseas adaptation criteria, Japan's adaptation criteria should be relaxed