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BMC Neurology Apr 2023Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy...
BACKGROUND
Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy predominantly proximal in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case of association of pathogenic variants on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen's congenital myotonia.
CASE PRESENTATION
We describe a patient with chronic proximal myopathy, subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan's anomaly, a hallmark of NLSD-M. A genetic panel was collected using next-generation sequencing (NGS) technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described.
CONCLUSIONS
Although uncommon, it is important to remember the possibility of association of pathogenic variants to explain a specific neuromuscular disease phenotype. The use of a range of complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.
Topics: Humans; Acyltransferases; Chloride Channels; Lipase; Muscular Diseases; Mutation; Myotonia; Myotonia Congenita
PubMed: 37106355
DOI: 10.1186/s12883-023-03195-6 -
Neuromuscular Disorders : NMD Mar 2023We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population...
We provide an up-to-date and accurate minimum point prevalence of genetically defined skeletal muscle channelopathies which is important for understanding the population impact, planning for treatment needs and future clinical trials. Skeletal muscle channelopathies include myotonia congenita (MC), sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (hyperPP), hypokalemic periodic paralysis (hypoPP) and Andersen- Tawil Syndrome (ATS). Patients referred to the UK national referral centre for skeletal muscle channelopathies and living in UK were included to calculate the minimum point prevalence using the latest data from the Office for National Statistics population estimate. We calculated a minimum point prevalence of all skeletal muscle channelopathies of 1.99/100 000 (95% CI 1.981-1.999). The minimum point prevalence of MC due to CLCN1 variants is 1.13/100 000 (95% CI 1.123-1.137), SCN4A variants which encode for PMC and SCM is 0.35/100 000 (95% CI 0.346 - 0.354) and for periodic paralysis (HyperPP and HypoPP) 0.41/100 000 (95% CI 0.406-0.414). The minimum point prevalence for ATS is 0.1/100 000 (95% CI 0.098-0.102). There has been an overall increase in point prevalence in skeletal muscle channelopathies compared to previous reports, with the biggest increase found to be in MC. This can be attributed to next generation sequencing and advances in clinical, electrophysiological and genetic characterisation of skeletal muscle channelopathies.
Topics: Humans; Paralysis, Hyperkalemic Periodic; Hypokalemic Periodic Paralysis; Prevalence; Channelopathies; High-Throughput Nucleotide Sequencing; NAV1.4 Voltage-Gated Sodium Channel; Mutation; Muscle, Skeletal; Myotonic Disorders; Andersen Syndrome
PubMed: 36796140
DOI: 10.1016/j.nmd.2023.01.007 -
Revista de Neurologia Feb 2023Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive...
INTRODUCTION
Myotonia congenita is the most common form of genetic myotonia and is caused by mutations in the CLCN1 gene. It can be inherited in an autosomal dominant or recessive manner. We present a series of cases to update its incidence in our environment, to describe its phenotype in relation to the genotype found, and we also review the mutations found, among which we provide a new, undescribed alteration.
CASES REPORT
The medical records of patients with a diagnosis of congenital myotonia studied and followed up in the pediatric neurology section in a tertiary hospital between the years 2015-2020 were reviewed. Demographic variables (age, sex), disease course (age of onset, symptoms and signs, time elapsed until diagnosis, clinical evolution), family history and evaluation of response to treatment were collected. Five cases with a clinical diagnosis of myotonia congenita were identified (three with Becker's disease and two with Thomsen's disease). The incidence in relation to the number of births is estimated at 1:15,000 newborns for cases with the Becker phenotype and 1:21,000 newborns for the Thomsen phenotypes. We found a probably pathogenic mutation not previously described (CLCN1: c.824T> C).
CONCLUSIONS
the approximate incidence in our environment was higher than previously known and we describe a new, undescribed mutation: c.824T> C with pathogenicity predictors that behaved like a Becker recessive phenotype but with an earlier debut.
Topics: Humans; Myotonia Congenita; Incidence; Chloride Channels; Mutation; Muscular Dystrophy, Duchenne; Pedigree
PubMed: 36782350
DOI: 10.33588/rn.7604.2021357 -
Experimental Neurology Apr 2023Non-dystrophic myotonias include several entities with possible clinical overlap, i.e. myotonia congenita caused by CLCN1 gene mutations, as well as paramyotonia...
Non-dystrophic myotonias include several entities with possible clinical overlap, i.e. myotonia congenita caused by CLCN1 gene mutations, as well as paramyotonia congenita and sodium channel myotonia caused by SCN4A gene mutations. Herein, we describe the clinical features of five relatives affected by clinical and neurophysiological myotonia, with an aspecific and mixed phenotype. Next-generation sequencing identified the novel p.K1302R variant in SCN4A and the p.H838P variant in CLCN1. Segregation of the two mutations with the disease was confirmed by genotyping affected and non-affected family members. Patch-clamp experiments showed that sodium currents generated by p.K1302R and WT hNav1.4 were very similar. Mutant channel showed a small negative shift (5 mV) in the voltage-dependence of activation, which increased the likelihood of the channel to open at more negative voltages. The p.H838P mutation caused a reduction in chloride current density and a small voltage-dependence shift towards less negative potentials, in agreement with its position into the CBS2 domain of the C-terminus. Our results demonstrated that the mild functional alterations induced by p.K1302R and p.H838P in combination may be responsible for the mixed myotonic phenotypes. The K1302R mutant was sensitive to mexiletine and lamotrigine, suggesting that both drugs might be useful for the K1302R carriers.
Topics: Humans; NAV1.4 Voltage-Gated Sodium Channel; Mutation; Myotonia; Myotonia Congenita; Phenotype; Chloride Channels
PubMed: 36720299
DOI: 10.1016/j.expneurol.2023.114342 -
Frontiers in Genetics 2022Myotonia congenita (MC) is a rare neuromuscular disease caused by mutations within the gene encoding skeletal muscle chloride channels. MC is characterized by delayed...
Myotonia congenita (MC) is a rare neuromuscular disease caused by mutations within the gene encoding skeletal muscle chloride channels. MC is characterized by delayed muscle relaxation during contraction, resulting in muscle stiffness. There is a lack of MC case reports and data on the prevalence among Malaysians. We report a clinical case of a 50-year-old woman presents with muscle stiffness and cramp episodes that started in early childhood. She had difficulty initiating muscle movement and presented with transient muscle weakness after rest, which usually improved after repeated contraction (warm-up phenomenon). She was diagnosed with MC after myotonic discharge on electromyography (EMG). Her brother had similar symptoms; however, no additional family members showed MC symptoms. Serum creatine kinase levels were elevated in both the proband and her brother with 447 U/L and 228 U/L recorded, respectively. Genetic analysis by whole-exome sequencing (WES) revealed a previously reported pathogenic gene variant c.1667T>A (p.I556N). Genetic screening of all family members revealed that the same variant was observed in the children of both the proband and her brother; however, the children did not present with either clinical or electrophysiological MC symptoms. The multiplex ligation-dependent probe amplification (MLPA) analysis conducted identified neither exon deletion nor duplication in . In conclusion, this report describes the first case of MC in Malaysia in which incomplete penetrance observed in this family is caused by a known pathogenic variant.
PubMed: 36659963
DOI: 10.3389/fgene.2022.972007 -
Experimental Neurology Mar 2023It has long been accepted that myotonia (muscle stiffness) in patients with muscle channelopathies is due to myotonic discharges (involuntary firing of action...
It has long been accepted that myotonia (muscle stiffness) in patients with muscle channelopathies is due to myotonic discharges (involuntary firing of action potentials). In a previous study, we identified a novel phenomenon in myotonic muscle: development of plateau potentials, transient depolarizations to near -35 mV lasting for seconds to minutes. In the current study we examined whether plateau potentials contribute to myotonia. A recessive genetic model (ClC mice) with complete loss of muscle chloride channel (ClC-1) function was used to model severe myotonia congenita with complete loss of ClC-1 function and a pharmacologic model using anthracene-9-carboxylic acid (9 AC) was used to model milder myotonia congenita with incomplete loss of ClC-1 function. Simultaneous measurements of action potentials and myoplasmic Ca from individual muscle fibers were compared to recordings of whole muscle force generation. In ClC muscle both myotonia and plateau potentials lasted 10s of seconds to minutes. During plateau potentials lasting 1-2 min, there was a gradual transition from high to low intracellular Ca, suggesting a transition in individual fibers from myotonia to flaccid paralysis in severe myotonia congenita. In 9 AC-treated muscles, both myotonia and plateau potentials lasted only a few seconds and Ca remained elevated during the plateau potentials, suggesting plateau potentials contribute to myotonia without causing weakness. We propose, that in myotonic muscle, there is a novel state in which there is contraction in the absence of action potentials. This discovery provides a mechanism to explain reports of patients with myotonia who suffer from electrically silent muscle contraction lasting minutes.
Topics: Mice; Animals; Myotonia; Myotonia Congenita; Muscle Contraction; Action Potentials; Muscle Fibers, Skeletal; Chloride Channels; Disease Models, Animal
PubMed: 36563835
DOI: 10.1016/j.expneurol.2022.114303 -
Frontiers in Neuroscience 2022Optically pumped magnetometers (OPM) are quantum sensors that enable the contactless, non-invasive measurement of biomagnetic muscle signals, i.e., magnetomyography...
Optically pumped magnetometers (OPM) are quantum sensors that enable the contactless, non-invasive measurement of biomagnetic muscle signals, i.e., magnetomyography (MMG). Due to the contactless recording, OPM-MMG might be preferable to standard electromyography (EMG) for patients with neuromuscular diseases, particularly when repetitive recordings for diagnostic and therapeutic monitoring are mandatory. OPM-MMG studies have focused on recording physiological muscle activity in healthy individuals, whereas research on neuromuscular patients with pathological altered muscle activity is non-existent. Here, we report a proof-of-principle study on the application of OPM-MMG in patients with neuromuscular diseases. Specifically, we compare the muscular activity during maximal isometric contraction of the left rectus femoris muscle in three neuromuscular patients with severe (Transthyretin Amyloidosis in combination with Pompe's disease), mild (Charcot-Marie-Tooth disease, type 2), and without neurogenic, but myogenic, damage (Myotonia Congenita). Seven healthy young participants served as the control group. As expected, and confirmed by using simultaneous surface electromyography (sEMG), a time-series analysis revealed a dispersed interference pattern during maximal contraction with high amplitudes. Furthermore, both patients with neurogenic damage (ATTR and CMT2) showed a reduced variability of the MMG signal, quantified as the signal standard deviation of the main component of the frequency spectrum, highlighting the reduced possibility of motor unit recruitment due to the loss of motor neurons. Our results show that recording pathologically altered voluntary muscle activity with OPM-MMG is possible, paving the way for the potential use of OPM-MMG in larger studies to explore the potential benefits in clinical neurophysiology.
PubMed: 36523432
DOI: 10.3389/fnins.2022.1010242 -
Brain : a Journal of Neurology Apr 2023Accurate determination of the pathogenicity of missense genetic variants of uncertain significance is a huge challenge for implementing genetic data in clinical...
Accurate determination of the pathogenicity of missense genetic variants of uncertain significance is a huge challenge for implementing genetic data in clinical practice. In silico predictive tools are used to score variants' pathogenicity. However, their value in clinical settings is often unclear, as they have not usually been validated against robust functional assays. We compared nine widely used in silico predictive tools, including more recently developed tools (EVE and REVEL) with detailed cell-based electrophysiology, for 126 CLCN1 variants discovered in patients with the skeletal muscle channelopathy myotonia congenita. We found poor accuracy for most tools. The highest accuracy was obtained with MutationTaster (84.58%) and REVEL (82.54%). Both of these scores showed poor specificity, although specificity was better using EVE. Combining methods based on concordance improved performance overall but still lacked specificity. Our calculated statistics for the predictive tools were different to reported values for other genes in the literature, suggesting that the utility of the tools varies between genes. Overall, current predictive tools for this chloride channel are not reliable for clinical use, and tools with better specificity are urgently required. Improving the accuracy of predictive tools is a wider issue and a huge challenge for effective clinical implementation of genetic data.
Topics: Humans; Channelopathies; Muscle, Skeletal; Chloride Channels; Myotonia Congenita; Mutation
PubMed: 36382348
DOI: 10.1093/brain/awac431 -
Acta Myologica : Myopathies and... 2022Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the gene (OMIM #614399)....
Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the gene (OMIM #614399). Phenotypic spectrum of EMARDD is variable, ranging from severe infantile forms in which patients are ventilator-dependent and die in childhood, to milder chronic disorders with a more favorable course (mild variant, mvEMARDD). Here we describe a 22 years old boy, offspring of consanguineous parents, presenting a congenital myopathic phenotype since infancy with elbow contractures and scoliosis. The patient developed a slowly progressive muscle weakness with impaired walking, rhinolalia, dysphagia, and respiratory involvement, which required noninvasive ventilation therapy since the age of 16 years. First muscle biopsy revealed unspecific muscle damage, with fiber size variation, internal nuclei and fibrosis. Myofibrillar alterations were noted at a second muscle biopsy including whorled fibres, cytoplasmic inclusion and minicores. Exome sequencing identified a homozygous mutation in gene, c.2096G > C (p.Cys699Ser), inherited by both parents. This variant, not reported in public databases of mutations, is expected to alter the structure of the protein and is therefore predicted to be probably damaging according to ACMG classification. In conclusion, we found a new likely pathogenic mutation in , which is responsible for a progressive form of mvEMARDD with myofibrillar alterations at muscle biopsy. Interestingly, the presence of mutations has not been reported in Italian population. Early diagnosis of MEGF10 myopathy is essential in light of recent results from in vivo testing demonstrating a potential therapeutic effect of SSRIs compounds.
Topics: Humans; Deglutition Disorders; Membrane Proteins; Muscular Diseases; Myotonia Congenita; Mutation; Muscle, Skeletal
PubMed: 36349186
DOI: 10.36185/2532-1900-076 -
International Journal of Molecular... Oct 2022Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30...
Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in ACTA1, two (8%) in KLHL40, and one in TPM2 (4%) and TPM3 (4%). In the NEB-related families, 25 different variants, 11 of them novel, were identified; splice site (10/25) and frame shift (9/25) mutations were the most common. Mutation c.24579 G>C was recurrent in three unrelated patients from the same region, suggesting a common ancestor. Clinically, the “typical” form was the more frequent and caused by mutations in the different NM genes. Phenotypic heterogeneity was observed among patients with mutations in the same gene. Respiratory involvement was very common and often out of proportion with limb weakness. Muscle MRI patterns showed variability within the forms and genes, which was related to the severity of the weakness. Considering the high frequency of NEB mutations and the complexity of this gene, NGS tools should be combined with CNV identification, especially in patients with a likely non-identified second mutation.
Topics: Brazil; Humans; Muscle Proteins; Muscle, Skeletal; Mutation; Myopathies, Nemaline; Myotonia Congenita
PubMed: 36233295
DOI: 10.3390/ijms231911995