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BioRxiv : the Preprint Server For... Jun 2024Pain is a prominent and debilitating symptom in myotonic disorders, yet its physiological mechanisms remain poorly understood. This study assessed preclinical pain-like...
Pain is a prominent and debilitating symptom in myotonic disorders, yet its physiological mechanisms remain poorly understood. This study assessed preclinical pain-like behavior in murine models of pharmacologically induced myotonia and myotonic dystrophy type 1 (DM1). In both myotonia congenita and DM1, impairment of the gene, which encodes skeletal muscle voltage-gated CLC-1 chloride channels, reduces chloride ion conductance in skeletal muscle cells, leading to prolonged muscle excitability and delayed relaxation after contraction. We used the CLC-1 antagonist anthracene-9- carboxylic acid (9-AC) at intraperitoneal doses of 30 or 60 mg/kg and HSA LR20b DM1 mice to model CLC-1-induced myotonia. Our experimental approach included pain behavioral testing, calcium imaging, and whole-cell current-clamp electrophysiology in mouse dorsal root ganglion (DRG) neurons. A single injection of 9-AC induced myotonia in mice, which persisted for several hours and resulted in long-lasting allodynic pain-like behavior. Similarly, HSA LR20b mice exhibited both allodynia and hyperalgesia. Despite these pain-like behaviors, DRG neurons did not show signs of hyperexcitability in either myotonic model. These findings suggest that myotonia induces nociplastic pain-like behavior in preclinical rodents, likely through central sensitization mechanisms rather than peripheral sensitization. This study provides insights into the pathophysiology of pain in myotonic disorders and highlights the potential of using myotonic mouse models to explore pain mechanisms and assess novel analgesics. Future research should focus on the central mechanisms involved in myotonia-induced pain and develop targeted therapies to alleviate this significant clinical burden.
PubMed: 38948724
DOI: 10.1101/2024.06.19.599732 -
Muscle & Nerve Jun 2024Type 1 myotonic dystrophy (DM1) is a neuromuscular disorder of multiple organ systems with important electrophysiologic (EP) manifestations, leading to a cumulative...
INTRODUCTION/AIMS
Type 1 myotonic dystrophy (DM1) is a neuromuscular disorder of multiple organ systems with important electrophysiologic (EP) manifestations, leading to a cumulative incidence of sudden death of 6.6%. Due to genetic anticipation, there is a pediatric subset of this patient population. However, most EP research on DM1 patients has been in adults, making cardiac care for pediatric patients difficult and directed by adult guidelines which often leads to cardiovascular implantable electronic device (CIED) implants. We sought to investigate the prevalence of CIEDs in the pediatric DM1 population.
METHODS
The Vizient® Clinical Data Base was queried from October 2019 to October 2023 for admissions with and without ICD-10 code for myotonic dystrophy (G71.11), with and without codes for presence of a pacemaker or ICD (Z95.0, Z95.810). Patients who were identified were stratified by age: Pediatric (0-21 years) and Adult (22-50 years).
RESULTS
Prevalence of CIED in pediatric DM1 was 2.1% and in adult DM1 was 15.8%. When comparing to pediatric and adult patients with CIED and without DM1, the odds ratio for CIED in pediatric DM1 was 48.8, compared to 23.3 for CIED in adult DM1.
DISCUSSION
There are pediatric DM1 patients who have received CIED despite a lack of data to inform this decision-making. Further research will be important to ensure appropriate use of CIED in this population and to develop appropriate guidelines to direct management.
PubMed: 38943290
DOI: 10.1002/mus.28188 -
Skin Research and Technology : Official... Jul 2024Patients with myotonic muscular dystrophy (MMD) were observed to have numerous basal cell carcinoma (BCC) and abnormal dysplastic nevi (DN) on non-sun exposed skin.... (Review)
Review
OBJECTIVE
Patients with myotonic muscular dystrophy (MMD) were observed to have numerous basal cell carcinoma (BCC) and abnormal dysplastic nevi (DN) on non-sun exposed skin. Simultaneously a large study published in the Journal of American Medical Association (JAMA) illustrated that patients with MMD have "overall" an increased risk for cancer development. Based on these findings, this author in 2010 postulated that dysregulation of RNA binding proteins (RBP), responsible for clinical manifestations of MMD, is also responsible for the development of BCC and melanoma.
METHODS
To report new research elucidating the etiology of melanoma, BCC, MMD-induced cancers, and potentially other environmentally induced malignancies.
RESULTS
Dysregulation of RBP induces aberrant mRNA splicing; recent data indicates that abnormal mRNA splicing not just plays a key role in the pathogenesis of melanoma but is a hallmark of essentially all human malignancies.
CONCLUSION
The author's hypothesis is that ultraviolet (UV) radiation induces DNA damage in intronic regions of a variety of genes. Furthermore, these UV-induced abnormal DNA dimers, repeats and mutations interfere with normal mRNA splicing thus producing abnormal proteins. These abnormal proteins in turn activate oncogenic pathways such as hedgehog, MAP kinase, and WNT.
Topics: Humans; Skin Neoplasms; Melanoma; Carcinoma, Basal Cell; Genetic Predisposition to Disease; Genetic Testing; Myotonic Dystrophy; Ultraviolet Rays
PubMed: 38937899
DOI: 10.1111/srt.13832 -
Medicina (Kaunas, Lithuania) Jun 2024: Although extracorporeal membrane oxygenation (ECMO) is an essential life-saving technique for patients with refractory cardiopulmonary shock, it can be fatal in... (Review)
Review
Critical Hemorrhage Caused by a Size-Mismatched Extracorporeal Membrane Oxygenation Cannula in a Patient with Myotonic Dystrophy Type 1: A Case Report and Literature Review.
: Although extracorporeal membrane oxygenation (ECMO) is an essential life-saving technique for patients with refractory cardiopulmonary shock, it can be fatal in certain cases. : A 19-year-old girl treated with ECMO presented with acute limb ischemia 2 days after cannula removal. The decannulation was performed percutaneously by an interventional cardiologist, and the vascular surgery department was consulted after the patient developed symptoms. The first suspected diagnosis was thrombosis due to incorrect use of the closure device. However, the artery had ruptured due to the insertion of a catheter with a cannula that was larger than the patient's artery. : Fortunately, excessive bleeding due to the size-mismatched cannula was prevented by an unintentional complication of the closing device, which saved the patient's life. She underwent a right common femoral artery thrombectomy and patch angioplasty. Hospital guidelines have changed regarding the surgical removal of ECMO cannulas. : This report aims to highlight the importance of two aspects that are critical to a successful outcome: individualized cannula selection followed by precise insertion and removal and postoperative evaluation of a patient's final status.
Topics: Humans; Extracorporeal Membrane Oxygenation; Female; Young Adult; Cannula; Hemorrhage; Myotonic Dystrophy; Femoral Artery; Thrombectomy; Adult
PubMed: 38929586
DOI: 10.3390/medicina60060969 -
Sleep Medicine Jun 2024Poor sleep is frequently reported in children with neuromuscular diseases (NMD) and cerebral palsy (CP) however breathing disorders during sleep are often the clinical...
OBJECTIVES
Poor sleep is frequently reported in children with neuromuscular diseases (NMD) and cerebral palsy (CP) however breathing disorders during sleep are often the clinical focus. Periodic limb movements (PLMs) have an increased prevalence in adults with NMD and may contribute to sleep disturbance in this population. We assessed the prevalence of PLMs in children with NMD or CP.
METHODS
Retrospective review of polysomnography (PSG) with leg electromyography in children age 1-18 years with NMD (including Duchenne muscular dystrophy, myotonic dystrophy, spinal muscular atrophy) or CP performed at a paediatric sleep centre 2004-2022.
RESULTS
Leg electromyography was available in at least 1 PSG in 239 children (125 NMD, 114 CP), and in 2 PSGs in 105 children (73 NMD, 32 CP). At initial PSG, 72 (30 %) were female with a median age 9y and respiratory disturbance index 3.5/h (interquartile range 1.3-9.9/h). Elevated PLM index (PLMI; >5/h) occurred in 9.6 % of each of the CP and NMD groups, quantified by initial PSG. Overall, PLMI increased from baseline (median 0, maximum 33/h) to follow-up (median 0, maximum 55.8/h; p < 0.05). In those with an elevated PLMI, arousal percentage attributable to PLMs was up to 25 % (median 7.5 %).
CONCLUSIONS
Elevated PLMI occurred at a higher prevalence in children with NMD and CP than reported in other clinic-referred paediatric populations. It is important that PLMs are not overlooked as identification and treatment may help improve sleep outcomes. Further research is required to understand the pathophysiology and consequences of PLMs specifically in this population.
PubMed: 38924830
DOI: 10.1016/j.sleep.2024.06.017 -
Journal of Neurology Jun 2024Myotonic dystrophy is a multisystem disorder characterized by widespread organic involvement including central nervous system symptoms. Although myotonic dystrophy...
BACKGROUND
Myotonic dystrophy is a multisystem disorder characterized by widespread organic involvement including central nervous system symptoms. Although myotonic dystrophy disease types 1 (DM1) and 2 (DM2) cover a similar spectrum of symptoms, more pronounced clinical and brain alterations have been described in DM1. Here, we investigated brain volumetric and white matter alterations in both disease types and compared to healthy controls (HC).
METHODS
MRI scans were obtained from 29 DM1, 27 DM2, and 56 HC. We assessed macro- and microstructural brain changes by surface-based analysis of cortical thickness of anatomical images and tract-based spatial statistics of fractional anisotropy (FA) obtained by diffusion-weighted imaging, respectively. Global MRI measures were related to clinical and neuropsychological scores to evaluate their clinical relevance.
RESULTS
Cortical thickness was reduced in both patient groups compared to HC, showing similar patterns of regional distribution in DM1 and DM2 (occipital, temporal, frontal) but more pronounced cortical thinning for DM1. Similarly, FA values showed a widespread decrease in DM1 and DM2 compared to HC. Interestingly, FA was significantly lower in DM1 compared to DM2 within most parts of the brain.
CONCLUSION
Comparisons between DM1 and DM2 indicate a more pronounced cortical thinning of grey matter and a widespread reduction in microstructural integrity of white matter in DM1. Future studies are required to unravel the underlying and separating mechanisms for the disease courses of the two types and their neuropsychological symptoms.
PubMed: 38896263
DOI: 10.1007/s00415-024-12511-0 -
Neuromuscular Disorders : NMD Jun 2024Hyperlipidemia is not uncommon in patients with hereditary myopathies who get older and also in several conditions in which it is frequently observed. Thus, using the... (Review)
Review
Hyperlipidemia is not uncommon in patients with hereditary myopathies who get older and also in several conditions in which it is frequently observed. Thus, using the common cholesterol reducing medications of the stains group could be considered. However, the side effects of these drugs include myalgia, myopathy and rhabdomyolysis typically associated with high serum creatine kinase (CK). Because high CK levels are very frequently found in hereditary myopathies, physicians are reluctant to use statins in such patients. Reviewing the literature about statin side effects in hereditary myopathies does not provide a clear evidence about the true risk of these drugs. This review critically describes the reported cases of statin side effects in several genetic myopathies and suggests some guidelines for conditions that are contra indicated for statin usage (particularly in mitochondrial disorders, metabolic myopathies, myotonic dystrophy type 2). Possible solutions to the dilemma of whether to use statins in hereditary myopathies are discussed (prescribing other cholesterol lowering agents and a carefully monitored treatment initiation of statins).
PubMed: 38889624
DOI: 10.1016/j.nmd.2024.06.004 -
Molecular Biology Reports Jun 2024Myotonia Congenita (MC) is a rare disease classified into two major forms; Thomsen and Becker disease caused by mutations in the CLCN1 gene, which affects muscle...
BACKGROUND
Myotonia Congenita (MC) is a rare disease classified into two major forms; Thomsen and Becker disease caused by mutations in the CLCN1 gene, which affects muscle excitability and encodes voltage-gated chloride channels (CLC-1). While, there are no data regarding the clinical and molecular characterization of myotonia in Egyptian patients.
METHODS
Herein, we report seven Egyptian MC patients from six unrelated families. Following the clinical diagnosis, whole-exome sequencing (WES) was performed for genetic diagnosis. Various in silico prediction tools were utilized to interpret variant pathogenicity. The candidate variants were then validated using Sanger sequencing technique.
RESULTS
In total, seven cases were recruited. The ages at the examination were ranged from eight months to nineteen years. Clinical manifestations included warm-up phenomenon, hand grip, and percussion myotonia. Electromyography was performed in all patients and revealed myotonic discharges. Molecular genetic analysis revealed five different variants. Of them, we identified two novel variants in the CLCN1 gene ( c.1583G > C; p.Gly528Ala and c.2203_2216del;p.Thr735ValfsTer57) and three known variants in the CLCN1 and SCN4A gene. According to in silico tools, the identified novel variants were predicted to have deleterious effects.
CONCLUSIONS
As the first study to apply WES among Egyptian MC patients, our findings reported two novel heterozygous variants that expand the CLCN1 mutational spectrum for MC diagnosis. These results further confirm that genetic testing is essential for early diagnosis of MC, which affects follow-up treatment and prognostic assessment in clinical practice.
Topics: Humans; Myotonia Congenita; Exome Sequencing; Chloride Channels; Female; Male; Egypt; Child; Adolescent; Mutation; Child, Preschool; Young Adult; Infant; NAV1.4 Voltage-Gated Sodium Channel; Adult; Pedigree; Electromyography
PubMed: 38877370
DOI: 10.1007/s11033-024-09646-8 -
Cureus May 2024Muscle diseases are of various types, viz., muscular dystrophies, inflammatory myopathies, myotonic disorders, congenital myopathies, and metabolic myopathies. They all...
BACKGROUND
Muscle diseases are of various types, viz., muscular dystrophies, inflammatory myopathies, myotonic disorders, congenital myopathies, and metabolic myopathies. They all present with muscle weakness, be it proximal or distal. The assessment of muscle biopsy with the help of enzyme histochemistry, histopathological, and immunohistochemical methods is an essential component in the diagnosis of neuromuscular disorders. The authors outline brief data on muscle diseases prevalent in the North Indian region.
METHODS
Muscle biopsy was done, and the biopsy was freshly frozen in liquid nitrogen and sections were taken on a cryostat. Slides were then stained with hematoxylin and eosin (H&E), modified Gomori trichome (MGT), nicotinamide adenine dinucleotide hydrogenase (NADH), and succinic dehydrogenase (SDH) stains. Further specific immunohistochemistry tests were also done.
RESULT
Out of n=16 cases, three cases were diagnosed as Becker's muscular dystrophy, two cases were diagnosed as inflammatory myopathy, four cases were diagnosed as Facioscapulohumeral muscular dystrophy, and one each case of dysferlinopathy and alpha sarcoglycanopathy.
CONCLUSION
Muscle diseases can cause different levels of physical disability and thus it is important to diagnose at the appropriate time to ensure proper treatment.
PubMed: 38860083
DOI: 10.7759/cureus.60084 -
Journal of Gastroenterology and... Jun 2024Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT... (Review)
Review
Although not often discussed, many of the neuromuscular disorders (NMDs) affect the gastrointestinal tract (GIT). Depending on the type of NMD, the prevalence of GIT involvement ranges from <5% (e.g. hereditary neuropathies, myofibrillar myopathies) to 100% (e.g. MNGIE, OPMD). Particularly in NMDs with multisystem affection, involvement of the GIT can dominate the clinical presentation or at least make up a significant part of the clinical picture. The most prominent representatives of NMDs with multisystem involvement are the mitochondrial disorders (MIDs) and the myotonic dystrophies. The best known syndromic MIDs with GIT involvement are MNGIE, MELAS, Leigh, and Pearson syndromes. Among neuropathies, GIT involvement is most commonly found in ALS and GBS. GIT involvement may also be a feature of myasthenia. The clinical manifestations of GIT involvement are diverse and can affect the entire GIT, from the teeth to the rectum, including the liver and pancreas. The most well-known clinical manifestations of GIT involvement are dysphagia, nausea, vomiting, reflux, hollow organ dysmotility, hepatopathy, diabetes, diarrhea, constipation, and fecal incontinence. Even if treatment can usually only be symptomatic, the therapeutic options are diverse, are often effective, and can significantly and beneficially influence the course of the underlying NMD.
PubMed: 38859699
DOI: 10.1111/jgh.16650