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Rinsho Shinkeigaku = Clinical Neurology May 2024A Japanese woman experienced slowness of movement in her early teens and difficulty in opening her hands during pregnancy. On admission to our hospital at 42 years of...
A Japanese woman experienced slowness of movement in her early teens and difficulty in opening her hands during pregnancy. On admission to our hospital at 42 years of age, she showed grip myotonia with warm-up phenomenon. However, she had neither muscle weakness, muscle atrophy, cold-induced symptomatic worsening nor episodes of transient weakness of the extremities. Needle electromyography of the first dorsal interosseous and anterior tibial muscles demonstrated myotonic discharges. Whole exome sequencing of the patient revealed a heterozygous single-base substitution in the CLCN1 gene (c.1028T>G, p.F343C). The same substitution was identified in affected members of her family (mother and brother) by Sanger sequencing, but not in healthy family members (father and a different brother). We diagnosed myotonia congenita (Thomsen disease) with a novel CLCN1 mutation in this pedigree. This mutation causes a single amino acid substitution in the I-J extracellular loop region of CLCN1. Amino acid changes in the I-J loop region are rare in an autosomal-dominantly inherited form of myotonia congenita. We think that this pedigree is precious to understand the pathogenesis of myotonia congenita.
Topics: Humans; Myotonia Congenita; Chloride Channels; Female; Pedigree; Adult; Mutation; Amino Acid Substitution; Male
PubMed: 38644209
DOI: 10.5692/clinicalneurol.cn-001929 -
International Journal of Cardiology Jul 2024Cardiac involvement represents a major cause of morbidity and mortality in patients with myotonic dystrophy type 1 (DM1) and prevention of sudden cardiac death (SCD) is...
BACKGROUND
Cardiac involvement represents a major cause of morbidity and mortality in patients with myotonic dystrophy type 1 (DM1) and prevention of sudden cardiac death (SCD) is a central part of patient care. We investigated the natural history of cardiac involvement in patients with DM1 to provide an evidence-based foundation for adjustment of follow-up protocols.
METHODS
Patients with genetically confirmed DM1 were identified. Data on patient characteristics, performed investigations (12 lead ECG, Holter monitoring and echocardiography), and clinical outcomes were retrospectively collected from electronic health records.
RESULTS
We included 195 patients (52% men) with a mean age at baseline evaluation of 41 years (range 14-79). The overall prevalence of cardiac involvement increased from 42% to 66% after a median follow-up of 10.5 years. There was a male predominance for cardiac involvement at end of follow-up (74 vs. 44%, p < 0.001). The most common types of cardiac involvement were conduction abnormalities (48%), arrhythmias (35%), and left ventricular systolic dysfunction (21%). Only 17% of patients reported cardiac symptoms. The standard 12‑lead ECG was the most sensitive diagnostic modality and documented cardiac involvement in 24% at baseline and in 49% at latest follow-up. However, addition of Holter monitoring and echocardiography significantly increased the diagnostic yield with 18 and 13% points at baseline and latest follow-up, respectively. Despite surveillance 35 patients (18%) died during follow-up; seven due to SCD.
CONCLUSIONS
In patients with DM1 cardiac involvement was highly prevalent and developed during follow-up. These findings justify lifelong follow-up with ECG, Holter, and echocardiography.
CLINICAL PERSPECTIVE
What is new? What are the clinical implications?
Topics: Humans; Myotonic Dystrophy; Male; Female; Adult; Middle Aged; Follow-Up Studies; Young Adult; Retrospective Studies; Adolescent; Aged; Electrocardiography, Ambulatory; Echocardiography; Heart Diseases; Electrocardiography
PubMed: 38643802
DOI: 10.1016/j.ijcard.2024.132070 -
Frontiers in Cellular Neuroscience 2024Myotonic dystrophy (DM) encompasses a spectrum of neuromuscular diseases characterized by myotonia, muscle weakness, and wasting. Recent research has led to the... (Review)
Review
Myotonic dystrophy (DM) encompasses a spectrum of neuromuscular diseases characterized by myotonia, muscle weakness, and wasting. Recent research has led to the recognition of DM as a neurological disorder. Cognitive impairment is a central nervous system condition that has been observed in various forms of DM. Neuroimaging studies have increasingly linked DM to alterations in white matter (WM) integrity and highlighted the relationship between cognitive impairment and abnormalities in WM structure. This review aims to summarize investigations into cognitive impairment and brain abnormalities in individuals with DM and to elucidate the correlation between these factors and the potential underlying mechanisms contributing to these abnormalities.
PubMed: 38638300
DOI: 10.3389/fncel.2024.1369332 -
Nature Communications Apr 2024Epigenetic defects caused by hereditary or de novo mutations are implicated in various human diseases. It remains uncertain whether correcting the underlying mutation...
Epigenetic defects caused by hereditary or de novo mutations are implicated in various human diseases. It remains uncertain whether correcting the underlying mutation can reverse these defects in patient cells. Here we show by the analysis of myotonic dystrophy type 1 (DM1)-related locus that in mutant human embryonic stem cells (hESCs), DNA methylation and H3K9me3 enrichments are completely abolished by repeat excision (CTG2000 expansion), whereas in patient myoblasts (CTG2600 expansion), repeat deletion fails to do so. This distinction between undifferentiated and differentiated cells arises during cell differentiation, and can be reversed by reprogramming of gene-edited myoblasts. We demonstrate that abnormal methylation in DM1 is distinctively maintained in the undifferentiated state by the activity of the de novo DNMTs (DNMT3b in tandem with DNMT3a). Overall, the findings highlight a crucial difference in heterochromatin maintenance between undifferentiated (sequence-dependent) and differentiated (sequence-independent) cells, thus underscoring the role of differentiation as a locking mechanism for repressive epigenetic modifications at the DM1 locus.
Topics: Humans; Myotonic Dystrophy; Heterochromatin; Cell Differentiation; DNA Methylation; Epigenesis, Genetic
PubMed: 38627364
DOI: 10.1038/s41467-024-47217-4 -
Neurological Sciences : Official... Apr 2024Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder characterized by myotonia and progressive muscle weakness. Beyond the primary symptoms, there is...
BACKGROUND AND PURPOSE
Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder characterized by myotonia and progressive muscle weakness. Beyond the primary symptoms, there is growing concern regarding a higher incidence of certain comorbidities in DM1 patients, including cancer, diabetes, thyroid dysfunction, and cataracts. This study was designed to examine the occurrence of these conditions among patients diagnosed with DM1 in South Korea, using data from the National Health Insurance Service database.
METHODS
The study undertook a comprehensive review of 3,842 patients diagnosed with DM1 between 2012 and 2018. We assessed the incidence of cancer and the prevalence of diabetes, thyroid dysfunction, and cataracts among these patients, comparing their rates to those in the general population.
RESULTS
In the study cohort, 463 out of 3,842 DM1 patients (12.04%) were diagnosed with cancer, indicating a substantial elevation in cancer risk with an overall standard incidence ratio of 1.9 (95% CI = 1.6-2.3, p < 0.01) when compared to the expected rates in the general population. Moreover, the prevalence of diabetes (15.2%) and thyroid dysfunction (17.6%) was noteworthy in the DM1 population. The mean age at which DM1 patients underwent cataract surgery was 55.07 years, noticeably younger than the mean age of 69.25 years for cataract surgery in the general population.
CONCLUSIONS
DM1 patients have a noteworthy occurrence of several comorbidities such as cancer, diabetes, thyroid dysfunction, and earlier cataract surgery. This highlights the importance of a comprehensive and integrative approach to the management and treatment of DM1, going beyond addressing only the primary neuromuscular symptoms. More research is required to understand the underlying mechanisms contributing to these comorbidities in DM1 patients, which may inform preventative measures and guide improvements in patient care.
PubMed: 38613590
DOI: 10.1007/s10072-024-07527-3 -
Proceedings of the National Academy of... Apr 2024Many Mendelian disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic...
Many Mendelian disorders, such as Huntington's disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional genetic factors may influence the rate of those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in the CAG repeat instability, impacting age at onset of HD. Strikingly, , previously unrelated to repeat instability, produced the strongest HD modification signals. Diverse haplotypes independently modify HD, with rare genetic variants diminishing DNA binding or nuclease activity of the FAN1 protein, hastening HD onset. However, the mechanism behind the frequent and the most significant onset-delaying haplotype lacking missense variations has remained elusive. Here, we illustrated that a microRNA acting on 3'-UTR (untranslated region) SNP rs3512, rather than transcriptional regulation, is responsible for the significant expression quantitative trait loci signal and allelic imbalance in messenger ribonucleic acid (mRNA), accounting for the most significant and frequent onset-delaying modifier haplotype in HD. Specifically, miR-124-3p selectively targets the reference allele at rs3512, diminishing the stability of mRNA harboring that allele and consequently reducing its levels. Subsequent validation analyses, including the use of antagomir and 3'-UTR reporter vectors with swapped alleles, confirmed the specificity of miR-124-3p at rs3512. Together, these findings indicate that the alternative allele at rs3512 renders the mRNA less susceptible to miR-124-3p-mediated posttranscriptional regulation, resulting in increased FAN1 levels and a subsequent delay in HD onset by mitigating CAG repeat instability.
Topics: Humans; 3' Untranslated Regions; Endodeoxyribonucleases; Exodeoxyribonucleases; Genome-Wide Association Study; Huntington Disease; MicroRNAs; Multifunctional Enzymes
PubMed: 38607933
DOI: 10.1073/pnas.2322924121 -
Epilepsia Open Jun 2024Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non-dystrophic myotonias. These disorders are electrophysiologically characterized...
OBJECTIVES
Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non-dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co-occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co-segregates myotonia, JME, or abnormal EEG without seizures was observed.
METHODS
All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant.
RESULTS
Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp-wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified.
SIGNIFICANCE
These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family.
PLAIN LANGUAGE SUMMARY
This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Electroencephalography; Epilepsy, Generalized; Italy; Myotonia; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Phenotype
PubMed: 38544349
DOI: 10.1002/epi4.12920 -
Frontiers in Neurology 2024Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder that affects multiple organs. In this study, we investigated symptoms of pain and presence of...
INTRODUCTION
Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder that affects multiple organs. In this study, we investigated symptoms of pain and presence of small and large fiber neuropathy in the juvenile and adult form of DM1.
METHOD
Twenty genetically verified DM1 patients were included. Pain was assessed, and neurological examination and investigations of the peripheral nervous system by quantification of small nerve fibers in skin biopsy, quantitative sensory testing and nerve conduction studies were performed. Results from skin biopsies were compared to healthy controls.
RESULT
Seventeen patients reported chronic pain. Large and/or small fiber abnormalities were present in 50% of the patients. The intraepidermal nerve fiber density was significantly lower in the whole group of patients compared to healthy controls.
CONCLUSION
Small-fiber neuropathy might be an important cause of pain in DM1.
PubMed: 38504800
DOI: 10.3389/fneur.2024.1375218 -
Cureus Feb 2024To report an instructive case involving destructive spondylitis and synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, presenting with torticollis and...
Dysphagia Secondary to Myotonic Dystrophy Unveiled in a Case of Destructive Spondylitis With Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) Syndrome Presenting As Torticollis.
To report an instructive case involving destructive spondylitis and synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome, presenting with torticollis and postoperative dysphagia without hoarseness, attributed to hidden myotonic dystrophy (DM). A 51-year-old male patient with a cervical deformity, who was previously managed conservatively for a metastatic tumor, underwent reconstruction surgery and subsequently experienced postoperative dysphagia. The presence of destructive spondylitis with torticollis, warranting prompt assessment to prevent paralysis, adds complexity to the delayed identification of DM. Given the rarity of DM, peculiar neurological symptoms and other systemic comorbidities did not lead to a preoperative diagnosis without prior knowledge. The patient's dysphagia induced respiratory arrest and required reintubation. Challenges in extubation and ventilator weaning arose due to hypercapnia. Superimposed COVID-19 infection elongated the duration of intubation. Extubation failed due to aspiration pneumonia and required a tracheotomy. Despite laryngeal elevation and preservation of the relaxation of the oesophageal entrance, the sensation and movement of the tracheopharynx were disturbed. The patient exhibited an oropharyngeal propulsive disorder, predominantly indicative of motor neuron disease. The patient's mother stated that his brother had been hospitalized for a long time after abdominal surgery. Finally, the patient was diagnosed with DM, which is known to cause post-anesthetic dysphagia. Recognizing the existence of severe destructive cervical spondylitis associated with SAPHO is crucial. Although DM is not very common, it is not classified as extremely rare. Therefore, surgeons should be mindful of the potential risks associated with general anesthesia in patients with DM. The complexity of preoperative conditions may hinder an accurate diagnosis. Recognizing and establishing preoperative expectations can assist surgeons in preventing complications, even if complex spinal surgery is required for patients with DM.
PubMed: 38496079
DOI: 10.7759/cureus.54271