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Neurologic Clinics Aug 2014Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. DM type 1 was first described over... (Review)
Review
Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. DM type 1 was first described over a century ago. More recently, a second form of the disease, DM type 2 was recognized, which results from repeat expansion in a different gene. Both disorders have autosomal dominant inheritance and multisystem features, including myotonic myopathy, cataract, and cardiac conduction disease. This article reviews the clinical presentation and pathophysiology of DM and discusses current management and future potential for developing targeted therapies.
Topics: Europe; Female; Humans; Male; Myotonic Dystrophy
PubMed: 25037086
DOI: 10.1016/j.ncl.2014.04.011 -
Acta Myologica : Myopathies and... Dec 2020The myotonic dystrophies are the commonest cause of adult-onset muscular dystrophy. Phenotypes of DM1 and DM2 are similar, but there are some important differences,... (Review)
Review
The myotonic dystrophies are the commonest cause of adult-onset muscular dystrophy. Phenotypes of DM1 and DM2 are similar, but there are some important differences, including the presence or absence of congenital form, muscles primarily affected (distal vs proximal), involved muscle fiber types (type 1 vs type 2 fibers), and some associated multisystemic phenotypes. There is currently no cure for the myotonic dystrophies but effective management significantly reduces the morbidity and mortality of patients. For the enormous understanding of the molecular pathogenesis of myotonic dystrophy type 1 and myotonic dystrophy type 2, these diseases are now called "spliceopathies" and are mediated by a primary disorder of RNA rather than proteins. Despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies. Gene therapy for myotonic dystrophy type 1 and myotonic dystrophy type 2 appears to be very close and the near future is an exciting time for clinicians and patients.
Topics: Humans; Microsatellite Repeats; Myotonic Dystrophy; Myotonin-Protein Kinase; RNA-Binding Proteins
PubMed: 33458578
DOI: 10.36185/2532-1900-026 -
Muscle & Nerve Oct 2020The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1... (Review)
Review
The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
Topics: Acetazolamide; Age of Onset; Carbonic Anhydrase Inhibitors; Chloride Channels; Electrodiagnosis; Electromyography; Fatigue; Genetic Testing; Humans; Lamotrigine; Mexiletine; Muscle Weakness; Muscle, Skeletal; Myalgia; Myotonia Congenita; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Practice Guidelines as Topic; Ranolazine; Sodium Channel Blockers; Voltage-Gated Sodium Channel Blockers
PubMed: 32270509
DOI: 10.1002/mus.26887 -
Neurologia Apr 2020Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of...
BACKGROUND AND OBJECTIVES
Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1.
MATERIAL AND METHODS
Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide.
RECOMMENDATIONS
The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives.
CONCLUSION
MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.
Topics: Deglutition Disorders; Follow-Up Studies; Genetic Counseling; Humans; Myotonic Dystrophy; Practice Guidelines as Topic
PubMed: 31003788
DOI: 10.1016/j.nrl.2019.01.001 -
Genes Feb 2022Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and... (Review)
Review
Myotonic dystrophies (DM) are the most common muscular dystrophies in adults, which can affect other non-skeletal muscle organs such as the heart, brain and gastrointestinal system. There are two genetically distinct types of myotonic dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), both dominantly inherited with significant overlap in clinical manifestations. DM1 results from CTG repeat expansions in the 3'-untranslated region (3'UTR) of the (dystrophia myotonica protein kinase) gene on chromosome 19, while DM2 is caused by CCTG repeat expansions in intron 1 of the (cellular nucleic acid-binding protein) gene on chromosome 3. Recent advances in genetics and molecular biology, especially in the field of RNA biology, have allowed better understanding of the potential pathomechanisms involved in DM. In this review article, core clinical features and genetics of DM are presented followed by a discussion on the current postulated pathomechanisms and therapeutic approaches used in DM, including the ones currently in human clinical trial phase.
Topics: 3' Untranslated Regions; Brain; Heart; Humans; Myotonic Dystrophy
PubMed: 35205411
DOI: 10.3390/genes13020367 -
International Journal of Molecular... Feb 2022Myotonic dystrophy (DM) is a dominantly inherited multisystemic disorder affecting various organs, such as skeletal muscle, heart, the nervous system, and the eye.... (Review)
Review
Myotonic dystrophy (DM) is a dominantly inherited multisystemic disorder affecting various organs, such as skeletal muscle, heart, the nervous system, and the eye. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by expanded CTG and CCTG repeats, respectively. In both forms, the mutant transcripts containing expanded repeats aggregate as nuclear foci and sequester several RNA-binding proteins, resulting in alternative splicing dysregulation. Although certain alternative splicing events are linked to the clinical DM phenotypes, the molecular mechanisms underlying multiple DM symptoms remain unclear. Interestingly, multi-systemic DM manifestations, including muscle weakness, cognitive impairment, cataract, and frontal baldness, resemble premature aging. Furthermore, cellular senescence, a critical contributor to aging, is suggested to play a key role in DM cellular pathophysiology. In particular, several senescence inducers including telomere shortening, mitochondrial dysfunction, and oxidative stress and senescence biomarkers such as cell cycle inhibitors, senescence-associated secretory phenotype, chromatin reorganization, and microRNA have been implicated in DM pathogenesis. In this review, we focus on the clinical similarities between DM and aging, and summarize the involvement of cellular senescence in DM and the potential application of anti-aging DM therapies.
Topics: Alternative Splicing; Cellular Senescence; Humans; Muscle, Skeletal; Myotonic Dystrophy; RNA-Binding Proteins
PubMed: 35216455
DOI: 10.3390/ijms23042339 -
Neurology India 2008Myotonia reflects a state of muscle fiber hyperexcitability. Impaired transmembrane conductance of either chloride or sodium ions results in myotonia. Myotonic disorders... (Review)
Review
Myotonia reflects a state of muscle fiber hyperexcitability. Impaired transmembrane conductance of either chloride or sodium ions results in myotonia. Myotonic disorders include the myotonic dystrophies and nondystrophic myotonias. Mutations in the genes encoding chloride (ClC-1) or sodium (SCN4A) channels expressed exclusively in skeletal muscle cause nondystrophic myotonias. Genetic defects in the myotonic dystrophies do not involve ion channel or its regulator proteins. Recent research supports a novel RNA-mediated disease mechanism of myotonia in the myotonic dystrophies. Myotonic dystrophy Type 1 is caused by CTG repeat expansion in the 3' untranslated region in the Dystrophia Myotonica Protein Kinase (DMPK) gene. Myotonic dystrophy Type 2 is caused by CCTG repeat expansion in the first intron in Zinc Finger Protein 9 (ZNF9) gene. The expanded repeat is transcribed in RNA and forms discrete inclusions in nucleus in both types of myotonic dystrophies. Mutant RNA sequesters MBNL1, a splice regulator protein and depletes MBNL1 from the nucleoplasm. Loss of MBNL1 results in altered splicing of ClC-1 mRNA. Altered splice products do not encode functional ClC-1 protein. Subsequent loss of chloride conductance in muscle membrane causes myotonia in the myotonic dystrophies. The purpose of this review is to discuss the clinical presentation, recent advances in understanding the disease mechanism with particular emphasis on myotonic dystrophies and potential therapy options in myotonic disorders.
Topics: Chloride Channels; Electromyography; Humans; Mutation; Myotonic Disorders; NAV1.4 Voltage-Gated Sodium Channel; Sodium Channels; Trinucleotide Repeat Expansion
PubMed: 18974556
DOI: 10.4103/0028-3886.43448 -
Tidsskrift For Den Norske Laegeforening... Sep 2023Myotonic dystrophy type 1 is one of the most common genetic neuromuscular diseases in adults. The disease not only affects the musculoskeletal system, but is... (Review)
Review
Myotonic dystrophy type 1 is one of the most common genetic neuromuscular diseases in adults. The disease not only affects the musculoskeletal system, but is multisystemic, and ocular involvement with cataract formation is a frequent additional finding. To avoid recurrence of secondary opacification that is difficult to treat, the cataract should not be treated with traditional lens replacement. This clinical review article presents ophthalmological findings in cases of myotonic dystrophy type 1 and describes a new surgical method for cataracts in this patient group.
Topics: Adult; Humans; Myotonic Dystrophy; Cataract; Eye; Face
PubMed: 37753768
DOI: 10.4045/tidsskr.22.0608 -
Chang Gung Medical Journal Aug 2005Myotonic dystrophies or dystrophia myotonica (DM) is a clinical syndrome that includes myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), myotonic... (Review)
Review
Myotonic dystrophies or dystrophia myotonica (DM) is a clinical syndrome that includes myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), myotonic dystrophy type 3 (DM3), and so forth. The terminology was recommended by the new nomenclature for myotonic dystrophies of an International Panel for Consensus. Previous studies have shown that DM1 is caused by the expansion of a cytosine-thymine-guanine (CTG) repeat in the DM protein kinase gene on chromosome 19, and DM2 is caused by an expansion of a cytosine-cytosine-thymine-guanine (CCTG) repeat in the zinc finger protein 9 (ZNF9) gene on chromosome 3. Because DM1 and DM2 have very similar clinical presentations, the diagnosis of these two disorders needs to be confirmed by molecular genetic analysis. Recently, DM3 was reported to include a multisystem myotonic disorder with frontotemporal dementia, and a linkage to chromosome 15q21-24. Although the age at onset, disease severity, and cerebral abnormality on a brain magnetic resonance spectrometry may correlate with the number of triplet repeats in the blood cells of DM1, it is too early to reach a conclusion. In Taiwan, the prevalence of DM1 is much lower than in Western countries. Previous studies have shown that the central nervous system symptomatology is correlated mainly with the white matter lesions in the brain MRI, but the CNS manifestations seem unrelated to the numbers of CTG triplet repeats in the blood cells. The inverse correlation between age at onset and CTG repeat length is significant only in patients with small expansions of about 100-250 triplet repeats. Transmission contraction of the repeat size is likely to occur in alleles with large repeats and is associated with paternal transmission. In congenital DM1, individual variability of muscle differentiation does occur, in spite of the same number of CTG repeats in the leukocytes.
Topics: Brain; Humans; Magnetic Resonance Imaging; Myotonic Dystrophy; Myotonin-Protein Kinase; Protein Serine-Threonine Kinases; Trinucleotide Repeats
PubMed: 16265841
DOI: No ID Found -
BMJ Case Reports May 2021
Topics: Hand Strength; Humans; Myotonia; Myotonia Congenita; Myotonic Dystrophy
PubMed: 33958356
DOI: 10.1136/bcr-2020-240779