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1.
BMC Neurol ; 22(1): 17, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996390

RESUMO

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary neuropathy, and CMT1A is the most common form; it is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Mutations in the transient sodium channel Nav1.4 alpha subunit (SCN4A) gene underlie a diverse group of dominantly inherited nondystrophic myotonias that run the spectrum from subclinical myopathy to severe muscle stiffness, disabling weakness, or frank episodes of paralysis. CASE PRESENTATION: We describe a Chinese family affected by both CMT1A and myotonia with concomitant alterations in both the PMP22 and SCN4A genes. In this family, the affected proband inherited the disease from his father in an autosomal dominant manner. Genetic analysis confirmed duplication of the PMP22 gene and a missense c.3917G > C (p. Gly1306Ala) mutation in SCN4A in both the proband and his father. The clinical phenotype in the proband showed the combined involvement of skeletal muscle and peripheral nerves. Electromyography showed myopathic changes, including myotonic discharges. MRI revealed the concurrence of neurogenic and myogenic changes in the lower leg muscles. Sural nerve biopsies revealed a chronic demyelinating and remyelinating process with onion bulb formations in the proband. The proband's father presented with confirmed subclinical myopathy, very mild distal atrophy and proximal hypertrophy of the lower leg muscles, pes cavus, and areflexia. CONCLUSION: This study reports the coexistence of PMP22 duplication and SCN4A mutation. The presenting features in this family suggested that both neuropathy and myopathy were inherited in an autosomal dominant manner. The proband had a typical phenotype of sodium channel myotonia (SCM) and CMT1A. However, his father with the same mutations presented a much milder clinical phenotype. Our study might expand the genetic and phenotypic spectra of neuromuscular disorders with concomitant mutations.


Assuntos
Artrogripose , Doença de Charcot-Marie-Tooth , Miotonia , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/genética , Humanos , Masculino , Proteínas da Mielina , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Proteínas
2.
Acta Neurol Taiwan ; 30(3): 113-118, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34841507

RESUMO

PURPOSE: Early distal muscle weakness and myotonia are typical clinical presentations in type I myotonic dystrophy (DM1). We present a DM1 case with unusual predominant proximal weakness without action myotonia. CASE REPORT: The chief complaint of this 48-year-old female was difficulty in raising her arms and frequent falling in recent years. On neurological examination, proximal muscle weakness was more pronounced than the distal muscle groups, in addition to facial involvement. Although she did not experience any action myotonia throughout her life, hand and tongue myotonia were readily inducible by percussion during neurological examination. The diagnosis of DM1 was later supported by electromyography and neuropathological studies, and confirmed by molecular testing. The pathological findings in this patient and the characteristic features in typical DM1 patients were briefly reviewed. CONCLUSION: The unusual presentation of this DM1 patient suggests the importance of comprehensive neurological examination including percussion of thenar and tongue muscles, even in a patient with atypical distribution of muscle weakness and without a clear personal and family history of myotonia. In addition to molecular testing, muscle biopsy remains supportive in making the diagnosis.


Assuntos
Miotonia , Distrofia Miotônica , Eletromiografia , Feminino , Humanos , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Músculo Esquelético , Miotonia/diagnóstico , Distrofia Miotônica/complicações , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/genética
7.
Cells ; 10(2)2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670307

RESUMO

Non-dystrophic myotonias have been linked to loss-of-function mutations in the ClC-1 chloride channel or gain-of-function mutations in the Nav1.4 sodium channel. Here, we describe a family with members diagnosed with Thomsen's disease. One novel mutation (p.W322*) in CLCN1 and one undescribed mutation (p.R1463H) in SCN4A are segregating in this family. The CLCN1-p.W322* was also found in an unrelated family, in compound heterozygosity with the known CLCN1-p.G355R mutation. One reported mutation, SCN4A-p.T1313M, was found in a third family. Both CLCN1 mutations exhibited loss-of-function: CLCN1-p.W322* probably leads to a non-viable truncated protein; for CLCN1-p.G355R, we predict structural damage, triggering important steric clashes. The SCN4A-p.R1463H produced a positive shift in the steady-state inactivation increasing window currents and a faster recovery from inactivation. These gain-of-function effects are probably due to a disruption of interaction R1463-D1356, which destabilizes the voltage sensor domain (VSD) IV and increases the flexibility of the S4-S5 linker. Finally, modelling suggested that the p.T1313M induces a strong decrease in protein flexibility on the III-IV linker. This study demonstrates that CLCN1-p.W322* and SCN4A-p.R1463H mutations can act alone or in combination as inducers of myotonia. Their co-segregation highlights the necessity for carrying out deep genetic analysis to provide accurate genetic counseling and management of patients.


Assuntos
Canais de Cloreto/genética , Mutação/genética , Miotonia Congênita/genética , Miotonia/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Miotonia Congênita/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo , Linhagem
9.
J Clin Neuromuscul Dis ; 22(3): 135-146, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33595997

RESUMO

ABSTRACT: Myotonic dystrophy type 2 (DM2) is an autosomal dominant disorder due to a (CCTG)n repeat expansion in intron 1 of the CNBP gene. In this article, we report the clinicopathologic findings in 50 patients seen at a single site over a 27 year period. DM2 was the fifth most common type of muscular dystrophy seen at our center with a 5-fold lower frequency as compared to DM1. Age of symptom onset ranged from 15 to 72 years, and the mean duration between symptom onset and diagnosis was 7.4 years. Weakness referable to the proximal lower extremities was the presenting symptom in 62% of patients. The degree of generalized weakness varied from severe in 30% to no weakness in 20% of patients. Clinical myotonia was noted in 18% and myotonic discharges on electromyography in 97% of patients. Pain symptoms were uncommon in our cohort. A significant correlation was noted between limb weakness and degree of muscle pathologic changes. There was no correlation between CCTG repeat size and other clinicopathologic findings. Six patients (12%) had cardiac abnormalities including one who developed progressive nonischemic dilated cardiomyopathy ultimately leading to cardiac transplantation. In 21 patients followed for 2 or more years, we noted a mean rate of decline in total Medical Research Council score of about 1% per year.


Assuntos
Distrofia Miotônica/diagnóstico , Adolescente , Adulto , Idoso , Estudos de Coortes , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular , Miotonia/diagnóstico , Tomografia Computadorizada por Raios X , Adulto Jovem
10.
J Neurol ; 268(5): 1708-1720, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33263785

RESUMO

INTRODUCTION: Non-dystrophic myotonias (NDM) are heterogeneous diseases caused by mutations in CLCN1 and SCN4A. The study aimed to describe the clinical and genetic spectrum of NDM in a large German cohort. METHODS: We retrospectively identified all patients with genetically confirmed NDM diagnosed in our center. The following data were analyzed: demographics, family history, muscular features, cardiac involvement, CK, EMG, genotype, other tested genes, treatment perceived efficacy. RESULTS: 70 patients (age 40.2 years ± 14.9; 52.8% males) were included in our study (48 NDM-CLCN1, 22 NDM-SCN4A). The most frequent presenting symptoms were myotonia (NDM-CLCN1 83.3%, NDM-SCN4A 72.2%) and myalgia (NDM-CLCN1 57.4%, NDM-SCN4A 52.6%). Besides a more prominent facial involvement in NDM-SCN4A and cold-sensitivity in NDM-CLCN1, no other significant differences were observed between groups. Cardiac arrhythmia or conduction defects were documented in sixNDM-CLCN1 patients (three of them requiring a pacemaker) and one patient with NDM-SCN4A. CK was normal in 40% of patients. Myotonic runs in EMG were detected in 89.1% of CLCN1 and 78.9% of SCN4A. 50% of NDM-CLCN1 patients had the classic c.2680C>T (p.Arg894*) mutation. 12 new genetic variants are reported. About 50% of patients were not taking any anti-myotonic drug at the last follow-up. The anti-myotonic drugs with the best patient's perceived efficacy were mexiletine and lamotrigine. CONCLUSION: This study highlights the relevant clinical overlap between NDM-CLCN1 and NDM-SCN4A patients and warrants the use of early and broad genetic investigation for the precise identification of the NDM subtype. Besides the clinical and genetic heterogeneity, the limited response to current anti-myotonic drugs constitutes a continuing challenge.


Assuntos
Miotonia Congênita , Miotonia , Adulto , Canais de Cloreto/genética , Feminino , Humanos , Masculino , Mutação , Miotonia/genética , Miotonia Congênita/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Estudos Retrospectivos
11.
Rev. colomb. anestesiol ; 48(3): 162-163, July-Sept. 2020. graf
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1149788

RESUMO

Classic myotonic dystrophy is a multisystem disorder that results from RNA toxicity and is one of the commonest adult onset muscular dystrophies. Patients often present with muscle stiffness from myotonia and dysphagia or dysarthria from laryngopharyngoesophageal muscle weakness. Benign electrocardiogram changes such as first degree atrioventricular block are commonly present and rarely merit further work up. Occasionally, patients develop advanced conduction defects which can unexpectedly progress to complete heart block perioperatively


La distrofia miotonica clásica es un trastorno multi-sistémico que resulta de la toxicidad del RNA y es una de las distrofias musculares más comunes en adultos. Los pacientes suelen presentar rigidez muscular por la miotonía, así como disfagia o disartria por debilidad muscular laringo-faríngea-esofágica. Los cambios benignos en el electrocardiograma, como el bloqueo auriculoventricular de primer grado, suelen estar presentes y rara vez merecen un análisis más profundo. Ocasionalmente, los pacientes desarrollan defectos de conduccion avanzados que pueden progresar inespera-damente para completar el bloqueo cardiaco perioperatorio.


Assuntos
Humanos , Bloqueio Atrioventricular , Bloqueio Cardíaco , Processamento de Imagem Assistida por Computador , RNA , Disartria , Eletrocardiografia , Doença do Sistema de Condução Cardíaco , Miotonia
13.
Neuromuscul Disord ; 30(7): 546-553, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32660787

RESUMO

Skeletal muscle channelopathies, including non-dystrophic myotonia and periodic paralysis, are rare hereditary disorders caused by mutations of various ion channel genes. To define the frequency of associated mutations of skeletal muscle channelopathies in Japan, clinical and genetic data of two academic institutions, which provides genetic analysis service, were reviewed. Of 105 unrelated pedigrees genetically confirmed, 66 pedigrees were non-dystrophic myotonias [CLCN1 (n = 30) and SCN4A (n = 36)], 11 were hyperkalemic periodic paralysis (SCN4A), and 28 were hypokalemic periodic paralysis [CACNA1S (n = 16) and SCN4A (n = 12)]. Of the 30 families with myotonia congenita, dominant form (Thomsen type) consisted 67%, and unique mutations, A298T, P480T, T539A, and M560T, not found in Western countries, were commonly identified in CLCN1. Hypokalemic periodic paralysis caused by SCN4A mutations consisted 43% in Japan, which was much higher than previous reports. Furthermore, the quality of life of the patients was assessed using the patient-reported outcome measures, SF-36 and INQoL, for 41 patients. This study indicated that the etiology of skeletal muscle channelopathies in Japan was not identical to previous reports from Western countries, and provided crucial information for genetics as well as future therapeutic interventions.


Assuntos
Canalopatias/genética , Músculo Esquelético/patologia , Mutação/genética , Adulto , Canais de Cálcio Tipo L , Feminino , Testes Genéticos , Nível de Saúde , Humanos , Paralisia Periódica Hipopotassêmica/genética , Japão , Masculino , Pessoa de Meia-Idade , Miotonia/genética , Transtornos Miotônicos/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Paralisia Periódica Hiperpotassêmica/genética , Linhagem , Qualidade de Vida , Inquéritos e Questionários , Adulto Jovem
14.
Dtsch Med Wochenschr ; 145(13): 887-894, 2020 07.
Artigo em Alemão | MEDLINE | ID: mdl-32615603

RESUMO

Muscle pain as a common symptom in daily practice frequently occurs as a non-specific accompanying symptom in multiple internal and neurological diseases. Primarily inflammatory or autoimmune muscular diseases are causing muscle pain. However, a number of non-inflammatory causes of pain can also be considered for differential diagnosis. These are presented in this article. In principle, a distinction must be made between focal and diffuse muscle pain. As an invasive diagnostic procedure, a muscle biopsy should only be performed as the last step in the diagnostic alogorithm. If diffuse muscle pain is only associated with slight muscle weakness or is completely absent, there is usually a primary rheumatic cause. Statins (HMG-CoA reductase inhibitors) can lead to rhabdomyolysis, muscle fiber atrophy and muscle necrosis by damaging the muscle fiber membrane. Myotonias are autosomal dominant or autosomal recessive inherited disorders of muscle function. The genetic defect leads to pronounced muscle stiffness. The cause of metabolic myopathies can be disorders of the carbohydrate, fat or purine metabolism. Fibromyalgia syndrome (FMS) is a non-inflammatory disease and, according to the current knowledge, recognized as the result of an exposure to physical, biological and psychosocial factors (biopsychological disease model). To help diagnosing FMS, pain regions and core symptoms (fatigue, sleep disturbances) can be detected using questionnaires (Widespread Pain Index [WPI] and Symptom Severity Scale [SSS]).


Assuntos
Mialgia/etiologia , Contratura/classificação , Contratura/diagnóstico , Contratura/etiologia , Diagnóstico Diferencial , Fibromialgia/classificação , Fibromialgia/diagnóstico , Fibromialgia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Cãibra Muscular/classificação , Cãibra Muscular/diagnóstico , Cãibra Muscular/etiologia , Debilidade Muscular/classificação , Debilidade Muscular/diagnóstico , Debilidade Muscular/etiologia , Doenças Musculares/classificação , Doenças Musculares/diagnóstico , Doenças Musculares/etiologia , Mialgia/classificação , Mialgia/diagnóstico , Miotonia/classificação , Miotonia/diagnóstico , Miotonia/etiologia , Fatores de Risco , Espasmo/classificação , Espasmo/diagnóstico , Espasmo/etiologia
15.
Neuromuscul Disord ; 30(7): 539-545, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32622512

RESUMO

The skeletal muscle channelopathies are a group of rare diseases and include non-dystrophic myotonia and periodic paralysis. Given their rarity, little has been published on the management of anaesthesia and pregnancy in this cohort despite being important aspects of care. We have conducted a large study of over 70 patients who underwent anaesthesia and 87 pregnancies to investigate the problems encountered following anaesthesia or during pregnancy. This was performed via patient surveys sent out to genetically confirmed channelopathy patients seen at the National Hospital for Neurology and Neurosurgery. Most significantly in our cohort, patients frequently experienced a worsening or precipitation of symptoms during pregnancy (75%) or following anaesthetic (31%). None of our patients developed malignant hyperthermia, although there are confirmed reports of this in patients with periodic paralysis and mutations in RYR1. There was a significantly higher number of miscarriages compared to the normal population. There was no significant difference in antenatal or delivery complications compared to the general population. However, three neonates did have complications, all of whom were found to carry mutations in SCN4A. This study highlights the importance of counselling patients and clinicians for the possibility of worsening symptoms during pregnancy or anaesthesia and the careful management of neonates following delivery.


Assuntos
Anestésicos/efeitos adversos , Canalopatias/fisiopatologia , Músculo Esquelético/fisiopatologia , Complicações na Gravidez/fisiopatologia , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Miotonia/fisiopatologia , Gravidez , Inquéritos e Questionários
16.
Neuromuscul Disord ; 30(7): 554-561, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32593548

RESUMO

Non-dystrophic myotonias are a group of rare neuromuscular diseases linked to SCN4A or CLCN1. Among the subtypes, myotonia permanens, associated with the Gly1306Glu variant of SCN4A, is a relatively less frequent but more severe form. Most reports of non-dystrophic myotonias describe European populations. Therefore, to expand the genetic and phenotypic spectrum of this disorder, we evaluated 30 Chilean patients with non-dystrophic myotonias for associated variants and clinical characteristics. SCN4A variants were observed in 28 (93%) of patients, including 25 (83%) with myotonia permanens due to the Gly1306Glu variant. Myotonia permanens was inherited in 24 (96%) patients; the mean age of onset was 6 months, and the initial symptoms were orbicularis oculi myotonia in 17 (74%) patients and larynx myotonia in 12 (52%) patients. The extraocular muscles were involved in 11 (44%) patients, upper limbs in 20 (80%), and lower limbs in 21 (84%). Thirteen (52%) patients experienced recurrent pain and 10 (40%) patients reported limitations in daily life activities. Carbamazepine reduced myotonia in eight treated patients. The high frequency of the Gly1306Glu variant in SCN4A in Chilean patients suggests a founder effect and expands its phenotypic spectrum.


Assuntos
Miotonia/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adolescente , Adulto , Criança , Chile , Estudos de Coortes , Feminino , Efeito Fundador , Humanos , Lactente , Masculino , Mutação , Transtornos Miotônicos/genética , Adulto Jovem
18.
Neuromuscul Disord ; 30(5): 427-430, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312586

RESUMO

We report the case of a patient suffering from duplicity of myotonic dystrophy type 1 and ulcerative colitis whose treatment for ulcerative colitis included repeated administrations of descending doses of methylprednisolone and in whom we found an association between methylprednisolone dosing and cessation of myotonia. Myotonia severity was expressed as relaxation time after voluntary contraction and as a patient-reported outcome using the Czech version of the Myotonia Behavior Scale. The patient was being treated for a flare of ulcerative colitis, starting with 32 mg of methylprednisolone and reducing the dose by 4 mg a week. The symptoms of myotonia began to wear off three weeks after starting methylprednisolone and had totally disappeared by four weeks after starting methylprednisolone. The first symptoms of myotonia returned about a month after the last dose of methylprednisolone and reached a peak of severity more than two months after the final dose.


Assuntos
Corticosteroides/administração & dosagem , Metilprednisolona/administração & dosagem , Miotonia/tratamento farmacológico , Distrofia Miotônica/tratamento farmacológico , Adulto , Colite Ulcerativa/tratamento farmacológico , Feminino , Humanos
19.
Neuromuscul Disord ; 30(5): 424-426, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32327288

RESUMO

Nav1.4 channelopathies due to SCN4A mutations can present with episodic attacks of myotonia triggered by fluctuation in the potassium level (potassium-aggravated myotonia). We report a case of potassium-aggravated myotonia due to Nav1.4-M1592V channelopathy with severe and long-lasting focal attacks of myotonia resembling dystonic posturing with diffuse muscle edema in the affected muscles in magnetic resonance imaging and almost constant presence of myotonic discharges in electromyography that can best be described as focal "status myotonicus".


Assuntos
Canalopatias/complicações , Canalopatias/genética , Miotonia/diagnóstico , Miotonia/etiologia , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adulto , Eletromiografia , Feminino , Humanos , Imageamento por Ressonância Magnética
20.
Exp Neurol ; 328: 113287, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32205118

RESUMO

The antiarrhythmic sodium-channel blocker mexiletine is used to treat patients with myotonia. However, around 30% of patients do not benefit from mexiletine due to poor tolerability or suboptimal response. Safinamide is an add-on therapy to levodopa for Parkinson's disease. In addition to MAOB inhibition, safinamide inhibits neuronal sodium channels, conferring anticonvulsant activity in models of epilepsy. Here, we investigated the effects of safinamide on skeletal muscle hNav1.4 sodium channels and in models of myotonia, in-vitro and in-vivo. Using patch-clamp, we showed that safinamide reversibly inhibited sodium currents in HEK293T cells transfected with hNav1.4. At the holding potential (hp) of -120 mV, the half-maximum inhibitory concentrations (IC50) were 160 and 33 µM at stimulation frequencies of 0.1 and 10 Hz, respectively. The calculated affinity constants of safinamide were dependent on channel state: 420 µM for closed channels and 9 µM for fast-inactivated channels. The p.F1586C mutation in hNav1.4 greatly impaired safinamide inhibition, suggesting that the drug binds to the local anesthetic receptor site in the channel pore. In a condition mimicking myotonia, i.e. hp. of -90 mV and 50-Hz stimulation, safinamide inhibited INa with an IC50 of 6 µM, being two-fold more potent than mexiletine. Using the two-intracellular microelectrodes current-clamp method, action potential firing was recorded in vitro in rat skeletal muscle fibers in presence of the chloride channel blocker, 9-anthracene carboxylic acid (9-AC), to increase excitability. Safinamide counteracted muscle fiber hyperexcitability with an IC50 of 13 µM. In vivo, oral safinamide was tested in the rat model of myotonia. In this model, intraperitoneal injection of 9-AC greatly increased the time of righting reflex (TRR) due to development of muscle stiffness. Safinamide counteracted 9-AC induced TRR increase with an ED50 of 1.2 mg/kg, which is 7 times lower than that previously determined for mexiletine. In conclusion, safinamide is a potent voltage and frequency dependent blocker of skeletal muscle sodium channels. Accordingly, the drug was able to counteract abnormal muscle hyperexcitability induced by 9-AC, both in vitro and in vivo. Thus, this study suggests that safinamide may have potential in treating myotonia and warrants further preclinical and human studies to fully evaluate this possibility.


Assuntos
Alanina/análogos & derivados , Benzilaminas/farmacologia , Músculo Esquelético/efeitos dos fármacos , Miotonia , Canal de Sódio Disparado por Voltagem NAV1.4/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Alanina/farmacologia , Animais , Células HEK293 , Humanos , Masculino , Ratos , Ratos Wistar
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