RESUMO
Non-dystrophic myotonias (NDM) are disabling genetic diseases that impact quality of life. To reduce the impact of NDM, patients develop coping strategies such as lifestyle adaptation and avoiding key triggers. To understand how myotonia affects patients' lives, the IMPACT survey, an online questionnaire on patient-reported outcomes, was developed based on international IMPACT questionnaire. The French IMPACT 2022 survey was completed by 47 NDM French patients. Besides muscle stiffness (98%), patients reported muscle pain (83%), falls (70%) and anxiety (77%). These issues negatively impacted abilities to work/study (49%), daily life at home (49%) and overall mobility outside (49%). Most patients (96%) reported ongoing pharmacological treatment (mexiletine, 91%) associated with improvement in muscle stiffness (100%) and reduction in falls (94%), muscle pain (87%) and anxiety (80%). Patients were moderately satisfied (19.1%), satisfied (42.6%) and very satisfied (29.8%) with the current management; 32% rated their quality of life positively (≥ 8 on 10-point scale). In conclusion, this French survey confirms the impact of myotonia on daily life and quality of life. The improvement in patient-reported outcomes in treated participants highlights the importance of managing myotonia with effective treatments. More work should be initiated to assess the importance of NDM symptom management and patients' adherence and compliance to treatment.
RESUMO
Andersen's syndrome is a rare disorder that has been defined with a triad: periodic paralysis, cardiac arrhythmia, and development anomalies. Muscle weakness has been reported in two-thirds of the patients. KCNJ2 remains the only gene linked to Andersen's syndrome; this gene encodes for the alpha-subunit of the strong inward-rectifier K+ channel Kir2.1. Several studies have shown that Andersen's syndrome mutations lead to a loss of function of the K+ channel activity in vitro. However, ex vivo studies on isolated patient muscle tissue have not been reported. We have performed muscle biopsies of controls and patients presenting with clinically and genetically defined Andersen's syndrome disorder. Myoblasts were cultured and characterized morphologically and functionally using the whole cell patch-clamp technique. No morphological difference was observed between Andersen's syndrome and control myoblasts at each passage of the cell culture. Cellular proliferation and viability were quantified in parallel with direct cell counts and showed no difference between control and Andersen's syndrome patients. Moreover, our data show no significant difference in myoblast fusion index among Andersen's syndrome and control patients. Current recordings carried out on myotubes revealed the absence of an inwardly rectifying Ba2+-sensitive current in affected patient cells. One consequence of the Ik1 current loss in Andersen's syndrome myotubes is a shift of the resting membrane potential toward depolarizing potentials. Our data describe for the first time the functional consequences of Andersen's syndrome mutations ex vivo and provide clues to the K+ channel pathophysiology in skeletal muscle.
Assuntos
Síndrome de Andersen/patologia , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/patologia , Adulto , Idoso , Síndrome de Andersen/genética , Síndrome de Andersen/fisiopatologia , Células Cultivadas , Humanos , Transporte de Íons , Masculino , Potenciais da Membrana , Músculo Esquelético/fisiopatologia , Mutação , Mioblastos/fisiologia , Técnicas de Patch-Clamp , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/fisiologiaRESUMO
INTRODUCTION: Nitrous oxide is frequently used for anesthesia. It may cause spinal cord toxicity. CASE REPORTS: We report two patients who presented gait disorders after nitrous oxide anesthesia. Physical examination revealed arms and legs pyramidal syndrome and abnormal proprioception, consistent with subacute combined degeneration of the spinal cord. Serum vitamin B12 level was extremely low. The patients improved with parenteral treatment with hydroxycobalamin. CONCLUSIONS: The inactivation of methionine synthase and L methylmalonylcoA mutase by nitrous oxide has been previously demonstrated. Anesthesia-related exposure to nitrous oxide may induce neurologic disorders even in patients with no preliminary vitamin B12 deficiency.
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Doenças do Sistema Nervoso/induzido quimicamente , Óxido Nítrico/farmacologia , Deficiência de Vitamina B 12/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/complicações , Doenças do Sistema Nervoso/complicaçõesRESUMO
UNLABELLED: The new variant of Creutzfeldt-Jakob disease (nvCJD) was first described in the UK in 1996 (16). The nvCJD differs from sporadic, genetic and iatrogenic CJD. Creutzfeldt-Jakob disease is closely associated with an abnormal isoform PrPSc of a cell-surface glycoprotein, prion protein (14). Molecular analysis suggests that nvCJD is caused by the same prion strain as bovine spongiform encephalopathy (BSE) (4, 10). To the end of September 2000, there have been 82 cases of nvCJD in the UK. We report the second French case of nvCJD to our knowledge (5, 13). CASE REPORT: This 36 year old woman was referred by a local general practitioner with a 6 month history of psychiatric symptoms of major depressive disorder. According to her family, the patient had suffered from personality change for several months before the onset of depression including apathy, emotional lability, infantile affect. There was no history of health problems. As she was admitted to the psychiatric department of our hospital in Paris suburbs, she presented a major depressive disorder. There were no specific psychiatric features allowing distinction from common depressive disorders, except a marked emotional lability. The patient's condition progressed rapidly within the following days. She presented memory impairment and disorientation. Drug treatments, clomipramine (125 mg/day) and venlafaxine (200 mg/day), were used with no benefit. She presented subsequently transient delusions and auditory hallucinations, fleeting for some hours. The predominant delusional themes were somatic type and pregnancy. The delusions were concomitant with delusions of the onset of cognitive impairment. The patient tested negative for the P 14.3.3 protein in the CSF. Computed tomography scan of the brain did not show any relevant abnormality. The electroencephalogram showed non specific slow wave activity. The neurological symptoms developed 7 months after the onset of depressive symptoms including ataxia, myoclonus, excessive daytime drowsiness, headache. After the onset of neurological symptoms, the illness progressed rapidly over the next 2 months with cognitive impairment, particularly memory impairment, myoclonus, ataxia, incontinence of urine and progressive immobility leading to dependency. CSF tests were negative. She was referred to a neurology department where the diagnosis was confirmed by brain biopsy (detailed elsewhere). The patient died in a state of akinetic mutism. DISCUSSION: The clinical features of our patient were consistent with previous descriptions of nvCJD, mainly those of the National CJD Surveillance Unit studies (17): early psychiatric symptoms, prolonged duration of illness (median: 14 months), earlier age at death, compared with sporadic CJD. Psychiatric symptoms occur in the clinical course in about a third of cases of sporadic CJD (3). In contrast, of the 35 cases that have died of nvCJD identified in the study by Will et al. (17), 34 suffered from early and prominent psychiatric symptoms, mainly depression and anxiety. In most of the patients, the first symptoms were psychiatric. Drug treatment was used in most cases, some patients had a transient improvement (18). The patient without psychiatric symptoms reported by the NCJDSU (17) was emotionally labile. Infantile affect and emotional lability, found in our patient, are frequently reported in other studies (1, 18). Schizophreniform disorders have been described during the clinical course, with auditory and visual hallucinations and paranoid delusions (17, 18). The insomnia and excessive daytime drowsiness our patient presented have been described in similar cases (18). Investigations are important to rule out alternative diagnoses. EEG records do not show periodic triphasic complexes as in sporadic CJD. The P 14.3.3 protein in the CSF is positive in half the cases of nvCJD (17). First neurological symptoms developed 6 months after the onset of psychiatric symptoms including ataxia, myoclonus and persistent painful sensory symptoms (17, 18). In most of the cases, MRI brain scans show bilateral pulvinar high signal (17), found subsequently in our patient and detailed elsewhere (13). The terminal stages are progressive cognitive impairment, helplessness and akinetic mutism. CONCLUSION: The first symptoms of this patient were purely psychiatric and difficult to distinguish from common psychiatric disorders. Clinical surveillance of human prion disease is crucial in France, as in UK. The link with BSE has dramatically highlighted the need for neurological and neuropsychological precise investigations.
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Síndrome de Creutzfeldt-Jakob/diagnóstico , Demência/diagnóstico , Transtorno Depressivo Maior/diagnóstico , Adulto , Biópsia , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/patologia , Síndrome de Creutzfeldt-Jakob/psicologia , Demência/patologia , Demência/psicologia , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/psicologia , Diagnóstico Diferencial , Feminino , Humanos , Transtornos da Personalidade/diagnóstico , Transtornos da Personalidade/psicologiaRESUMO
Nondystrophic myotonias are characterized by muscle stiffness triggered by voluntary movement. They are caused by mutations in either the CLCN1 gene in myotonia congenita or in the SCN4A gene in paramyotonia congenita and sodium channel myotonias. Clinical and electrophysiological phenotypes of these disorders have been well described. No concomitant mutations in both genes have been reported yet. We report five patients from three families showing myotonia with both chloride and sodium channel mutations. Their clinical and electrophysiological phenotypes did not fit with the phenotype known to be associated with the mutation initially found in SCN4A gene, which led us to screen and find an additional mutation in CLCN1 gene. Our electrophysiological and clinical observations suggest that heterozygous CLCN1 mutations can modify the clinical and electrophysiological expression of SCN4A mutation.
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Canais de Cloreto/genética , Mutação/genética , Miotonia Congênita/genética , Adolescente , Adulto , Análise Mutacional de DNA , Eletrofisiologia , Humanos , Masculino , Modelos Moleculares , FenótipoAssuntos
Doenças da Coluna Vertebral , Malformações Vasculares , Angiografia , Humanos , Coluna VertebralRESUMO
BACKGROUND: Myotonia is unusual in infants, and not well-known. METHODS: We describe neonatal life-threatening features of myotonia caused by de novo mutations in the muscle sodium channel gene SCN4A. RESULTS: Three male neonates initially displayed episodic laryngospasms, with face and limb myotonia appearing later. We found SCN4A de novo mutations in these neonates: p.Gly1306Glu in 2 unrelated cases and a novel mutation p.Ala799Ser in the third. Two patients survived their respiratory attacks and were efficiently treated by sodium channel blockers (mexiletine, carbamazepine) following diagnosis of myotonia. CONCLUSION: Severe neonatal episodic laryngospasm is a new phenotype caused by a sodium channelopathy, which can be alleviated by channel blockers.
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Laringismo/genética , Mutação/genética , Canais de Sódio/genética , Feminino , Humanos , Recém-Nascido , Repetições de Microssatélites/genética , Canal de Sódio Disparado por Voltagem NAV1.4RESUMO
Ion channels are transmembrane proteins that allow ions to flow in or out of the cell. Sodium and potassium channel activation and inactivation are the basis of action potential's production and conduction. During the past 15 years, ion channels have been implicated in diseases that have come to be known as the channelopathies. Over 30 mutations of the muscle channel gene SCN4A, which encodes the muscle voltage-gated sodium channel, have been described and associated with neuromuscular disorders like hypo- and hyper-kalaemic periodic paralyses (hypoPP and hyperPP), paramyotonia congenita, sodium channel myotonias and congenital myasthenic syndrome. Different mutations within the same gene (SCN4A) cause distinct clinical disorders, while mutations in different channel genes may result in similar phenotypes. In addition, identical sodium channel mutations can result in different clinical phenotypes (hyperPP or paramyotonia) in different members of the same family, suggesting that the genetic background and perhaps other epigenetic factors may influence the clinical expression of a particular mutation. This article reviews the clinical features of the skeletal muscle sodium channel diseases and highlights the phenotypic or genetic overlap in these disorders.
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Músculo Esquelético/fisiopatologia , Transtornos Miotônicos/genética , Canais de Sódio/genética , Humanos , Conformação Proteica , Estrutura Secundária de Proteína , Canais de Sódio/metabolismoRESUMO
BACKGROUND: Periodic paralysis is classified into hypokalemic (hypoPP) and hyperkalemic (hyperPP) periodic paralysis according to variations of blood potassium levels during attacks. OBJECTIVE: To describe new mutations in the muscle sodium channel gene SCN4A that cause periodic paralysis. METHODS: A thorough clinical, electrophysiologic, and molecular study was performed of four unrelated families who presented with periodic paralysis. RESULTS: The nine affected members had episodes of muscle weakness reminiscent of both hyperPP and hypoPP. A provocative test with potassium chloride was positive in two patients. However, repeated and carefully performed tests of blood potassium levels during attacks resulted in normal potassium levels. Remarkably, two patients experienced hypokalemic episodes of paralysis related to peculiar provocative factors (corticosteroids and thyrotoxicosis). Similarly to hyperPP, electromyography in nine patients revealed increased compound muscle action potentials after short exercise and a delayed decline during rest after long exercise as well as myotonic discharges in one patient. With use of molecular genetic analysis of the gene SCN4A, three new mutations were found affecting codon 675. They resulted in an amino acid substitution of a highly conserved arginine (R) to either a glycine (G), a glutamine (Q), or a tryptophan (W). Interestingly, hypoPP is caused by both mutations affecting nearby codons as well as the change of an arginine into another amino acid. CONCLUSION: A potassium-sensitive and normokalemic type of periodic paralysis caused by new SCN4A mutations at codon 675 is reported.