RESUMEN
Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target.
Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Canalopatías/genética , Mutación/genética , Miotonía/genética , Trastornos Miotónicos/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Parálisis Periódicas Familiares/genética , Animales , Humanos , Ratones , LinajeRESUMEN
INTRODUCTION: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials. METHODS: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods. RESULTS: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning. CONCLUSION: QMA is an automated, non-invasive technique for evaluating myotonia in NDM.
Asunto(s)
Prueba de Esfuerzo/métodos , Fuerza de la Mano/fisiología , Debilidad Muscular/diagnóstico , Debilidad Muscular/fisiopatología , Miotonía/diagnóstico , Miotonía/fisiopatología , Adulto , Anciano , Canales de Cloruro/genética , Diagnóstico por Computador/métodos , Diagnóstico por Computador/normas , Prueba de Esfuerzo/normas , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Mutación , Miotonía/genética , Canales de Sodio/genética , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The aim is to review the recent findings in relation to the genetics, pathophysiology, clinical phenotypes, investigation and treatment of the nondystrophic myotonias (NDMs) and periodic paralyses. RECENT FINDINGS: The number of pathogenic mutations causing NDMs and periodic paralyses in known genes continues to expand. In addition, a mutation has been identified in the ryanodine receptor gene manifesting as an atypical periodic paralysis phenotype. Another recent study indicated that thyrotoxic hypokalaemic periodic paralysis is determined by mutations in a novel gene encoding an inwardly rectifying potassium channel, Kir2.6. Work studying molecular mechanisms indicates that 90% of the known mutations causing hypokalaemic periodic paralysis (HypoPP) result in loss of positively charged arginine residues in the S4 segments of either SCN4A or CACNA1S, possibly creating a gating-pore current that may be important in the pathogenesis of HypoPP. Recent studies evaluating clinical features and health status in NDM patients have provided more detailed insights into the significant morbidity associated with these diseases. Ultrasound has been successfully used to demonstrate muscle abnormalities in NDM patients and magnetic resonance spectroscopy studies applied to HypoPP patients suggest that this technique can demonstrate both disease-related and treatment-related changes. SUMMARY: Recent discoveries in the skeletal muscle channelopathies have increased our understanding of the genetics and pathophysiology of these diseases. Studies reporting imaging techniques raise the possibility of improved disease monitoring and better outcome measures for clinical trials. Randomized controlled trials to establish an evidence base upon which to recommend standard treatments are required.
Asunto(s)
Canalopatías , Músculo Esquelético , Miotonía , Parálisis Periódicas Familiares , Canalopatías/genética , Canalopatías/patología , Canalopatías/fisiopatología , Diagnóstico Diferencial , Humanos , Canales Iónicos/genética , Canales Iónicos/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Mutación , Miotonía/genética , Miotonía/patología , Miotonía/fisiopatología , Parálisis Periódicas Familiares/genética , Parálisis Periódicas Familiares/patología , Parálisis Periódicas Familiares/fisiopatologíaRESUMEN
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.
Asunto(s)
Anestésicos/efectos adversos , Canalopatías/fisiopatología , Músculo Esquelético/fisiopatología , Complicaciones del Embarazo/fisiopatología , Femenino , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Miotonía/fisiopatología , Embarazo , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations. METHODS: Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed. RESULTS: Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. RYR1 analysis confirmed likely pathogenic variants in all 3 cases. CONCLUSIONS: RYR1 mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.
Asunto(s)
Mutación/genética , Mialgia/genética , Parálisis Periódicas Familiares/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Electromiografía , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/fisiopatología , Mialgia/diagnóstico por imagen , Mialgia/fisiopatología , Parálisis Periódicas Familiares/diagnóstico por imagen , Parálisis Periódicas Familiares/fisiopatología , FenotipoRESUMEN
Non-dystrophic myotonias (NDM) are characterised by muscle stiffness during voluntary movement owing to delayed skeletal muscle relaxation caused by mutations in the chloride (CLCN1) and sodium (SCN4A) skeletal muscle channel genes. Late onset acid maltase deficiency (AMD) is characterised by progressive respiratory and proximal muscle weakness; electrical but not clinical myotonia can be observed. Case report of a unique patient with concurrent NDM and AMD. We describe the clinical presentation and management of a patient with two rare neuromuscular disorders. This case illustrates the importance of reopening the differential diagnosis in patients who do not conform to the typical natural history of a specific disease.
Asunto(s)
Canales de Cloruro/genética , ADN/genética , Predisposición Genética a la Enfermedad , Músculo Esquelético/metabolismo , Mutación , Miotonía Congénita/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Adulto , Biopsia , Canales de Cloruro/metabolismo , Análisis Mutacional de ADN , Genotipo , Humanos , Masculino , Contracción Muscular/fisiología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Miotonía Congénita/patología , Miotonía Congénita/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.4/metabolismoRESUMEN
We assessed the presence, frequency and pattern of MRI abnormalities in non-dystrophic myotonia patients. We reviewed T1-weighted and STIR (short-tau-inversion-recovery) 3T MRI sequences of lower limb muscles at thigh and calf level in 21 patients with genetically confirmed non-dystrophic myotonia: 11 with CLCN1 mutations and 10 with SCN4A mutations, and 19 healthy volunteers. The MRI examinations of all patients showed hyperintensity within muscles on either T1-weighted or STIR images. Mild extensive or marked T1-weighted changes were noted in 10/21 patients and no volunteers. Muscles in the thigh were equally likely to be affected but in the calf there was sparing of tibialis posterior. Oedema was common in calf musculature especially in the medial gastrocnemius with STIR hyperintensity observed in 18/21 patients. In 10/11 CLCN1 patients this included a previously unreported "central stripe", also present in 3/10 SCN4A patients but no volunteers. Degree of fatty infiltration correlated with age (rho=0.46, p<0.05). Muscle MRI is frequently abnormal in non-dystrophic myotonia providing evidence of fatty infiltration and/or oedema. The pattern is distinct from other myotonic disorders; in particular the "central stripe" has not been reported in other conditions. Correlations with clinical parameters suggest a potential role for MRI as a biomarker.
Asunto(s)
Músculo Esquelético/patología , Trastornos Miotónicos/genética , Trastornos Miotónicos/patología , Adulto , Anciano , Canales de Cloruro/genética , Femenino , Humanos , Imagenología Tridimensional , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Adulto JovenRESUMEN
OBJECTIVES: To obtain minimum point prevalence rates for the skeletal muscle channelopathies and to evaluate the frequency distribution of mutations associated with these disorders. METHODS: Analysis of demographic, clinical, electrophysiologic, and genetic data of all patients assessed at our national specialist channelopathy service. Only patients living in the United Kingdom with a genetically defined diagnosis of nondystrophic myotonia or periodic paralysis were eligible for the study. Prevalence rates were estimated for England, December 2011. RESULTS: A total of 665 patients fulfilled the inclusion criteria, of which 593 were living in England, giving a minimum point prevalence of 1.12/100,000 (95% confidence interval [CI] 1.03-1.21). Disease-specific prevalence figures were as follows: myotonia congenita 0.52/100,000 (95% CI 0.46-0.59), paramyotonia congenita 0.17/100,000 (95% CI 0.13-0.20), sodium channel myotonias 0.06/100,000 (95% CI 0.04-0.08), hyperkalemic periodic paralysis 0.17/100,000 (95% CI 0.13-0.20), hypokalemic periodic paralysis 0.13/100,000 (95% CI 0.10-0.17), and Andersen-Tawil syndrome (ATS) 0.08/100,000 (95% CI 0.05-0.10). In the whole sample (665 patients), 15 out of 104 different CLCN1 mutations accounted for 60% of all patients with myotonia congenita, 11 out of 22 SCN4A mutations for 86% of paramyotonia congenita/sodium channel myotonia pedigrees, and 3 out of 17 KCNJ2 mutations for 42% of ATS pedigrees. CONCLUSION: We describe for the first time the overall prevalence of genetically defined skeletal muscle channelopathies in England. Despite the large variety of mutations observed in patients with nondystrophic myotonia and ATS, a limited number accounted for a large proportion of cases.