RESUMEN
INTRODUCTION: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. METHODS: Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. RESULTS: In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. DISCUSSION: Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.
Asunto(s)
Miotonía Congénita/complicaciones , Miotonía Congénita/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Potenciales de Acción , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Disnea/etiología , Ejercicio Físico/fisiología , Femenino , Flecainida/uso terapéutico , Heterocigoto , Humanos , Hipertrofia , Lactante , Recién Nacido , Laringismo/etiología , Masculino , Persona de Mediana Edad , Debilidad Muscular/etiología , Mutación , Miotonía Congénita/tratamiento farmacológico , Miotonía Congénita/fisiopatología , Canal de Sodio Activado por Voltaje NAV1.4/fisiología , Fenotipo , Ruidos Respiratorios/etiología , Enfermedades Respiratorias/etiología , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Adulto JovenRESUMEN
Myotonic dystrophy type 1 (DM1) is one of the most variable inherited human disorders. It is characterized by the involvement of multiple tissues and is caused by the expansion of a highly unstable CTG repeat. Variation in disease severity is partially accounted for by the number of CTG repeats inherited. However, the basis of the variable tissue-specific symptoms is unknown. We have determined that an unusual Dutch family co-segregating DM1, Charcot-Marie-Tooth neuropathy, encephalopathic attacks and early hearing loss, carries a complex variant repeat at the DM1 locus. The mutation comprises an expanded CTG tract at the 5'-end and a complex array of CTG repeats interspersed with multiple GGC and CCG repeats at the 3'-end. The complex variant repeat tract at the 3'-end of the array is relatively stable in both blood DNA and the maternal germ line, although the 5'-CTG tract remains genetically unstable and prone to expansion. Surprisingly though, even the pure 5'-CTG tract is more stable in blood DNA and the maternal germ line than archetypal DM1 alleles of a similar size. Complex variant repeats were also identified at the 3'-end of the CTG array of approximately 3-4% of unrelated DM1 patients. The observed polarity and the stabilizing effect of the variant repeats implicate a cis-acting modifier of mutational dynamics in the 3'-flanking DNA. The presence of such variant repeats very likely contributes toward the unusual symptoms in the Dutch family and additional symptomatic variation in DM1 via affects on both RNA toxicity and somatic instability.
Asunto(s)
Mutación , Distrofia Miotónica/genética , Expansión de Repetición de Trinucleótido , Repeticiones de Trinucleótidos , Alelos , Femenino , Humanos , Masculino , LinajeRESUMEN
The primary autoantigen in myasthenia gravis, the acetylcholine receptor (AChR), is clustered and anchored in the postsynaptic membrane of the neuromuscular junction by rapsyn. Previously, we found that overexpression of rapsyn by cDNA transfection protects AChRs in rat muscles from antibody-mediated loss in passive transfer experimental autoimmune myasthenia gravis (EAMG). Here, we determined whether rapsyn overexpression can reduce or even reverse AChR loss in muscles that are already damaged by chronic EAMG, which mimics the human disease. Active immunization against purified AChR was performed in female Lewis rats. Rapsyn overexpression resulted in an increase in total muscle membrane AChR levels, with some AChR at neuromuscular junctions but much of it in extrasynaptic membrane regions. At the ultrastructural level, most endplates in rapsyn-treated chronic EAMG muscles showed increased damage to the postsynaptic membrane. Although rapsyn overexpression stabilized AChRs in intact or mildly damaged endplates, the rapsyn-induced increase of membrane AChR enhanced autoantibody binding and membrane damage in severe ongoing disease. Thus, these results show the complexity of synaptic stabilization of AChR during the autoantibody attack. They also indicate that the expression of receptor-associated proteins may determine the severity of autoimmune diseases caused by anti-receptor antibodies.
Asunto(s)
Expresión Génica , Placa Motora/metabolismo , Proteínas Musculares/biosíntesis , Miastenia Gravis Autoinmune Experimental/metabolismo , Receptores Colinérgicos/metabolismo , Membranas Sinápticas/metabolismo , Animales , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Enfermedad Crónica , Femenino , Humanos , Placa Motora/genética , Placa Motora/inmunología , Placa Motora/ultraestructura , Proteínas Musculares/genética , Proteínas Musculares/inmunología , Miastenia Gravis Autoinmune Experimental/genética , Miastenia Gravis Autoinmune Experimental/inmunología , Miastenia Gravis Autoinmune Experimental/patología , Ratas , Ratas Endogámicas Lew , Receptores Colinérgicos/inmunología , Membranas Sinápticas/inmunologíaRESUMEN
Myasthenia gravis is usually caused by autoantibodies to the acetylcholine receptor (AChR). The AChR is clustered and anchored in the postsynaptic membrane of the neuromuscular junction (NMJ) by a cytoplasmic protein called rapsyn. We previously showed that resistance to experimental autoimmune myasthenia gravis (EAMG) in aged rats correlates with increased rapsyn concentration at the NMJ. It is possible, therefore, that endogenous rapsyn expression may be an important determinant of AChR loss and neuromuscular transmission failure in the human disease, and that upregulation of rapsyn expression could be used therapeutically. To examine first a potential therapeutic application of rapsyn upregulation, we induced acute EAMG in young rats by passive transfer of AChR antibody, mAb 35, and used in vivo electroporation to over-express rapsyn unilaterally in one tibialis anterior. We looked at the compound muscle action potentials (CMAPs) in the tibialis anterior, at rapsyn and AChR expression by quantitative radioimmunoassay and immunofluorescence, and at the morphology of the NMJs, comparing the electroporated and untreated muscles, as well as the control and EAMG rats. In control rats, transfected muscle fibres had extrasynaptic rapsyn aggregates, as well as slightly increased rapsyn and AChR concentrations at the NMJ. In EAMG rats, despite deposits of the membrane attack complex, the rapsyn-overexpressing muscles showed no decrement in the CMAPs, no loss of AChR, and the majority had normal postsynaptic folds, whereas endplates of untreated muscles showed typical AChR loss and morphological damage. These data suggest not only that increasing rapsyn expression could be a potential treatment for selected muscles of myasthenia gravis patients, but also lend support to the hypothesis that individual differences in innate rapsyn expression could be a factor in determining disease severity.
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Proteínas Musculares/genética , Miastenia Gravis Autoinmune Experimental/genética , Receptores Colinérgicos/genética , Regulación hacia Arriba/genética , Potenciales de Acción/fisiología , Enfermedad Aguda , Animales , Electromiografía/métodos , Femenino , Técnica del Anticuerpo Fluorescente/métodos , Inmunohistoquímica/métodos , Microscopía Confocal/métodos , Microscopía Electrónica/métodos , Proteínas Musculares/análisis , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Miastenia Gravis Autoinmune Experimental/patología , Miastenia Gravis Autoinmune Experimental/fisiopatología , Unión Neuromuscular/genética , Unión Neuromuscular/patología , Unión Neuromuscular/fisiopatología , Radioinmunoensayo/métodos , Ratas , Ratas Endogámicas Lew , Transmisión Sináptica/genética , Transmisión Sináptica/fisiologíaRESUMEN
In nine patients with Guillain-Barré syndrome (GBS), stimulation single-fiber electromyography (SFEMG) and serological studies were performed in the acute stage of the illness. Increased jitter and intermittent blocking of muscle fiber action potentials occurred to a varying degree in all patients. Five patients had elevated titers of antiganglioside antibodies. The most remarkable EMG phenomenon was the occurrence in all patients of impulse blocking at normal or slightly increased jitter. The assumption that this phenomenon was due to an axolemmal dysfunction was confirmed by the occurrence in two patients of concomitant blocking of two muscle fiber action potentials at strictly normal jitter values. In one patient this sign of axonal dysfunction was demonstrated with SFEMG at voluntary activation. In another patient, concomitant blocking was associated with greatly increased but completely independent jitter of both components. The results of this study show that both a disorder of neuromuscular transmission and an axolemmal dysfunction play a role in the pathophysiology of GBS.
Asunto(s)
Axones/fisiología , Membrana Celular/fisiología , Síndrome de Guillain-Barré/fisiopatología , Placa Motora/fisiopatología , Potenciales de Acción/fisiología , Adolescente , Adulto , Anciano , Estimulación Eléctrica , Electromiografía , Femenino , Antebrazo/fisiopatología , Síndrome de Guillain-Barré/inmunología , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiología , Músculo Esquelético/inmunología , Músculo Esquelético/fisiopatología , Conducción Nerviosa/fisiología , Unión Neuromuscular/fisiopatologíaRESUMEN
OBJECTIVE: To test the hypothesis that footrests contribute to active control of sitting balance. DESIGN: Cross-sectional group study. SETTING: Rehabilitation center. PARTICIPANTS: Ten persons with complete low thoracic (T9-12) spinal cord injury (SCI), 10 persons with complete lumbar (L1-5) SCI, and 10 matched able-bodied controls. INTERVENTION: An elastically suspended footrest. MAIN OUTCOME MEASURES: Reaching distance, time needed to perform a bimanual forward-reaching movement, center of pressure displacement, and muscle activity. RESULTS: Controls performed the forward-reaching movement slower and with less forward acceleration of the center of mass (COM) in the chair with the elastic footrest. Furthermore, they revealed a typical change in muscle activity patterns when the solid footrest was replaced by the elastic one. Persons with SCI performed the forward-reaching movement equally fast in both footrest conditions, but those with lumbar SCI showed less forward acceleration of the COM, whereas persons with thoracic SCI revealed more forward acceleration of the COM in the chair with the elastic footrest. Muscle activity patterns in persons with SCI did not indicate alternative muscle use through possible compensations or reflex activity. CONCLUSIONS: Regarding wheelchair design, footrest condition does not seem to affect the range in which manual activities of daily living can be performed, but it does affect how they are performed.
Asunto(s)
Pie/fisiopatología , Paraplejía/fisiopatología , Paraplejía/rehabilitación , Equilibrio Postural/fisiología , Postura/fisiología , Silla de Ruedas , Adulto , Estudios Transversales , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatologíaRESUMEN
OBJECTIVES: To determine (1) whether use of an ankle-foot orthosis (AFO) by patients with ankle dorsiflexor paresis leads to decreased muscle activity, immediately or 6 weeks after AFO use, and (2) whether this decrease (if present) differs between healthy and paretic subjects. DESIGN: Cross-sectional and longitudinal randomized case-control study. SETTING: Rehabilitation research center in the Netherlands. PARTICIPANTS: Fourteen healthy persons and 29 patients with foot drop. INTERVENTIONS: Muscle activity was measured by surface electromyography. Electromyographic reproducibility was tested in 14 healthy volunteers walking with and without AFO. Acute changes in muscle activity from AFO use were compared between the 14 healthy persons and the 29 patients with foot drop. Adaptation effects of AFO use after 6 weeks were studied in 29 patients, randomly chosen 16 of whom had started using an AFO at the first measurement. MAIN OUTCOME MEASURES: Amount of change in mean rectified electromyographic activity (delta value) between walking with and without AFO. Follow-up measurements were conducted after 3 and 6 weeks. RESULTS: Correlation coefficients, reflecting within-subject reproducibility, varied between.68 and.96 (mean,.86). In patients and healthy subjects, tibialis anterior muscle activity decreased by 7% and 20% (P = .01, P = .04), respectively, when using an AFO. In patients, this decrease was measured in the overall activity during the gait cycle; in healthy subjects, it was measured in the first 15% of the gait cycle. Overall electromyographic activity did not change during 6 weeks; delta values per muscle did not change during follow-up in the AFO group. CONCLUSION: AFO use immediately reduced muscle activity of the ankle dorsiflexors. However, using an AFO for 6 weeks did not lead to a generally lower electromyographic activity level nor did the amount of activity reduction accumulate in comparison with patients who did not use an AFO. It is, therefore, safe to use an AFO, even with recently paretic patients.