RESUMEN
OBJECTIVE: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). METHODS: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. RESULTS: The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. CONCLUSIONS: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. CLASSIFICATION OF EVIDENCE: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/patología , Progresión de la Enfermedad , Carbonato de Litio/uso terapéutico , Tamizaje Masivo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Tamizaje Masivo/tendencias , Persona de Mediana Edad , Proyectos de Investigación/tendencias , Adulto JovenRESUMEN
The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.
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Trastornos Miotónicos/diagnóstico , Trastornos Miotónicos/genética , Animales , Humanos , Miotonía/diagnóstico , Miotonía/genética , Miotonía/terapia , Trastornos Miotónicos/terapiaRESUMEN
Inclusion body myositis (IBM) is the most common idiopathic inflammatory myopathy occurring in patients over the age of 50 years and probably accounts for about 30% of all inflammatory myopathies. Muscle biopsy characteristically reveals endomysial inflammation, small groups of atrophic fibres, eosinophilic cytoplasmic inclusions and muscle fibres with one or more rimmed vacuoles. However, any given biopsy may lack these histopathological abnormalities; the clinical examination is often the key to diagnosis. Early and often asymmetrical weakness and atrophy of the quadriceps and flexor forearm muscles (ie, wrist and finger flexors) are the clinical hallmarks of IBM. The pathogenesis of IBM is unknown. It may be autoimmune inflammatory myopathy or a primary degenerative myopathy with a secondary inflammatory. A prevailing theory is that there is an overproduction of beta-amyloid precursor protein in muscle fibres that is somehow cleaved into abnormal beta-amyloid, and the accumulation of the latter is somehow toxic to muscle fibres. However, there are many problems with this theory and more work needs to be done. Unfortunately, IBM is generally refractory to therapy. Further research into the pathogenesis, along with both preliminary small pilot trials and larger double blind, placebo controlled efficacy trials, are needed to make progress in our understanding and therapeutic approach for this disorder.
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Miositis por Cuerpos de Inclusión , Esclerosis Amiotrófica Lateral/diagnóstico , Diagnóstico Diferencial , Humanos , Inmunosupresores/uso terapéutico , Miositis por Cuerpos de Inclusión/diagnóstico , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Miositis por Cuerpos de Inclusión/etiología , Miositis por Cuerpos de Inclusión/patología , Polimiositis/diagnóstico , Pronóstico , ProteómicaRESUMEN
The major types of idiopathic inflammatory myopathy include dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM) and immune mediated necrotising myopathy (NM). These myositides appear clinically, histologically and pathogenically distinct. DM, PM and immune mediated NM are responsive to immunosuppressive therapy, in contrast with IBM which is generally refractory to therapy. Greater understanding of the pathogenic bases of these disorders should hopefully lead to better treatment. We need well designed, prospective, double blind, placebo controlled trials in order to determine the best therapeutic options for these different disorders.
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Miositis/patología , Miositis/terapia , Antiinflamatorios/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Miositis/etiología , Factores de RiesgoRESUMEN
To develop diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), a retrospective series of patients' records diagnosed by sexpert consensus as CIDP or other chronic polyneuropathies were analyzed. Classification and regression tree analysis was applied to 150 patients to derive a classification rule. According to the rule, diagnosis of CIDP required that a patient have a chronic non-genetic polyneuropathy, progressive for at least eight weeks, without a serum paraprotein and either 1) recordable compound muscle action potentials in > or =75% of motor nerves and either abnormal distal latency in >50% of nerves or abnormal motor conduction velocity in >50% of nerves or abnormal F wave latency in >50% of nerves; or 2) symmetrical onset of motor symptoms, symmetrical weakness of four limbs, and proximal weakness in > or =1 limb. When validated in 117 patients, the rule had 83% sensitivity (95% confidence interval 69%-93%) and 97% specificity (95% confidence interval 89%-99%) and performed better than published criteria.
Asunto(s)
Técnicas de Diagnóstico Neurológico/normas , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Humanos , Guías de Práctica Clínica como Asunto , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
We developed a disease-specific, 10-point functional rating scale for patients with inclusion body myositis (IBMFRS). The IBMFRS was utilized as a secondary outcome measure in a multicenter pilot trial of the clinical safety and tolerability of high-dose beta interferon-1a. In this trial, 28 IBM patients completed the IBMFRS at baseline and monthly for 6 months. The IBMFRS showed statistically significant correlations (P < 0.001) with maximal voluntary isometric contraction, manual muscle testing, handgrip dynamometry, and the amyotrophic lateral sclerosis (ALS) functional rating scale (ALSPRS). Compared to these other outcome measures, the IBMFRS was also the most sensitive measure of change over the course of the study.
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Evaluación de la Discapacidad , Miositis por Cuerpos de Inclusión/fisiopatología , Índice de Severidad de la Enfermedad , Actividades Cotidianas , Humanos , Proyectos Piloto , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Inclusion-body myositis (IBM) is an inflammatory muscle disease that has proven resistant to treatment. Tumor necrosis factor molecules have been detected in muscle biopsies from patients with IBM. Etanercept is a TNFalpha receptor fusion protein that binds and inactivates tumor necrosis factor. Nine patients were treated with etanercept at a dose of 25 mg, two times a week for an average of 17 +/- 6.1 months. Each patient was evaluated using quantitative strength testing. Their data were compared to two different control groups. The first control group consisted of patients who participated in trials of beta-interferon-1A and had received placebo. There was no significant difference. The second control group was a natural history cohort of IBM patients. There was no statistically significant difference between the treated group and the natural history group at 6 and 12 months when looking at elbow flexors, or 6 months when looking at hand grip. In the treated patients there was a small but significant improvement (p = 0.002) in handgrip at 12 months.
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Inmunoglobulina G/uso terapéutico , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Estudios de Cohortes , Progresión de la Enfermedad , Etanercept , Fuerza de la Mano , Humanos , Contracción Isométrica/efectos de los fármacos , Proyectos Piloto , Insuficiencia del TratamientoRESUMEN
The authors report four patients with a syndrome of painless bilateral isolated phrenic neuropathy. Electrophysiologic testing demonstrated active denervation restricted to the diaphragm. Long-term recovery was poor. The authors conclude that bilateral isolated phrenic neuropathy is a cause of painless diaphragmatic paralysis distinguishable from immune brachial plexus neuropathy and other neuromuscular disorders with similar clinical presentation.
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Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Nervio Frénico/fisiopatología , Parálisis Respiratoria/fisiopatología , Adulto , Anciano , Antiinflamatorios/uso terapéutico , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Neuropatías del Plexo Braquial/inmunología , Neuropatías del Plexo Braquial/fisiopatología , Diagnóstico Diferencial , Disnea/diagnóstico , Disnea/inmunología , Disnea/fisiopatología , Electromiografía , Femenino , Lateralidad Funcional/fisiología , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Conducción Nerviosa/inmunología , Dolor/inmunología , Dolor/fisiopatología , Enfermedades del Sistema Nervioso Periférico/inmunología , Nervio Frénico/inmunología , Nervio Frénico/patología , Prednisona/uso terapéutico , Parálisis Respiratoria/diagnóstico , Parálisis Respiratoria/inmunología , Insuficiencia del TratamientoRESUMEN
The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-inactivation appeared to explain the clinical manifestations in only one of the two families.
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Huesos/anomalías , Diafragma/fisiopatología , Enfermedades Musculares/complicaciones , Enfermedades Musculares/genética , Mutación/genética , Proteínas Tirosina Fosfatasas/genética , Adulto , Preescolar , Análisis Mutacional de ADN , Diafragma/patología , Femenino , Lateralidad Funcional/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Heterocigoto , Humanos , Recién Nacido , Patrón de Herencia/genética , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Debilidad Muscular/patología , Debilidad Muscular/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/fisiopatología , Linaje , Fenotipo , Proteínas Tirosina Fosfatasas no Receptoras , Inactivación del Cromosoma X/genéticaAsunto(s)
Neuropatías del Plexo Braquial/etiología , Distrofia Muscular Facioescapulohumeral/cirugía , Complicaciones Posoperatorias/etiología , Costillas/cirugía , Escápula/cirugía , Adulto , Placas Óseas , Hilos Ortopédicos , Descompresión Quirúrgica , Electromiografía , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Músculo Esquelético/patología , Rango del Movimiento Articular , Síndrome del Desfiladero Torácico/diagnóstico , Síndrome del Desfiladero Torácico/etiología , Síndrome del Desfiladero Torácico/cirugíaAsunto(s)
Distrofia Muscular Facioescapulohumeral/complicaciones , Distrofia Muscular Facioescapulohumeral/diagnóstico , Miastenia Gravis/complicaciones , Miastenia Gravis/diagnóstico , Anciano , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular Facioescapulohumeral/terapia , Miastenia Gravis/terapiaRESUMEN
OBJECTIVE: To provide an evidence-based statement to guide physicians in the management of Guillain-Barré syndrome (GBS). METHODS: Literature search and derivation of evidence-based statements concerning the use of immunotherapy were performed. RESULTS: Treatment with plasma exchange (PE) or IV immunoglobulin (IVIg) hastens recovery from GBS. Combining the two treatments is not beneficial. Steroid treatment given alone is not beneficial. RECOMMENDATIONS: 1) PE is recommended for nonambulant adult patients with GBS who seek treatment within 4 weeks of the onset of neuropathic symptoms. PE should also be considered for ambulant patients examined within 2 weeks of the onset of neuropathic symptoms; 2) IVIg is recommended for nonambulant adult patients with GBS within 2 or possibly 4 weeks of the onset of neuropathic symptoms. The effects of PE and IVIg are equivalent; 3) Corticosteroids are not recommended for the management of GBS; 4) Sequential treatment with PE followed by IVIg, or immunoabsorption followed by IVIg is not recommended for patients with GBS; and 5) PE and IVIg are treatment options for children with severe GBS.
Asunto(s)
Síndrome de Guillain-Barré/terapia , Inmunoterapia , Corticoesteroides/uso terapéutico , Adulto , Niño , Medicina Basada en la Evidencia , Predicción , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Técnicas de Inmunoadsorción , Intercambio Plasmático , Resultado del TratamientoRESUMEN
BACKGROUND: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial. METHODS: A placebo-controlled ALS clinical trial included a natural history phase, followed by a 6-month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared. RESULTS: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores. CONCLUSIONS: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.
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Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Factores de Crecimiento Nervioso/uso terapéutico , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Esclerosis Amiotrófica Lateral/fisiopatología , Brazo/fisiopatología , Método Doble Ciego , Estudios de Seguimiento , Humanos , Pierna/fisiopatología , Contracción Muscular , Músculo Esquelético/fisiopatología , Examen Físico/métodos , Control de Calidad , Ensayos Clínicos Controlados Aleatorios como Asunto/tendencias , Proyectos de Investigación , Músculos Respiratorios/fisiopatología , Estadística como Asunto , Resultado del Tratamiento , Capacidad VitalRESUMEN
BACKGROUND: Conduction block is considered an essential finding for the distinction between motor neuropathies and lower motor neuron disorders. Only a small number of reports describe patients with multifocal motor neuropathies who lack overt conduction block, although in these cases other features of demyelination still suggest the presence of a demyelinating disorder. In contrast, a purely axonal multifocal motor neuropathy has not been described. METHODS: This report describes nine patients with slowly or nonprogressive multifocal motor neuropathies who had purely axonal electrodiagnostic features. RESULTS: GM1 antibodies titers were normal in all nine cases. Six patients were treated with either prednisone or IV immunoglobulin and three showed convincing improvement. CONCLUSIONS: These findings suggest an immune-mediated motor neuropathy with axonal electrophysiologic features that appears to be distinct from both multifocal motor neuropathy and established motor neuron disorders.
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Axones/patología , Enfermedades Desmielinizantes/diagnóstico , Conducción Nerviosa , Polineuropatías/diagnóstico , Adolescente , Adulto , Anciano , Antiinflamatorios/uso terapéutico , Electromiografía , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Polineuropatías/tratamiento farmacológico , Polineuropatías/fisiopatología , Prednisona/uso terapéuticoRESUMEN
Although most muscle disorders produce proximal weakness, some myopathies may manifest predominantly or exclusively distal weakness. Although several congenital, inflammatory, or metabolic myopathies may produce mainly distal weakness, there are several distinct entities, typically referred to as distal myopathies. Most of these are inherited conditions. The distal myopathies are rare, but characteristic clinical and histological features aid in their identification. Advances in molecular genetics have led to the identification of the gene lesions responsible for several of these entities and have also expanded our understanding of the genetic relationships of distal myopathies to other inherited disorders of muscle. This review summarizes current knowledge of the clinical and molecular aspects of the distal myopathies.
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Distrofias Musculares/diagnóstico , Distrofias Musculares/genética , Adulto , Niño , Desmina/genética , Humanos , Distrofias Musculares/clasificaciónRESUMEN
There is still no consensus as to which physiologic marker should be used as a trigger for the initiation of non-invasive positive pressure ventilation (NPPV) in patients with amyotrophic lateral sclerosis (ALS). Current practice parameters recommend that the decision to begin treatment be based upon forced vital capacity (FVC) measurements. A prospective, randomized study was performed in 20 ALS patients who had an FVC of 70-100%. Patients received baseline assessments including: ALS functional rating scale-respiratory version (ALSFRS-R), pulmonary symptom scale, Short form 36 (SF-36), FVC%, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and nocturnal oximetry. Patients were randomized to receive NPPV based upon nocturnal oximetry studies suggesting oxygen desaturation <90% for one cumulative minute ("early intervention") or a FVC <50% ("standard of care"). At enrollment, there was no significant correlation between FVC% and the ALSFRS-R, symptom score, MEP, MIP, or duration of nocturnal desaturation <90%. An increase in the vitality subscale of the SF-36 was demonstrated in 5/6 patients randomized to "early intervention" with NPPV. Our data indicate that FVC% correlates poorly with respiratory symptoms and suggests that MIP and nocturnal oximetry may be more sensitive measures of early respiratory insufficiency. In addition, intervention with NPPV earlier than our current standard of care may result in improved quality of life.
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Hipoventilación/diagnóstico , Hipoventilación/fisiopatología , Enfermedad de la Neurona Motora/fisiopatología , Pruebas de Función Respiratoria , Progresión de la Enfermedad , Humanos , Hipoventilación/etiología , Enfermedad de la Neurona Motora/complicaciones , Enfermedad de la Neurona Motora/terapia , Oximetría , Respiración con Presión Positiva , Valor Predictivo de las Pruebas , Estudios Prospectivos , Calidad de Vida , Índice de Severidad de la Enfermedad , Método Simple Ciego , Encuestas y Cuestionarios , Capacidad VitalRESUMEN
OBJECTIVE: To evaluate the efficacy of gabapentin in increasing muscle strength of patients with spinal muscular atrophy (SMA). BACKGROUND: Preclinical data in experimental models of motor neuron disease suggest a neuroprotective effect of gabapentin. METHODS: Gabapentin (1200 mg), or placebo, was administered three times daily in a randomized, double-blind trial for 12 months. The primary outcome measure was the average percent change from baseline, based on the measurement of strength in four muscles (elbow flexion and hand grip bilaterally) for each patient. Drug efficacy was examined by comparing the percent change in strength for patients on drug vs. placebo. Secondary efficacy variables included: forced vital capacity (FVC), SMA functional rating scale (SMAFRS), and mini-Sickness Impact Profile (SIP). RESULTS: Eighty-four patients, with type II or III SMA, were enrolled at eight sites across the United States. There were no differences in baseline features. There was no difference between the placebo and drug groups in any outcome measure. CONCLUSIONS: This study demonstrates the feasibility of this trial design and provides data for the design of future clinical trials in SMA.
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Acetatos/uso terapéutico , Aminas , Ácidos Ciclohexanocarboxílicos , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Ácido gamma-Aminobutírico , Adulto , Brazo/fisiopatología , Método Doble Ciego , Estudios de Factibilidad , Femenino , Gabapentina , Fuerza de la Mano , Humanos , Masculino , Contracción Muscular/efectos de los fármacos , Índice de Severidad de la Enfermedad , Perfil de Impacto de Enfermedad , Atrofias Musculares Espinales de la Infancia/fisiopatología , Resultado del Tratamiento , Estados Unidos , Capacidad Vital/efectos de los fármacosRESUMEN
OBJECTIVE: Mutations in the skeletal muscle gene dysferlin cause two autosomal recessive forms of muscular dystrophy: Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). The purpose of this study was to define the genomic organization of the dysferlin gene and conduct mutational screening and a survey of clinical features in 21 patients with defined molecular defects in the dysferlin gene. METHODS: Genomic organization of the gene was determined by comparing the dysferlin cDNA and genomic sequence in P1-derived artificial chromosomes (PACs) containing the gene. Mutational screening entailed conformational analysis and sequencing of genomic DNA and cDNA. Clinical records of patients with defined dysferlin gene defects were reviewed retrospectively. RESULTS: The dysferlin gene encompasses 55 exons spanning over 150 kb of genomic DNA. Mutational screening revealed nine novel mutations associated with MM. The range of onset in this patient group was narrow with a mean of 19.0 +/- 3.9 years. CONCLUSION: This study confirms that the dysferlin gene is mutated in MM and LGMD2B and extends understanding of the timing of onset of the disease. Knowledge of the genomic organization of the gene will facilitate mutation detection and investigations of the molecular biologic properties of the dysferlin gene.
Asunto(s)
Proteínas de la Membrana , Proteínas Musculares/genética , Distrofias Musculares/genética , Mutación/genética , Adolescente , Adulto , Niño , Mapeo Cromosómico , Disferlina , Exones , Femenino , Genotipo , Humanos , Intrones , Masculino , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.
Asunto(s)
Arritmias Cardíacas/genética , Cromosomas Humanos Par 17 , Facies , Parálisis Periódicas Familiares/genética , Canales de Potasio de Rectificación Interna , Canales de Potasio/genética , Alelos , Secuencia de Aminoácidos , Animales , Canales de Calcio/genética , Cartilla de ADN , Salud de la Familia , Femenino , Expresión Génica , Ligamiento Genético , Genotipo , Humanos , Masculino , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.4 , Oocitos/fisiología , Técnicas de Placa-Clamp , Linaje , Fenotipo , Canales de Sodio/genética , XenopusRESUMEN
Diabetic radiculoplexopathy is commonly viewed as a condition affecting the lower extremities. However, other regions may also be affected and the presence of upper extremity involvement has rarely been emphasized. Our goal was to illustrate the clinical features of arm involvement in this condition. Of 60 patients with diabetic lumbosacral radiculoplexopathy, we identified 9 who also had upper extremity involvement. The study included 8 men and 1 woman, ranging in age from 36 to 71 years. Upper limb involvement developed simultaneously with the onset of lower limb disorder in 1 patient, preceded it by 2 months in another patient, and occurred between 3 weeks and 15 months later in the remaining 7. In 5 cases, arm involvement developed after symptoms in the legs began to improve. The upper extremity weakness affected the hands and forearms most severely. It was unilateral in 5 patients and bilateral but asymmetric in 4. Pain was often present, but it was not a prominent feature. In most patients, neurologic deficits in the arms improved spontaneously after 2-9 months. We conclude that diabetic radiculoplexopathy may involve the cervical region before, after, or simultaneously with the lumbosacral syndrome. The upper limb process is similar to that in the legs, with subacutely progressive weakness and pain followed by spontaneous recovery.