RESUMO
OBJECTIVE: Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder. METHOD: Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months. RESULTS: The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions. SIGNIFICANCE: Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation.
Assuntos
Anticonvulsivantes/uso terapêutico , Dieta Cetogênica , Epilepsia/dietoterapia , Epilepsia/tratamento farmacológico , Adulto , Epilepsia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Serina-Treonina Quinases/genética , Estudos Retrospectivos , Convulsões/prevenção & controle , Resultado do Tratamento , Adulto JovemRESUMO
Genome-wide association studies are utilized for gene discovery in common diseases. Genotypes of large groups of unrelated patients are compared to controls. This has become feasible due to the recent technical advances in genomics and convincing positive results are now regularly being published. This review is an accessible introduction to the genetic and technical knowledge needed to interpret such studies. Genome-wide association studies are being applied to many neurologic diseases. Here we use idiopathic generalized epilepsy as an example to highlight the phenotyping, sample size, and statistical issues that must be addressed in such studies. These studies are likely to transform our understanding of complex neurologic diseases in the next few years.
Assuntos
Mapeamento Cromossômico/métodos , Ensaios Clínicos como Assunto , Estudo de Associação Genômica Ampla/métodos , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , HumanosRESUMO
The oxidation of glutathione catalyzed by a combination of low concentrations of disulfides and copper and iron ions (as they occur in the blood plasma) was investigated and compared with data obtained in vivo studies. At pH 7.4 and 37 degrees C oxidation of glutathione (3 mmol/L) in a solution saturated with oxygen could be induced from 0 to 3, 5, 10, and 21 nmol/min and mL by the addition of 0.1, 1.0, 10, and 100 mumol/L CuCl2, respectively. The presence of 50 mumol/L cystinylbisglycine as an additional component increased the rate of oxidation by a factor between two and three. Cystine was only about one third as active as cystinylbisglycine, and trans-4,5-dihydroxy-1,2-dithiane, the disulfide derivative of dithiothreitol, was even less effective in propagating glutathione oxidation. FeCl2 in combination with the disulfides was 30 times less active than copper as a catalyst. With plasmalike concentrations of the reactants, a rate of glutathione oxidation of 0.2 to 0.8 nmol/min and mL, depending on the availability of free plasma copper, could be approximated. This rate corresponds to 8% to 30% of total plasma glutathione oxidation.
