RESUMO
Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.
Assuntos
Epilepsias Parciais/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Canais de Potássio Ativados por Sódio , Morte Súbita do Lactente/genéticaRESUMO
The objective of this study was to identify developmental trajectories of developmental/behavioral phenotypes and possibly their relationship to epilepsy and genotype by analyzing developmental and behavioral features collected prospectively and longitudinally in a cohort of patients with Dravet syndrome (DS). Thirty-four patients from seven Italian tertiary pediatric neurology centers were enrolled in the study. All patients were examined for the SCN1A gene mutation and prospectively assessed from the first years of life with repeated full clinical observations including neurological and developmental examinations. Subjects were found to follow three neurodevelopmental trajectories. In the first group (16 patients), an initial and usually mild decline was observed between the second and the third year of life, specifically concerning visuomotor abilities, later progressing towards global involvement of all abilities. The second group (12 patients) showed an earlier onset of global developmental impairment, progressing towards a generally worse outcome. The third group of only two patients ended up with a normal neurodevelopmental quotient, but with behavioral and linguistic problems. The remaining four patients were not classifiable due to a lack of critical assessments just before developmental decline. The neurodevelopmental trajectories described in this study suggest a differential contribution of neurobiological and genetic factors. The profile of the first group, which included the largest fraction of patients, suggests that in the initial phase of the disease, visuomotor defects might play a major role in determining developmental decline. Early diagnosis of milder cases with initial visuomotor impairment may therefore provide new tools for a more accurate habilitation strategy.
Assuntos
Progressão da Doença , Epilepsias Mioclônicas/complicações , Transtornos do Neurodesenvolvimento/genética , Criança , Pré-Escolar , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Estudos ProspectivosAssuntos
Diabetes Mellitus Tipo 1/epidemiologia , Adolescente , Adulto , Idade de Início , Anticorpos/análise , Anticonvulsivantes/uso terapêutico , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Criança , Pré-Escolar , Comorbidade , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/epidemiologia , Epilepsia Generalizada/imunologia , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: Total sleep time and slow-wave sleep (SWS) are frequently reported to be reduced in anorectics. A preliminary study showed that slow-wave activity (SWA, 0.5-4.5 Hz) is decreased in anorectic adolescents. The present study investigates whether this reduction is the result of the increased sleep fragmentation or is dependent on an intrinsic weakness of SWA-producing mechanisms. DESIGN: Statistical analysis of spectral electroencephalogram data recorded during sleep from a group of anorectics and a control group. SETTING: Polysomnographic data were recorded in single rooms in the hospital for 1 night following an adaptation night. PARTICIPANTS: 20 adolescent anorectic girls (13.9 +/- 2.0 years) and 12 age-matched control subjects. INTERVENTIONS: Refeeding and psychotherapy. MEASUREMENTS AND RESULTS: Anorectics had an increase of wakefulness after sleep onset, a higher number of arousals, and a reduction of SWS and SWA during total sleep time. No relationship between the reduction of SWA and duration of illness was found, while a relationship between SWA decrease and the level of emaciation (body mass index) was present. The analysis limited to the first non-rapid eye movement sleep cycle did not show any difference between the 2 groups in the number of awakenings and arousals. Nevertheless, anorectics showed a reduction of SWS and SWA. CONCLUSIONS: Sleep of anorectic patients seems to be characterized by an impairment of SWA-producing mechanisms independent of the increased sleep fragmentation. This is probably related to the primary pathophysiologic characteristics of the illness but could also reflect secondary functional and anatomic alterations of the brain.