RESUMO
OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.
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Epilepsia Generalizada , Epilepsia Reflexa , Mioclonia , Humanos , Sequenciamento do Exoma , Helicase IFIH1 Induzida por Interferon/genética , Epilepsia Reflexa/genética , Eletroencefalografia , Pálpebras , Proteínas de Transporte/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
The ring 14 syndrome is a rare condition caused by the rearrangement of one chromosome 14 into a ring-like structure. The formation of the ring requires two breakpoints and loss of material from the short and long arms of the chromosome. Like many other chromosome syndromes, it is characterized by multiple congenital anomalies and developmental delays. Typical of the condition are retinal anomalies and drug-resistant epilepsy. These latter manifestations are not found in individuals who are carriers of comparable 14q deletions without formation of a ring (linear deletions). To find an explanation for this apparent discrepancy and gain insight into the mechanisms leading to seizures, we reviewed and compared literature cases of both ring and linear deletion syndrome with respect to both their clinical manifestations and the role and function of potentially epileptogenic genes. Knowledge of the epilepsy-related genes in chromosome 14 is an important premise for the search of new and effective drugs to combat seizures. Current clinical and molecular evidence is not sufficient to explain the known discrepancies between ring and linear deletions.
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Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Anormalidades Craniofaciais/genética , Epilepsia/genética , Anormalidades do Olho/genética , Deficiência Intelectual/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/complicações , Dineínas do Citoplasma/genética , RNA Helicases DEAD-box/genética , Proteínas de Ligação a DNA/genética , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/genética , Epilepsia/complicações , Anormalidades do Olho/complicações , Fatores de Transcrição Forkhead/genética , Humanos , Deficiência Intelectual/complicações , Microcefalia/complicações , Microcefalia/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fatores de Transcrição Otx/genética , Fenótipo , Presenilina-1/genética , Retina/anormalidades , Ribonuclease III/genética , Cromossomos em Anel , Fatores de Transcrição/genética , Proteínas de Transporte Vesicular/genéticaRESUMO
We report on a patient with terminal deletion of the long arm of chromosome 14 displaying brain interhemispheric fusion limited to the midline anterior frontal cortex associated with hypoplastic corpus callosum and incomplete rotation of the left hippocampus in a clinical setting of motor and intellectual disability with poor language, and social behavior abnormalities with aggressiveness. Some possible correlations between clinical signs and symptoms and various aspects of the complex brain malformation are briefly discussed and compared with other known abnormalities of chromosome 14. The different neuropathology of the most common forms and the new forms of holoprosencephaly recently described is also discussed and leads us to suggest classifying the interhemispheric fusion of this case as a "minimal" form of holoprosencephaly. This appears to be the first description in a 14q deletion patient.
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Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Holoprosencefalia/genética , Encéfalo/diagnóstico por imagem , Lobo Frontal/diagnóstico por imagem , Holoprosencefalia/classificação , Holoprosencefalia/diagnóstico por imagem , Humanos , Masculino , Neuroimagem , Adulto JovemRESUMO
OBJECTIVES: To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity. METHODS: Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography-functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level-dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)-specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables. RESULTS: The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex. SIGNIFICANCE: Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways.
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Mapeamento Encefálico , Ondas Encefálicas/fisiologia , Epilepsias Parciais/patologia , Córtex Visual/fisiopatologia , Vias Visuais/fisiologia , Adolescente , Criança , Eletroencefalografia , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Oxigênio/sangue , Estatística como Assunto , Córtex Visual/diagnóstico por imagemRESUMO
PURPOSE: Increased evidence of subnormal neuropsychological functioning in new-onset childhood epilepsy has been obtained, although results are still rare and controversial. With a prospective study, we aimed to define the very early neuropsychological profile of children with benign epilepsy with centrotemporal spikes (BECTS), including executive functions (EF) because of their key role in learning. Additionally, we enrolled drug-naïve children, with a NREM sleep frequency of discharges <85% and with a Performance Intelligence Quotient equal or superior to 85, in order to exclude additional effects on the neuropsychological functioning. METHODS: Fifteen school-aged children with BECTS (mean age: 8.8years, standard deviation [SD]: 2.4years) and fifteen healthy children (mean age: 9.2years, [SD]: 2.5years) were enrolled and assessed with a comprehensive neuropsychological battery. The assessment included domain-specific standardized tests of language, EF, academic skills, visuomotor and visuospatial skills, and short-term memory. A p-value<0.05 was considered significant. RESULTS: Significant differences between patients and controls emerged with respect to 3 domains. Language was affected in color naming (p=.026), spoonerism (p=.003), and phonemic synthesis (p=.009). Executive functions appeared inadequate in the five point test with respect to the number of correct figures (p=.003) and errors (p=.008). In the domain of academic skills, significant differences between groups emerged regarding the number of mistakes in nonword writing (p=.001), nonword reading speed (p=.027), nonword reading number of mistakes (p=.019), and word reading errors (p=.023). DISCUSSION: Results showed that children with new-onset BECTS may demonstrate a range of neuropsychological dysfunctions, particularly affecting executive attention, despite a normal IQ, a low frequency of NREM sleep discharges, and the absence of drugs. These difficulties indicate a frontal dysfunction with cascading effects on language and academic skills. The inclusion of EF in the assessment battery and in the intervention since the very onset is warranted in order to avoid further and persistent academic difficulties.
Assuntos
Epilepsia Rolândica/diagnóstico , Epilepsia Rolândica/psicologia , Função Executiva/fisiologia , Testes Neuropsicológicos , Adolescente , Atenção/fisiologia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsia Rolândica/fisiopatologia , Feminino , Humanos , Aprendizagem/fisiologia , Masculino , Memória de Curto Prazo/fisiologia , Estudos Prospectivos , LeituraRESUMO
OBJECTIVE: The mismatch negativity (MMN) is an objective measure of central auditory discrimination. MMN alterations have been shown in children with language and/or developmental disorders. In benign focal epilepsies, neuropsychological disorders are often reported and linked to interictal epileptic discharges (IEDs) during non-rapid eye movement (NREM) sleep. There are few studies reporting MMN in children with benign epilepsy with centrotemporal spikes (BECTS) and sleep IEDs. Moreover, no MMN recording has yet been reported in atypical BECTS children with continuous spike-and-wave during sleep (CSWS). We retrospectively compared MMN in typical and atypical BECTS children, particularly addressing the impact of NREM sleep IEDs on auditory discrimination. Moreover, we attempted a neuropsychological characterization of patients. METHODS: The MMN was recorded in 9 normal controls and 23 patients (14 typical BECTS and 9 atypical BECTS) in an oddball paradigm with syllable stimuli. MMN, sleep electroencephalography (EEG) and neuropsychological evaluation were realized in the same testing session. RESULTS: Measurable MMN responses to speech stimuli were identified in both the control and patient groups. A significant difference between control and atypical BECTS children was found with respect to amplitude (p = 0.0061). Atypical BECTS also showed a lower MMN amplitude with respect to typical BECTS, but this difference did not reach statistical significance (p = 0.0545). Statistical comparisons between groups revealed no differences in latency. Among the neuropsychological variables, academic difficulties were significantly more prominent in the patients with atypical BECTS (p = 0.04). SIGNIFICANCE: CSWS EEG pattern affects auditory discrimination and may have a long-lasting impact on academic skills acquisition, whereas in typical BECTS children with a lower degree of IED NREM sleep, plastic brain reorganization or the preservation of participating networks may prevent such difficulty. Early electrophysiologic identification of auditory discrimination deficits in epileptic children could be used in early rehabilitation, thereby reducing the risk of developing neuropsychological disorders.
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Córtex Cerebral/fisiopatologia , Variação Contingente Negativa/fisiologia , Epilepsia Rolândica/patologia , Epilepsia Rolândica/fisiopatologia , Potenciais Evocados Auditivos/fisiologia , Fases do Sono/fisiologia , Estimulação Acústica , Adolescente , Criança , Cognição/fisiologia , Eletroencefalografia , Epilepsia Rolândica/classificação , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Estudos RetrospectivosRESUMO
OBJECTIVE: To present the clinical features and the results of laboratory investigations in three patients with spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME), a rare condition caused by mutations in the N-acylsphingosine amidohydrosilase 1 (ASAH1) gene. METHODS: The patients were submitted to clinical evaluation, neurophysiologic investigations (that included wakefulness and sleep electroencephalography [EEG], video-polygraphic recording with jerk-locked back-averaging, multimodal evoked potentials, and electromyography), brain magnetic resonance imaging (MRI), biochemical screening, muscle and skin biopsies, and molecular genetic analysis. RESULTS: The main clinical features were onset in childhood with proximal muscular weakness, generalized epilepsy with absences and myoclonic seizures, cognitive impairment of variable degree; the course was progressive with muscle wasting and uncontrolled epileptic seizures. In one patient, earlier onset before the age of 2 years was associated with a more complex clinical picture, with abnormal eye movements, progressive cognitive impairment, and a more rapid and severe course. EEG/polygraphic data were consistent with PME, demonstrating generalized spike-and-wave discharges, evidence of positive and negative myoclonia, and prominent photosensitivity. In one patient, transcranial magnetic stimulation showed a hyperexcitable motor cortex, whereas somatosensory evoked potentials were unaffected. Possible involvement of the central acoustic and visual pathways was suggested by abnormal auditory and visual evoked potentials. Muscle biopsies showed typical signs of neurogenic damage. Molecular genetic analysis showed mutations of the ASAH1 gene. SIGNIFICANCE: Our data indicate that SMA-PME associated with ASAH1 mutations is a genetically distinct condition with specific clinical and neurophysiologic features. Further studies are warranted to explore the role of the ASAH1 gene in muscle and brain function.
Assuntos
Ceramidase Ácida/genética , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/genética , Mutação/genética , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Potenciais Evocados/genética , Feminino , Humanos , Neuroimagem , Estimulação Transcraniana por Corrente ContínuaRESUMO
Benign Epilepsy with centrotemporal spikes (BECTS) is considered a benign type of epilepsy; nevertheless a significant number of children present clear and heterogeneous cognitive deficits such as memory disturbances. Thus far, evidence about memory impairment has been less than conclusive. To clarify the quality of memory functioning in BECTS children, an analysis of existing findings has been conducted trying to identify the type of memory deficits and their underlying factors. Short- and long-term declarative memory are impaired in BECTS children, with both verbal and non-verbal material; co-occurrence of attentional, linguistic and behavioral disturbances is reported. In children with continuous spikes and waves during the slow-wave sleep pattern the normal downscaling of slow-wave activity is absent, disrupting plastic brain processes of sleep-related memory consolidation. In BECTS children, NREM sleep interictal epileptiform discharges (IED) may interfere in the dialogue between temporal and frontal cortex, causing declarative memory deficits: the role of NREM sleep IED acquires a special importance, leading to methodological guidance and suggesting aims for future researches in the field of childhood neuroscience.
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Epilepsia Rolândica/fisiopatologia , Transtornos da Memória/fisiopatologia , Humanos , Sono/fisiologiaRESUMO
Frontal lobe epilepsy is a common focal epilepsy in children and is often difficult to treat. Adrenocorticotropic hormone (ACTH) or steroids have been used for patients with several forms of medically intractable epilepsy. We evaluated the short, medium, and long-term evolution of patients with frontal lobe epilepsy and secondary bilateral synchrony on the EEG, who received ACTH treatment. Patients were recruited for an add-on trial during clinical practice, and data was retrospectively analysed. The study group comprised 6 patients treated with ACTH. The effects of ACTH were assessed in the short term (at the end of a 6-week period of ACTH treatment), medium term (at 6 months after the end of treatment), and long term (at 12 months after the end of treatment). At short-term follow-up, ACTH treatment was effective for all types of seizures in 5 of 6 patients and ineffective in 1 patient. All patients who were seizure-free at the end of ACTH treatment maintained an excellent outcome, remaining seizure-free at the end of follow-up. Our study demonstrates that ACTH may represent an effective treatment for frontal lobe epilepsy with secondary bilateral synchrony. Further double-blind prospective studies are required to confirm our initial findings.
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Hormônio Adrenocorticotrópico/uso terapêutico , Epilepsia do Lobo Frontal/tratamento farmacológico , Adolescente , Idade de Início , Encéfalo/patologia , Criança , Pré-Escolar , Resistência a Medicamentos , Eletroencefalografia , Epilepsia do Lobo Frontal/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Resultado do TratamentoRESUMO
The International League Against Epilepsy (ILAE) Commission report on classification and terminology indicates that "diagnosing an individual as having an encephalopathic course requires demonstration of a failure to develop as expected relative to the same-aged peers or to regress in abilities." In this chapter, basing our discussion on the theoretical framework of neuroconstructivism, on the latest results deriving from functional neuroimaging and on the concept of system epilepsy, we use continuous spike-waves during slow-wave sleep (CSWS) as an example of how non-rapid eye movement (NREM) sleep spikes interfere with the organization and consolidation of neuropsychological networks in the sensitive phase of development, affecting also interconnected systems. Indeed, recent discoveries show that the normal overnight downscaling of slow wave activity (SWA) from the first to the last hours of sleep is absent in electrical status epilepticus during sleep (ESES) patients, thus impairing the neural process and possibly the local plastic changes associated with learning and other cognitive functions. Moreover, specific patterns of spike-induced activation (especially in perisylvian and/or prefrontal areas) and deactivation of default mode network (DMN) have been shown in patients with CSWS. Consequently, to date, we may conceive that the possible mechanisms underlying neuropsychological disorders in encephalopathic epilepsy (EE) may be double, since NREM sleep interictal epileptic discharges (IEDs) induce both a pathologic activation in epileptogenic areas and a pathologic deactivation of DMN beyond the epileptogenic zone. The growing body of literature on the effects of ESES in CSWS provides us with increasing knowledge on the complexity of brain development and a better understanding of plasticity, enlightening the pathogenesis of damage on developing neuropsychological functions. Finally, the need for an individually tailored interpretation of the neuropsychological testing results, expected to integrate neurophysiology and functional neuroimaging data, is suggested.
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Encefalopatias/terapia , Epilepsia/terapia , Neuropsicologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Encefalopatias/patologia , Encefalopatias/psicologia , Eletroencefalografia , Epilepsia/patologia , Epilepsia/psicologia , Humanos , Testes Neuropsicológicos , Sono/fisiologia , Estado Epiléptico/fisiopatologiaRESUMO
Reports of childhood epilepsies in temporal association with vaccination have had a great impact on the acceptance of vaccination programs by health care providers, but little is known about this possible temporal association and about the types of seizures following vaccinations. For these reasons the Italian League Against Epilepsy (LICE), in collaboration with other Italian scientific societies, has decided to generate Guidelines on Vaccinations and Epilepsy. The aim of Guidelines on Vaccinations and Epilepsy is to present recent unequivocal evidence from published reports on the possible relationship between vaccines and epilepsy in order to provide information about contraindications and risks of vaccinations in patients with epilepsy. The following main issues have been addressed: (1) whether contraindications to vaccinations exist in patients with febrile convulsions, epilepsy, and/or epileptic encephalopathies; and (2) whether any vaccinations can cause febrile seizures, epilepsy, and/or epileptic encephalopathies. Diphtheria-tetanus-pertussis (DTP) vaccination and measles, mumps, and rubella vaccination (MMR) increase significantly the risk of febrile seizures. Recent observations and data about the relationships between vaccination and epileptic encephalopathy show that some cases of apparent vaccine-induced encephalopathy could in fact be caused by an inherent genetic defect with no causal relationship with vaccination.
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Epilepsia/induzido quimicamente , Epilepsia/epidemiologia , Guias de Prática Clínica como Assunto/normas , Vacinação/efeitos adversos , Ensaios Clínicos como Assunto/normas , Epilepsia/diagnóstico , Humanos , Itália/epidemiologia , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversosRESUMO
PURPOSE: To characterize epileptic phenotype, electroencephalography (EEG) features, and epileptic evolution in patients with ring 14 r(14) syndrome. METHODS: Twenty-two patients with ring chromosome 14 were enrolled in the study. We examined age at onset, seizure semiology and frequency at onset and at follow-up, drug responsiveness/resistance, and interictal/ictal EEG data. The degree of severity of the epileptic phenotype negatively influences child cognitive development. KEY FINDINGS: The incidence of epilepsy in patients with r(14) syndrome is virtually 100%, characterized by early onset, polymorphic seizures, and drug-resistant seizures. In addition, we ascertained focal secondarily generalized epilepsy, seizure cluster tendency, frequent status epilepticus, and a rather typical epilepsy evolution. EEG abnormalities consisted of slow background activity with pseudoperiodic bursts of generalized slow waves in the early stage, focal frontotemporal or temporoposterior slow waves with multifocal spikes interposed, and unusual rhythmic fast recruiting posterior spikes followed by secondary generalization. The degree of severity of the epileptic phenotype negatively influences child cognitive development. SIGNIFICANCE: This study provides a more precise definition of seizure types, natural history, and drug responsiveness of r(14) syndrome, a highly epileptogenic chromosomal condition.
Assuntos
Encéfalo/fisiopatologia , Epilepsia/genética , Idade de Início , Pré-Escolar , Cromossomos Humanos Par 14/fisiologia , Eletroencefalografia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Cromossomos em AnelRESUMO
PURPOSE: To investigate whether patients with typical absence seizures (TAS) starting in the first 3 years of life, conformed to Panayiotopoulos's definition of childhood absence epilepsy (CAE), show different electroclinical course than those not fulfilling CAE criteria. METHODS: In this multicenter retrospective study, we choose a fixed duration follow-up of 36 months to examine the electroclinical course of epilepsy in all children with TAS starting before 3 years of age. The probands who fulfilled Panayiotopoulos's criteria for CAE were classified as having pure early onset absence epilepsy (P-EOAE), whereas those who did not as nonpure EOAE (NP-EOAE). In addition, these two groups of patients were further stratified according to the number of antiepileptic drugs taken to obtain initial seizure control (mono-, bi-, and tritherapy). KEY FINDINGS: Patients with P-EOAE (n = 111) showed earlier initial seizure control (p = 0.030) and better seizure-free survival curve (p = 0.004) than those with NP-EOAE (n = 77). No mutation in SLC2A1 gene or abnormal neuroimaging was observed in P-EOAE. Among patients with NP-EOAE, those receiving tritherapy showed increased risk of structural brain abnormalities (p = 0.001) or SLC2A1 mutations (p = 0.001) but fewer myoclonic features (p = 0.031) and worse seizure-free survival curve (p = 0.047) than those treated with mono- and bitherapy. Children with NP-EOAE had 2.134 the odds of having relapse during the follow-up compare to those with P-EOAE. SIGNIFICANCE: Children with early onset TAS who did meet Panayiotopoulos's criteria showed a favorable course of epilepsy, whereas patients not fulfilling Panayiotopoulos's criteria showed increased risk of relapse at long-term follow-up.
Assuntos
Epilepsia Tipo Ausência/diagnóstico , Idade de Início , Encéfalo/fisiopatologia , Pré-Escolar , Eletroencefalografia , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/fisiopatologia , Feminino , Transportador de Glucose Tipo 1/genética , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores SexuaisRESUMO
Benign epilepsy with centrotemporal spikes (BECTS) is an idiopathic focal epileptic syndrome in childhood. It is called "benign" because the seizure and cognitive outcomes are usually favorable, but a significant number of children with BECTS present heterogeneous cognitive deficits correlated to NREM sleep epileptiform discharges. The atypical evolutions of BECTS form a spectrum of conditions suggesting that slow sleep nocturnal interictal epileptiform discharges (IEDs) specifically determine the neuropsychological deficit. Few follow-up studies of neuropsychological outcome in BECTS are available, and very often, slow sleep has not been recorded throughout night sleep. The present study analyzed the long-term effects of IEDs during NREM sleep on neuropsychological development in children with rolandic spikes. Thirty-three children with a diagnosis of BECTS were monitored for at least two years. Results show that these children are at higher risk for residual verbal difficulties, and the abnormal neuropsychological development is significantly correlated with a greater frequency of NREM sleep discharges, school-age epilepsy onset, and a higher number of antiepileptic drugs (AEDs). The findings are discussed in terms of how slow sleep IEDs affect the consolidation of verbal skills during critical epochs of neuropsychological development.
Assuntos
Ondas Encefálicas/fisiologia , Transtornos Cognitivos/etiologia , Deficiências do Desenvolvimento/etiologia , Epilepsia Rolândica/complicações , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Estudos Longitudinais , Masculino , Psicometria , Índice de Gravidade de Doença , Transtornos do Sono-Vigília/etiologiaRESUMO
INTRODUCTION: Raynaud-Claes syndrome is a very rare X-linked condition, characterized by intellectual disability, impaired language development, brain abnormalities, facial dysmorphisms and drug-resistant epilepsy. It is caused by loss-of-function variants in the CLCN4 gene, which encodes the 2Cl-/Hâ¯+â¯exchanger ClC-4, prominently expressed in the hippocampus and cerebellum. Different genotypic variants have been described, each exhibiting specific phenotypic characteristics. The loss-of-function variant p.Gly544Arg in the CLCN4 gene has been described in only two male probands, but there are no reports on phenotypic characterization in females. CASE PRESENTATION: We present a 30-year-old Italian woman with early-onset drug-resistant epilepsy, developmental and epileptic encephalopathy, developmental delay, absence of verbal language development, behavioral impairment with autistic features, and clusters of seizures during catamenial periods. The interictal EEG showed slight inconstant slowing of the background rhythm, with abnormal frontal predominant mu like rhythm and generalized spike and polyspike wave discharges, which increased in frequency during drowsiness. A brain MRI showed slight cranio-encephalic asymmetry and a smaller size of the left hippocampus. The whole exome sequencing (WES) revealed a de novo heterozygous c.1630Gâ¯>â¯A variant in the CLCN4 gene, resulting in the amino acid substitution p.Gly544Arg (rs587777161), consistent with Raynaud-Claes syndrome. DISCUSSION AND CONCLUSION: Our patient is the first case of a de novo p.Gly544Arg variant of the CLCN4 gene in a female proband, confirming that female patients with Raynaud-Claes syndrome can be as severely affected as the male counterparts. Our case expands the phenotypic characterization of different genotypic CLCN4 variants, which can become crucial in the future for early diagnosis if targeted therapy becomes available.
Assuntos
Canais de Cloreto , Epilepsia Generalizada , Humanos , Feminino , Adulto , Epilepsia Generalizada/genética , Mutação de Sentido Incorreto , Canais de Cloreto/genética , Deficiências do Desenvolvimento/genética , Substituição de AminoácidosRESUMO
PURPOSE: Unverricht-Lundborg disease (EPM1A) is frequently due to an unstable expansion of a dodecamer repeat in the CSTB gene, whereas other types of mutations are rare. EPM1A due to homozygous expansion has a rather stereotyped presentation with prominent action myoclonus. We describe eight patients with five different compound heterozygous CSTB point or indel mutations in order to highlight their particular phenotypical presentations and evaluate their genotype-phenotype relationships. METHODS: We screened CSTB mutations by means of Southern blotting and the sequencing of the genomic DNA of each proband. CSTB messenger RNA (mRNA) aberrations were characterized by sequencing the complementary DNA (cDNA) of lymphoblastoid cells, and assessing the protein concentrations in the lymphoblasts. The patient evaluations included the use of a simplified myoclonus severity rating scale, multiple neurophysiologic tests, and electroencephalography (EEG)-polygraphic recordings. To highlight the particular clinical features and disease time-course in compound heterozygous patients, we compared some of their characteristics with those observed in a series of 40 patients carrying the common homozygous expansion mutation observed at the C. Besta Foundation, Milan, Italy. KEY FINDINGS: The eight compound heterozygous patients belong to six EPM1A families (out of 52; 11.5%) diagnosed at the Laboratory of Genetics of the Galliera Hospitals in Genoa, Italy. They segregated five different heterozygous point or indel mutations in association with the common dodecamer expansion. Four patients from three families had previously reported CSTB mutations (c.67-1G>C and c.168+1_18del); one had a novel nonsense mutation at the first exon (c.133C>T) leading to a premature stop codon predicting a short peptide; the other three patients from two families had a complex novel indel mutation involving the donor splice site of intron 2 (c.168+2_169+21delinsAA) and leading to an aberrant transcript with a partially retained intron. The protein dose (cystatin B/ß-actin) in our heterozygous patients was 0.24 ± 0.02, which is not different from that assessed in patients bearing the homozygous dodecamer expansion. The compound heterozygous patients had a significantly earlier disease onset (7.4 ± 1.7 years) than the homozygous patients, and their disease presentations included frequent myoclonic seizures and absences, often occurring in clusters throughout the course of the disease. The seizures were resistant to the pharmacologic treatments that usually lead to complete seizure control in homozygous patients. EEG-polygraphy allowed repeated seizures to be recorded. Action myoclonus progressively worsened and all of the heterozygous patients older than 30 years were in wheelchairs. Most of the patients showed moderate to severe cognitive impairment, and six had psychiatric symptoms. SIGNIFICANCE: EPM1A due to compound heterozygous CSTB mutations presents with variable but often markedly severe and particular phenotypes. Most of our patients presented with the electroclinical features of severe epilepsy, which is unexpected in homozygous patients, and showed frequent seizures resistant to pharmacologic treatment. The presence of variable phenotypes (even in siblings) suggests interactions with other genetic factors influencing the final disease presentation.
Assuntos
Cistatina B/genética , Mutação INDEL/genética , Fenótipo , Mutação Puntual/genética , Síndrome de Unverricht-Lundborg/genética , Estimulação Acústica , Adolescente , Adulto , Cistatina B/metabolismo , Análise Mutacional de DNA , Eletrodiagnóstico , Eletroencefalografia , Potenciais Evocados Auditivos do Tronco Encefálico , Heterozigoto , Humanos , Imunoprecipitação , Imageamento por Ressonância Magnética , Masculino , Exame Neurológico , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all subjects an evaluation of the autonomic system was performed using the Neuroscope. RESULTS: Common features were gaze avoidance, repetitive head movements and hand stereotypies. The autonomic evaluation disclosed eight cases with the Forceful breather cardiorespiratory phenotype and two cases with the Apneustic breather phenotype. CONCLUSIONS: The clinical picture remains within the RTT spectrum but some symptoms are more pronounced in addition to the very early onset of seizures. The cardiorespiratory phenotype was dominated by Forceful breathers, while Feeble breathers were not found, differently from the general Rett population, suggesting a specific behavioral and cardiorespiratory phenotype of the RTT the Hanefeld variant.
Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/complicações , Síndrome de Rett/genética , Adolescente , Doenças do Sistema Nervoso Autônomo/genética , Encéfalo/patologia , Criança , Pré-Escolar , Avaliação da Deficiência , Eletroencefalografia , Epilepsia/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Proteína 2 de Ligação a Metil-CpG/genética , Fenótipo , Síndrome de Rett/diagnóstico , Índice de Gravidade de DoençaRESUMO
To the best of our knowledge, this is the first report of simultaneous grasping of the 3 leaflets during TriClip (Abbott Cardiovascular) implantation. The final valve configuration with a triple orifice resembled the result of the clover surgical technique. This technique should be considered in selected cases of challenging grasping.
RESUMO
PURPOSE: Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS. METHODS: The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7. RESULTS: Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved. CONCLUSIONS: Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.
Assuntos
Canabidiol , Síndrome de Lennox-Gastaut , Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Clobazam/uso terapêutico , Consenso , Fenfluramina/uso terapêutico , Humanos , Lamotrigina , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Qualidade de Vida , Topiramato/uso terapêutico , Ácido Valproico/uso terapêuticoRESUMO
Alternating hemiplegia of childhood is a neurological disorder characterized by episodes of hemiplegia, various non-epileptic paroxysmal events and global neurological impairment. Characterization of the evolution and outcome into adulthood has not been sufficiently investigated. The goal of this study was to elucidate the natural history of alternating hemiplegia within a large cohort of 157 patients, as part of the European Network for Research on Alternating Hemiplegia project. A questionnaire was formulated to determine the severity of both paroxysmal and global neurological impairment and address progression of the disorder by allocating data to specific age epochs up to and over 24 years of age. Patients in early age groups were consistently present in subsequent later age groups and for each patient, data were collected for each corresponding age epoch. The study was based on predominantly retrospective and, for a period of 2 years, prospective data. At inclusion, patients were aged from 9 months to 52 years. The median age at diagnosis was 20 months. All patients experienced hemiplegic attacks; 86.5% reported episodes of bilateral weakness, 88% dystonic attacks, 53% epileptic seizures, 72% developed chorea and/or dystonia and 92% mental retardation. When data over the course of the illness were examined for the whole cohort, the severity of symptoms did not appear to change, with the exception of abnormal ocular movements and hypotonia that regressed, but did not disappear into adulthood (from 86 to 36% and 76 to 36%, respectively). No statistically significant correlation between a history of severe paroxysmal hemiplegic/dystonic episodes and a worse neurological outcome was identified. Seven patients died, some of whom experienced severe plegic attacks or epileptic seizures at the time of death. History of severe plegic/dystonic attacks was not found to be an aggravating factor for deceased patients. Our results provide evidence that the natural history of alternating hemiplegia is highly variable and unpredictable for individual patients. However, we did not find evidence to support a steadily progressive and degenerative course of the disorder when patients were analysed as a group. For a minority of patients, a risk of sudden death was associated with more severe neurological impairment. The European Network for Research on Alternating Hemiplegia Registry, validated by our study, includes all major neurological signs and symptoms of alternating hemiplegia and may thus be used as a precedent for the progressive inclusion and follow-up of patients as well as a reference for genetic studies and treatment trials.