RESUMO
Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a-/- zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities.
Assuntos
Doença de Lafora , Animais , Doença de Lafora/tratamento farmacológico , Doença de Lafora/genética , Doença de Lafora/metabolismo , Mutação , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Convulsões , Trealose/farmacologia , Ubiquitina-Proteína Ligases/genética , Peixe-Zebra/metabolismoRESUMO
Over the past 10 years, the increasingly important role played by next-generation sequencing panels in the genetic diagnosis of epilepsy has led to a growing list of gene variants and a plethora of new scientific data. To date, however, there is still no consensus on what constitutes the "ideal panel design," or on the most rational criteria for selecting the best candidates for gene-panel analysis, even though both might optimize the cost-benefit ratio and the diagnostic efficiency of customized gene panels. Even though more and more laboratories are adopting whole-exome sequencing as a first-tier diagnostic approach, interpreting, "in silico," a set of epilepsy-related genes remains difficult. In the light of these considerations, we performed a systematic review of the targeted gene panels for epilepsy already reported in the available scientific literature, with a view to identifying the best criteria for selecting patients for gene-panel analysis, and the best way to design an "ideal," gold-standard panel that includes all genes with an established role in epilepsy pathogenesis, as well as those that might help to guide decisions regarding specific medical interventions and treatments. Our analyses suggest that the usefulness and diagnostic power of customized gene panels for epilepsy may be greatest when these panels are confined to rationally selected, relatively small, pools of genes, and applied in more carefully selected epilepsy patients (those with complex forms of epilepsy). A panel containing 64 genes, which includes the 45 genes harboring a significant number of pathogenic variants identified in previous literature, the 32 clinically actionable genes, and the 21 ILAE (International League Against Epilepsy) recommended genes, may represent an "ideal" core set likely able to provide the highest diagnostic efficiency and cost-effectiveness and facilitate gene prioritization when testing patients with whole-exome/whole-genome sequencing.
Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Testes Genéticos/métodos , Epilepsia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Sequenciamento do ExomaRESUMO
Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the "Nationwide Italian Collaborative Network of Mitochondrial Diseases" (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5-92 years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19 years (range, 0.2-68; < 3 years in 14/97 (14%), 3-19 years in 36/97 (37%), > 19 years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50-100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification.
Assuntos
Epilepsia/epidemiologia , Doenças Mitocondriais/epidemiologia , Convulsões/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos Transversais , Epilepsia/complicações , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Estudos Retrospectivos , Convulsões/complicações , Inquéritos e Questionários , Adulto JovemRESUMO
Psychogenic nonepileptic seizures (PNES) are episodic manifestations that mimic epileptic seizures (ES) although not associated with electroencephalogram (EEG) abnormalities. Psychogenic nonepileptic seizures and ES, however, can often cooccur. Emotional distress in adolescents can trigger PNES, but the psychopathological and personality features are still unknown. The aim of this study was to explore psychopathological features in a sample of referred youth with PNES, with or without ES, compared with a control group with ES. Thirty-four patients aged 12 to 21â¯years, 19 females and 15 males, were included in the study, 15 patients with PNES, 7 with PNES and ES, and 12 with ES. The three groups were compared according to psychiatric categorical diagnoses, psychopathological dimensions, life stressors, and personality traits, including alexithymia, interpersonal reactivity, and resilience, all assessed with structured measures. Patients with PNES, with or without ES, were more severely impaired, had a higher incidence of mood disorders, more frequent lifetime traumatic experiences, and lower resilience. All the three groups presented alexythimic traits and emotional dysregulation. Major limitations are the small sample size and the lack of a control group of healthy subjects. Disentagling psychopathological characteristics in PNES can help clinicians to focus diagnostic approaches and therapeutic interventions.
Assuntos
Epilepsia , Transtornos Mentais , Adolescente , Adulto , Criança , Eletroencefalografia , Epilepsia/complicações , Feminino , Humanos , Masculino , Psicopatologia , Convulsões/complicações , Convulsões/diagnóstico , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Frontal lobe epilepsy (FLE) is often associated with psychiatric features, although the factors predisposing to the concurrence of these conditions have yet to be determined, especially in younger children. We aimed at defining possible clinical and electroencephalography (EEG) features that may enhance the psychiatric risk in pediatric FLE. METHOD: We performed a structured psychiatric assessment of 59 children with FLE, using both categorical and dimensional approaches, correlated psychopathology with epilepsy data, and cognitive development. RESULTS: About 1/3 of patients with FLE displayed intellectual disability (ID), and more than 2/3 displayed psychiatric disorders, including depression, disruptive behaviors, anxiety, and bipolar/psychotic disorders. Psychiatric dimensions such as impulse control problems, attentional deficits, social problems, and aggressive behaviors were frequent features of FLE. Intellectual disability was associated with an earlier onset of psychiatric disorders and more frequent disruptive behavior disorders and aggressiveness. Long-standing epilepsy and bilateral or anterior frontal EEG abnormalities also increased the risk of psychopathology. Finally, right-hemisphere lesions were associated with disruptive behavior disorders, fast EEG rhythms with attention/memory problems, and phases of seizure remission with impulse control problems. CONCLUSIONS: Clinical and EEG markers of increased psychopathological risk may help in defining consistent at-risk subgroups within FLE and improving early diagnosis, prognosis, and treatment. Categorical and dimensional approaches to psychiatric diagnosis may generate new research hypotheses and support the investigation of the complex pathophysiological bases shared by different neurodevelopmental disturbances.
Assuntos
Eletroencefalografia/métodos , Epilepsia do Lobo Frontal/fisiopatologia , Epilepsia do Lobo Frontal/psicologia , Lobo Frontal/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia , Adolescente , Adulto , Atenção/fisiologia , Criança , Pré-Escolar , Cognição/fisiologia , Epilepsia do Lobo Frontal/diagnóstico por imagem , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Convulsões/psicologia , Adulto JovemRESUMO
OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.
Assuntos
Caderinas/genética , Síndromes Epilépticas/genética , Síndromes Epilépticas/terapia , Adolescente , Adulto , Idade de Início , Transtorno Autístico/complicações , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/psicologia , Masculino , Fenótipo , Protocaderinas , Estudos Retrospectivos , Convulsões , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Psychiatric and behavioral problems are frequent comorbidities of epilepsy, although their clinical and electroencephalographic (EEG) correlates remain uncertain. In this study, we have assessed the frequency of psychopathological problems in a cohort of children with epilepsy, and established their main clinical and EEG-associated features. METHODS: One hundred fifty-nine young patients with epilepsy were recruited and assessed through the Child Behavior Checklist for preschool-aged children (CBCL 1 1/2-5) or for school-aged children (CBCL 6-18). Child Behavior Checklist (CBCL) results were then correlated to the main clinical and EEG data. RESULTS: We found emotional and behavioral problems in about half of the children in our sample. Internalizing, social, and attention problems were more common than externalizing features. Moderate intellectual disability, a nonidiopathic etiology of epilepsy, a poor control of seizures, and antiepileptic polytherapies, as well as an early age at seizure-onset and a longer duration of the disorder, were all associated with specific behavioral and emotional problems. A temporal site of interictal EEG abnormalities also enhanced the risk for psychiatric comorbidities, especially in the externalizing domain. CONCLUSIONS: Several clinical and EEG features are associated with an increased risk for emotional and behavioral comorbidities in children with epilepsy. Their identification may foster an early diagnosis and appropriate care, limiting the worsening of psychiatric symptoms and their impact on quality of life and health status. A better understanding of the underlying clinical and molecular mechanisms is needed to further improve prevention and treatment interventions.
Assuntos
Transtornos do Comportamento Infantil/psicologia , Emoções , Epilepsia/psicologia , Controle Interno-Externo , Comportamento Problema/psicologia , Convulsões/psicologia , Adolescente , Anticonvulsivantes/uso terapêutico , Lista de Checagem , Criança , Transtornos do Comportamento Infantil/epidemiologia , Pré-Escolar , Comorbidade , Eletroencefalografia/efeitos adversos , Epilepsia/tratamento farmacológico , Feminino , Nível de Saúde , Humanos , Masculino , Qualidade de VidaRESUMO
Short QT3 syndrome (SQT3S) is a cardiac disorder characterized by a high risk of mortality and associated with mutations in Kir2.1 (KCNJ2) channels. The molecular mechanisms leading to channel dysfunction, cardiac rhythm disturbances and neurodevelopmental disorders, potentially associated with SQT3S, remain incompletely understood. Here, we report on monozygotic twins displaying a short QT interval on electrocardiogram recordings and autism-epilepsy phenotype. Genetic screening identified a novel KCNJ2 variant in Kir2.1 that (i) enhanced the channel's surface expression and stability at the plasma membrane, (ii) reduced protein ubiquitylation and degradation, (iii) altered protein compartmentalization in lipid rafts by targeting more channels to cholesterol-poor domains and (iv) reduced interactions with caveolin 2. Importantly, our study reveals novel physiological mechanisms concerning wild-type Kir2.1 channel processing by the cell, such as binding to both caveolin 1 and 2, protein degradation through the ubiquitin-proteasome pathway; in addition, it uncovers a potential multifunctional site that controls Kir2.1 surface expression, protein half-life and partitioning to lipid rafts. The reported mechanisms emerge as crucial also for proper astrocyte function, suggesting the need for a neuropsychiatric evaluation in patients with SQT3S and offering new opportunities for disease management.
Assuntos
Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Transtorno Autístico/genética , Epilepsia/genética , Sistema de Condução Cardíaco/anormalidades , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Animais , Astrocitoma/metabolismo , Transtorno Autístico/patologia , Caveolina 1/metabolismo , Caveolina 2/metabolismo , Linhagem Celular , Criança , Epilepsia/patologia , Estudos de Associação Genética , Células HEK293 , Sistema de Condução Cardíaco/patologia , Humanos , Masculino , Mutação , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Gêmeos Monozigóticos , Xenopus laevis/embriologiaRESUMO
Interictal electroencephalogram (EEG) abnormalities are frequently associated with autism spectrum disorders (ASD), although their relationship with the clinical features of ASD, particularly the regressive onset, remains controversial. The aim of this study was to investigate whether the characteristics of interictal EEG abnormalities might help to distinguish and predict definite phenotypes within the heterogeneity of ASD. We reviewed the awake and sleep interictal EEGs of 220 individuals with idiopathic ASD, either with or without a history of seizures. EEG findings were analyzed with respect to a set of clinical variables to explore significant associations. A brain morphometry study was also carried out on a subgroup of patients. EEG abnormalities were seen in 154/220 individuals (70%) and were mostly focal (p < 0.01) with an anterior localization (p < 0.001). They were detected more frequently during sleep (p < 0.01), and were associated with a regressive onset of ASD (p < 0.05), particularly in individuals with focal temporal localization (p < 0.05). This association was also stronger in regressive patients with concurrent macrocephaly, together with a relative volumetric reduction of the right temporal cortex (p < 0.05). Indeed, concurrence of temporal EEG abnormalities, regression and macrocephaly might possibly define a distinct endophenotype of ASD. EEG-based endophenotypes could be useful to untangle the complexity of ASD, helping to establish anatomic or pathophysiologic subtypes of the disorder.
Assuntos
Transtorno do Espectro Autista/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico , Megalencefalia/fisiopatologia , Convulsões/diagnóstico , Lobo Temporal/fisiopatologia , Transtorno do Espectro Autista/diagnóstico , Encéfalo/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Masculino , Fenótipo , Convulsões/complicações , SonoRESUMO
BACKGROUND: With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have strong genetic background. Macrocephaly also represents a well-known endophenotype in subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in early development and predisposing to the disorder. We attempted to estimate the association of gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP) and cranial overgrowth, analyzing two genes previously reported to be associated with autism and macrocephaly. METHODS: We analyzed the coding sequences and exon-intron boundaries of GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the PTEN gene in the subsample with macrocephaly. RESULTS: Among 81 individuals with ASD, 31 had concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile ("extreme" macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one case with "extreme" macrocephaly, autism, intellectual disability and seizures. CONCLUSIONS: We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly comorbidity. The identification of a novel frameshift variant of PTEN in a patient with "extreme" macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in autism-epilepsy comorbidity. Working on clinical endophenotypes might be of help to address genetic studies and establish actual causative correlations in autism-epilepsy.
Assuntos
Anormalidades Múltiplas/genética , Transtorno Autístico/genética , Epilepsia/genética , Megalencefalia/genética , PTEN Fosfo-Hidrolase/genética , Proteínas/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Ciclo Celular , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Dados de Sequência Molecular , Adulto JovemRESUMO
PURPOSE: Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients. METHODS: We studied 35 patients with PCDH19 gene-related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them. KEY FINDINGS: Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity. SIGNIFICANCE: Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder.
Assuntos
Sintomas Afetivos/genética , Caderinas/genética , Predisposição Genética para Doença/genética , Mutação/genética , Convulsões/genética , Adolescente , Adulto , Sintomas Afetivos/complicações , Criança , Pré-Escolar , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Biologia Computacional , Análise Mutacional de DNA , Eletroencefalografia , Feminino , Seguimentos , Humanos , Testes Neuropsicológicos , Protocaderinas , Convulsões/complicações , Gravação em Vídeo , Adulto JovemRESUMO
Chromosome 22q11.2 microduplication syndrome is characterized by a variable and usually mild phenotype and by incomplete penetrance. Neurological features of the syndrome may entail intellectual or learning disability, motor delay, and other neurodevelopmental disorders. However, seizures or abnormal EEG are reported in a few cases. We describe a 6-year-old girl with microduplication of chromosome 22q11.2 and epilepsy with continuous spikes and waves during sleep (CSWS). Her behavioral disorder, characterized by hyperactivity, impulsiveness, attention deficit, and aggressiveness, became progressively evident a few months after epilepsy onset, suggesting a link with the interictal epileptic activity characterizing CSWS. We hypothesize that, at least in some cases, the neurodevelopmental deficit seen in the 22q11.2 microduplication syndrome could be the consequence of a disorder of cerebral electrogenesis, suggesting the need for an EEG recording in affected individuals. Moreover, an array-CGH analysis should be performed in all individuals with cryptogenic epilepsy and CSWS.
Assuntos
Duplicação Cromossômica/fisiologia , Cromossomos Humanos Par 22/genética , Fases do Sono/genética , Estado Epiléptico/genética , Encéfalo/fisiopatologia , Criança , Cromossomos Humanos Par 22/fisiologia , Eletroencefalografia , Feminino , Humanos , Fases do Sono/fisiologia , Estado Epiléptico/fisiopatologia , SíndromeRESUMO
BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heterogeneous diagnostic category, encompassing several endophenotypes and comorbidities, including sleep problems. However, no predictor of clinical long-term trajectories or comorbidity has yet been established. Sleep EEG has been proposed as a potential tool for evaluating the synaptic strength during development, as well as the cortical thickness, which is presumed to be altered in ADHD. We investigated whether the slope of the Slow Waves (SWs), a microstructural parameter of the sleep EEG, was a potential predictive parameter for psychiatric comorbidities and neuropsychological dimensions in ADHD. METHODS: 70 children (58 m; 8.76 ± 2.77 y) with ADHD who underwent psychiatric and neurologic evaluations and a standard EEG recording during naps were investigated. After sleep EEG analysis, we grouped the extracted SWs in bins of equal amplitude and then measured the associations, through generalized linear regression, between their maximum downward slopes (MDS) and the individual scores obtained from clinical rating scales. RESULTS: The presence of Multiple Anxiety Disorders was positively associated with MDS of medium amplitude SWs in temporo-posterior left areas. The Child Behavior Checklist scores showed negative associations in the same areas for small SWs. The presence of autistic traits was positively associated with MDS of high amplitude SWs in bilateral anterior and temporal left areas. The WISC-IV Processing Speed Index showed negative associations with MDS of small-to-medium SWs in anterior and temporal right areas, while positive associations in posterior and temporal left areas. CONCLUSIONS: Consistency of association clusters' localization on the scalp suggests that variations in the local MDS, revealing alterations of local synaptic strength and/or in daytime use of certain cortical circuits, could underlie specific neurodevelopmental trajectories resulting in different ADHD clinical phenotypes.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , SonoRESUMO
The inwardly-rectifying potassium channel Kir4.1 is a major player in the astrocyte-mediated regulation of [K(+)](o) in the brain, which is essential for normal neuronal activity and synaptic functioning. KCNJ10, encoding Kir4.1, has been recently linked to seizure susceptibility in humans and mice, and is a possible candidate gene for Autism Spectrum Disorders (ASD). In this study, we performed a mutational screening of KCNJ10 in 52 patients with epilepsy of "unknown cause" associated with impairment of either cognitive or communicative abilities, or both. Among them, 14 patients fitted the diagnostic criteria for ASD. We identified two heterozygous KCNJ10 mutations (p.R18Q and p.V84M) in three children (two unrelated families) with seizures, ASD, and intellectual disability. The mutations replaced amino acid residues that are highly conserved throughout evolution and were undetected in about 500 healthy chromosomes. The effects of mutations on channel activity were functionally assayed using a heterologous expression system. These studies indicated that the molecular mechanism contributing to the disorder relates to an increase in either surface-expression or conductance of the Kir4.1 channel. Unlike previous syndromic associations of genetic variants in KCNJ10, the pure neuropsychiatric phenotype in our patients suggests that the new mutations affect K(+) homeostasis mainly in the brain, by acting through gain-of-function defects. Dysfunction in astrocytic-dependent K(+) buffering may contribute to autism/epilepsy phenotype, by altering neuronal excitability and synaptic function, and may represent a new target for novel therapeutic approaches.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/metabolismo , Epilepsia/metabolismo , Deficiência Intelectual/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adolescente , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Pré-Escolar , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Adulto JovemRESUMO
PURPOSE: To describe clinical and neuropsychological features of six consecutive sporadic girls with protocadherin 19 (PCDH19) mutations. METHODS: Following recent descriptions of PCDH19 mutation in girls with epilepsy, we sequenced this gene in patients with infantile or early childhood seizures onset, either focal or generalized, without an obvious etiology. KEY FINDINGS: Mean age at the time of the study was 13.5 ± 11 years. Mean age at seizure onset was 15.5 ± 11 months (range 9-38). All patients experienced clusters of either focal or generalized seizures, precipitated during febrile illness in five patients. Attacks were very frequent at onset, but they became less numerous during follow-up. Ictal electroencephalography (EEG) showed temporal lobe involvement in five patients. Periictal EEG showed focal or multifocal epileptiform and slow abnormalities. Cognitive impairment became obvious after seizure onset in three patients and was associated with autistic features in two. Genetic analysis revealed five new and one known de novo PCDH19 mutation that were missense in four and frameshift in two. Variants are clustered in the large exon 1, corresponding to the extracellular domain of the PCDH19 protein. SIGNIFICANCE: Our findings emphasize that de novo PCDH19 mutations are associated with infantile or early childhood onset of febrile or afebrile seizures often occurring in clusters. Cognitive impairment is not constantly present and autistic features are observed in some patients. Most patients have a "stormy" seizure onset, often related to fever; however, seizure severity does not clearly correlate with the degree of cognitive deficit. PCDH19 is likely a major epilepsy gene; phenotypes associated with mutations of this gene range from epileptic encephalopathies to mild epilepsy, yet large series of patients will be necessary to fully delineate phenotypic spectrum.
Assuntos
Caderinas/genética , Epilepsia/genética , Idade de Início , Encéfalo/fisiopatologia , Pré-Escolar , Eletroencefalografia , Epilepsia/fisiopatologia , Feminino , Mutação da Fase de Leitura/genética , Humanos , Lactente , Mutação de Sentido Incorreto/genética , Fenótipo , Protocaderinas , Convulsões/genéticaRESUMO
Epilepsy is a common, often severe, feature of LAMA2-related muscular dystrophy (LAMA2-RD) and could represent its onset and main manifestation, even in the absence of overt muscle involvement. To date, there is no systematic characterization of epilepsy in LAMA2-RD, and its impact on neurodevelopment and on the clinical course remains poorly established. In view of this knowledge gap, we conducted a systematic review of the literature and, as an illustrative example, reported the clinical case of a boy with late-onset LAMA2-related limb-girdle muscular dystrophy presenting with severe epilepsy. Our analyses of the literature data revealed a mean age at first seizure of 8 years, with significant differences between early- versus late-onset disease (5.78 ± 4.11 and 9.00 ± 2.65 years, respectively; p = 0.0007), and complete versus partial merosin deficiency (5.33 ± 3.70 and 10.36 ± 5.49 years, respectively; p = 0.0176). A generalized onset was the most common seizure presentation, regardless of merosin expression levels or the timing of muscular distrophy onset. Cortical malformations were not significantly associated with an earlier epilepsy onset, and were found to be quasi-significantly associated with a greater incidence of focal, or focal and generalized, onset seizures. No clear conclusions could be reached on the electrophysiological and neurodevelopmental features of the disorder, or on the relative efficacy of anti-epileptic treatments; further research on these aspects is needed. This systematic review helps to show that epilepsy in LAMA2-RD may be more than an ancillary manifestation of the disease, but rather one of its core features. A targeted and prompt electroencephalographic and epilepsy assessment, in addition to the specific neuromuscular workup, is therefore mandatory in early clinical management to pursue the best possible outcome for affected children.
Assuntos
Epilepsia , Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Criança , Eletroencefalografia , Epilepsia/genética , Humanos , Laminina/genética , Masculino , Distrofias Musculares/complicações , Distrofias Musculares/genéticaRESUMO
A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved in the disorder, and this may in part explain why some individuals with depression are resistant to serotonergic therapies. Among these, emerging evidence suggests a role for the astrocytic inward rectifier potassium channel 4.1 (Kir4.1) as an important modulator of neuronal excitability and glutamate metabolism. To discuss the relationship between Kir4.1 dysfunction and depression, a systematic review was performed according to the PRISMA statement. Searches were conducted across PubMed, Scopus, and Web of Science by two independent reviewers. Twelve studies met the inclusion criteria, analyzing Kir4.1 relationships with depression, through in vitro, in vivo, and post-mortem investigations. Increasing, yet not conclusive, evidence suggests a potential pathogenic role for Kir4.1 upregulation in depression. However, the actual contribution in the diverse subtypes of the disorder and in the comorbid conditions, for example, the epilepsy-depression comorbidity, remain elusive. Further studies are needed to better define the clinical phenotype associated with Kir4.1 dysfunction in humans and the molecular mechanisms by which it contributes to depression and implications for future treatments.
Assuntos
Depressão/metabolismo , Depressão/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Humanos , Ketamina , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Regulação para Cima/efeitos dos fármacosRESUMO
Attention deficit hyperactivity disorder (ADHD) is commonly associated with sleep problems, possibly due to shared pathophysiology. Microstructural sleep electroencephalographic (EEG) alterations may likely represent markers of disordered cortical maturation in ADHD, although literature data are still conflicting, deserving further assessment. After having systematically reviewed the literature, we included 11 studies from 598 abstracts, and assessed 23 parameters of cyclic alternating pattern (CAP), four parameters of sleep EEG power and one parameter of sleep graphoelements through 29 meta-analyses and, when possible, univariate meta-regressions. Slow wave activity (SWA) in ADHD was significantly higher in early childhood and lower in late childhood/adolescence compared to controls, with an inversion point at 10 years. Total CAP rate and CAP A1 index in non-rapid eye movement (NREM) stage 2 sleep, and CAP A1 rate in NREM sleep were significantly lower in ADHD patients than controls. SWA and CAP A1 changes are therefore possible markers of altered cortical maturation in ADHD, consistently with the neuropsychological deficits characterizing the disorder, likely fostering earlier detection of at-risk/milder conditions, and more tailored therapeutic interventions.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Sono de Ondas Lentas , Adolescente , Criança , Pré-Escolar , Eletroencefalografia , Humanos , Polissonografia , SonoRESUMO
Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity. For this reason, the diagnosis of MDs continues to be difficult, with the new "genotype first" approach still failing to diagnose a large group of patients. With the aim of investigating possible relationships between clinical and/or biochemical phenotypes and definitive molecular diagnoses, we performed a retrospective multicenter study of 111 pediatric patients with clinical suspicion of MD. In this cohort, the strongest predictor of a molecular (in particular an mtDNA-related) diagnosis of MD was neuroimaging evidence of basal ganglia (BG) involvement. Regression analysis confirmed that normal BG imaging predicted negative genetic studies for MD. Psychomotor regression was confirmed as an independent predictor of a definitive diagnosis of MD. The findings of this study corroborate previous data supporting a role for neuroimaging in the diagnostic approach to MDs and reinforce the idea that mtDNA sequencing should be considered for first-line testing, at least in specific groups of children.