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BACKGROUND: The neuropeptide oxytocin (OT) is crucial in several conditions, such as lactation, parturition, mother-infant interaction, and psychosocial function. Moreover, OT may be involved in the regulation of eating behaviors. METHODS: This review briefly summarizes data concerning the role of OT in eating behaviors. Appropriate keywords and medical subject headings were identified and searched for in PubMed/MEDLINE. References of original articles and reviews were screened, examined, and selected. RESULTS: Hypothalamic OT-secreting neurons project to different cerebral areas controlling eating behaviors, such as the amygdala, area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus nerve. Intracerebral/ventricular OT administration decreases food intake and body weight in wild and genetically obese rats. OT may alter food intake and the quality of meals, especially carbohydrates and sweets, in humans. DISCUSSION: OT may play a role in the pathophysiology of eating disorders with potential therapeutic perspectives. In obese patients and those with certain eating disorders, such as bulimia nervosa or binge/compulsive eating, OT may reduce appetite and caloric consumption. Conversely, OT administered to patients with anorexia nervosa may paradoxically stimulate appetite, possibly by lowering anxiety which usually complicates the management of these patients. Nevertheless, OT administration (e.g., intranasal route) is not always associated with clinical benefit, probably because intranasally administered OT fails to achieve therapeutic intracerebral levels of the hormone. CONCLUSION: OT administration could play a therapeutic role in managing eating disorders and disordered eating. However, specific studies are needed to clarify this issue with regard to dose-finding and route and administration time.
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Anorexia Nervosa , Ocitocina , Humanos , Feminino , Ratos , Animais , Ocitocina/fisiologia , Comportamento Alimentar/fisiologia , Hipotálamo , ObesidadeRESUMO
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
A stepwise increase in the utilization of ketogenic dietary therapies for drug-resistant epilepsy has been observed in Italy in the last decade, although it is still considered often underused in many centers when compared to other countries. The Dietary Therapy Study Group of the Italian League against Epilepsy proposes practical recommendations to improve shared knowledge and facilitate the application of ketogenic dietary therapies, optimizing its efficacy and tolerability. The experts involved (11 child neuropsychiatrists, two adult neurologists, one psychologist, one pharmacologist, one pediatric endocrinologist, one representative of patients' associations, and three dietitians and clinical nutritionists) responded to a survey on current clinical practice issues and were asked to discuss controversial topics related to supplementation, long-term maintenance, transition, and a multidisciplinary approach to ketogenic dietary therapies. Practical indications for patient selection, diet initiation, management, side effects prevention, and follow-up are provided.
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OBJECTIVES: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. METHODS: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. RESULTS: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0-9) while at last follow-up was 11 years (IQR 5-18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). SIGNIFICANCE: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes.
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Epilepsias Mioclônicas , Epilepsia , Síndromes Epilépticas , Humanos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Estudos Retrospectivos , Epilepsias Mioclônicas/tratamento farmacológico , Síndromes Epilépticas/genéticaRESUMO
This retrospective study assessed long-term effectiveness of add-on perampanel (PER) in patients with Lennox-Gastaut syndrome (LGS). Outcomes included time to PER failure and time to seizure relapse in responders. PER failure was defined as either discontinuation of PER or initiation of another treatment. Seizure relapse in responders was defined as occurrence of a seizure in seizure-free patients and increase of at least 50% in average monthly seizure frequency for those who were responders. Eighty-seven patients were included. Treatment failure occurred in 52 (59.8%) subjects at a median time of 12 months. Treatment failure was due to lack of efficacy in 27 (52.0%) patients, lack of tolerability in 14 (27.0%), and both reasons in 11 (21.0%). A slower titration was associated with a lower risk of PER failure compared to faster titration schedules, and the occurrence of adverse events increased the risk of treatment failure. Thirty-six patients (41.4%) were responders during a median follow-up of 11 months. Seizure relapse occurred in 13 of 36 (36.1%) patients after a median time of 21 months. The overall rate of seizure responders was 23 of 87 (26.4%) at the end of follow-up. This study provides real-world evidence on the effectiveness of PER as adjunctive treatment in LGS patients.
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Síndrome de Lennox-Gastaut , Humanos , Síndrome de Lennox-Gastaut/tratamento farmacológico , Estudos Retrospectivos , Anticonvulsivantes/uso terapêutico , Resultado do Tratamento , Convulsões/tratamento farmacológicoRESUMO
PURPOSE: To report the efficacy and tolerability of brivaracetam (BRV) in add-on therapy in pediatric patients with severe drug-resistant epilepsy. Prognostic factors of clinical outcome were also analyzed. METHODS: This Italian multicenter retrospective observational study was conducted on 45 pediatric patients with severe drug-resistant epilepsy, treated with BRV for at least 1 month and with a follow-up >6 months. Demographic, clinical, and treatment variables were assessed at T0 (baseline, BRV introduction) and T1 (6 months after BRV introduction). The response was defined as ≥50% seizure frequency reduction; responders and non-responders were then compared to assess potential prognostic factors. RESULTS: Forty-five patients (M = 28, mean age 12.4+/-4.4 years) were enrolled (focal epilepsy=14; generalized epilepsy=2; epileptic encephalopathy=29). At T1, 19/45 patients (42.2%) were responders (≥50% seizure frequency reduction), with 4 patients (8.9%) achieving a ≥ 75% seizure reduction and 2 patients (4.4%) becoming seizure free. Epilepsy onset at >12 months of age (p = 0.001), disease duration ≤6 years (p = 0.036), and lower seizure frequency at baseline (p = 0.008) were the prognostic factors significantly associated with a better prognosis. No significant difference emerged for demographics, epilepsy types/etiology, intellectual disability, or therapy variables. At T1, 21 patients (46.6%) discontinued BRV, mainly due to lack of efficacy (13 subjects; 28.9%) and adverse events in 8 patients (17.8%). CONCLUSION: Brivaracetam was an effective and tolerated treatment in pediatric patients with severe drug-resistant epilepsy, especially when the seizure onset was at >12 months of age, the epilepsy duration ≤6 years, and the seizure frequency before BRV treatment was low. Further and controlled studies are needed.
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Epilepsia Resistente a Medicamentos , Epilepsia Generalizada , Epilepsia , Humanos , Criança , Adolescente , Anticonvulsivantes/efeitos adversos , Resultado do Tratamento , Quimioterapia Combinada , Pirrolidinonas/efeitos adversos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológicoRESUMO
Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.
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BACKGROUND: In the first section of this review, we examined the neuroanatomical and neurochemical data on hunger and satiety centers, glucose receptors, sensorial influences on eating behavior, and regulation of energy requirements. The second section is devoted to orexigenic and anorexigenic hormones. OBJECTIVE: This paper aimed to overview and summarize data regarding the role of neuroendocrine regulation of food intake and eating behavior. METHODS: Appropriate keywords and MeSH terms were identified and searched in MEDLINE/ PubMed. References of original articles and reviews were examined. RESULTS: Hunger and satiety center are located in the lateral (LH) and ventromedial hypothalamus (VMH). Lasting aphagia has been observed following a lesion of LH, while hyperphagia is induced by LH stimulation. On the other hand, increased food intake after VMH lesion and aphagia following VMH stimulation in hungry animals has also been reported. Intracellular glucopenia triggers food intake by reducing neuronal activity at the satiety center level. Moreover, sensory influences are regulated by food palatability as the positive hedonic evaluation of food and energy requirement indicates the average amount of food energy needed to balance energy expenditure. Orexigenic and anorexigenic hormones secreted from the gastrointestinal tract and adipose tissue regulate brain areas involved in eating behavior via gastric afferent vagal nerve, circumventricular organ area postrema, or transporter system. Finally, oxytocin (OT) plays a role in reward-related eating by inhibiting sugar intake and decreasing palatable food intake by suppressing the reward circuitry in the brain. Moreover, the anorectic effect of nesfatin-1 is abolished by an OT antagonist.
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Comportamento Alimentar , Hipotálamo , Animais , Sistemas Neurossecretores , Ocitocina/fisiologia , Ingestão de Alimentos/fisiologiaRESUMO
OBJECTIVE AND BACKGROUND: Sleep disorders (SD) are very common in childhood, especially in certain genetic syndromes. Tuberous Sclerosis Complex (TSC) is a genetic syndromesassociated with a high rate of SD, although these are still under-recognized. The aim of this study was to assess the prevalence of SD in TSC, and to evaluate the relationship between sleep, epilepsy and TSC-associated neuropsychiatric disorders (TAND). METHODS: We administered the Sleep Disturbance Scale for Children (SDSC) and the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) to parents of 177 children with TSC referring to different Italian centers. We also collected information on epilepsy and TAND. RESULTS: SDSC score was positive in 59.3% of patients, being positive in 30.4% of patients without and in 63.6% of those with epilepsy (p = 0.005). However, in a multivariate logistic model considering antiseizure medications and nocturnal seizures, epilepsy ceased to be a significant risk factor for positive SDSC (OR = 2.4; p = 0.17). As for TAND, SDSC was positive in 67.9% of patients with and in 32.5% of those without TAND (p < 0.001). After adding in a multivariate logistic model active epilepsy, age, and pharmacotherapies, TAND continued to be a significant risk factor for positive SDSC (p = 0.01, OR = 1.11). CONCLUSIONS: Our results revealed a high prevalence of SD in children with TSC. Epilepsy didn't increase the risk for SD, while a very strong association was found with TAND. An early detection of SD is of utmost importance in order to plan an individualized treatment, that in some cases might also ameliorate behavior and attention.
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Transtornos do Sono-Vigília , Esclerose Tuberosa , Adolescente , Lista de Checagem , Criança , Humanos , Pais , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/epidemiologia , Inquéritos e Questionários , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/epidemiologiaRESUMO
Sodium appetite is an innate behavior occurring in response to sodium depletion that induces homeostatic responses such as the secretion of the mineralocorticoid hormone aldosterone from the zona glomerulosa of the adrenal cortex and the stimulation of the peptide hormone angiotensin II (ANG II). The synergistic action of these hormones signals to the brain the sodium appetite that represents the increased palatability for salt intake. This narrative review summarizes the main data dealing with the role of mineralocorticoid and ANG II receptors in the central control of sodium appetite. Appropriate keywords and MeSH terms were identified and searched in PubMed. References to original articles and reviews were examined, selected, and discussed. Several brain areas control sodium appetite, including the nucleus of the solitary tract, which contains aldosterone-sensitive HSD2 neurons, and the organum vasculosum lamina terminalis (OVLT) that contains ANG II-sensitive neurons. Furthermore, sodium appetite is under the control of signaling proteins such as mitogen-activated protein kinase (MAPK) and inositol 1,4,5-thriphosphate (IP3). ANG II stimulates salt intake via MAPK, while combined ANG II and aldosterone action induce sodium intake via the IP3 signaling pathway. Finally, aldosterone and ANG II stimulate OVLT neurons and suppress oxytocin secretion inhibiting the neuronal activity of the paraventricular nucleus, thus disinhibiting the OVLT activity to aldosterone and ANG II stimulation.
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Apetite , Receptores de Angiotensina/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transdução de Sinais , Sódio na Dieta/metabolismo , Angiotensina II/metabolismo , Animais , HumanosRESUMO
BACKGROUND: In addition to the well-known role played in lactation and parturition, Oxytocin (OT) and OT receptor (OTR) are involved in many other aspects such as the control of maternal and social behavior, the regulation of the growth of the neocortex, the maintenance of blood supply to the cortex, the stimulation of limbic olfactory area to mother-infant recognition bond, and the modulation of the autonomic nervous system via the vagal pathway. Moreover, OT and OTR show antiinflammatory, anti-oxidant, anti-pain, anti-diabetic, anti-dyslipidemic and anti-atherogenic effects. OBJECTIVE: The aim of this narrative review is to summarize the main data coming from the literature dealing with the role of OT and OTR in physiology and pathologic conditions focusing on the most relevant aspects. METHODS: Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. RESULTS: We report the most significant and updated data on the role played by OT and OTR in physiology and different clinical contexts. CONCLUSION: Emerging evidence indicates the involvement of OT system in several pathophysiological mechanisms influencing brain anatomy, cognition, language, sense of safety and trust and maternal behavior, with the possible use of exogenous administered OT in the treatment of specific neuropsychiatric conditions. Furthermore, it modulates pancreatic ß-cell responsiveness and lipid metabolism leading to possible therapeutic use in diabetic and dyslipidemic patients and for limiting and even reversing atherosclerotic lesions.
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Ocitocina/metabolismo , Ocitocina/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Fisiológicos Celulares/efeitos dos fármacos , Fenômenos Fisiológicos Celulares/fisiologia , Feminino , Humanos , Masculino , Ocitocina/farmacologia , Gravidez , Receptores de Ocitocina/metabolismo , Transdução de Sinais/fisiologia , Comportamento SocialRESUMO
OBJECTIVE: We describe a multicenter experience with vagus nerve stimulator implantation in pediatric patients with drug-resistant epilepsy. Our goal was to assess vagus nerve stimulation efficacy and identify potential predictors of favorable outcome. METHODS: This is a retrospective study. Inclusion criteria: ≤18 years at time of vagus nerve stimulator implantation, at least 1 year of follow-up. All patients were previously found to be unsuitable for an excisional procedure. Favorable clinical outcome and effective vagus nerve stimulation therapy were defined as seizure reduction >50%. Outcome data were reviewed at 1, 2, 3, and 5 years after vagus nerve stimulator implantation. Fisher exact test and multiple logistic regression analysis were employed. RESULTS: Eighty-nine patients met inclusion criteria. Responder rate (seizure frequency reduction >50%) at 1-year follow-up was 25.8% (4.5% seizure-free). At last follow-up, 31.5% had a favorable outcome and 5.2% were seizure free. The only factor significantly predicting favorable outcome was time to vagus nerve stimulator implantation, with the best outcome achieved when vagus nerve stimulator implantation was performed within 3 years of seizure onset. Implantation between 3 and 5 years after epilepsy onset correlated with better long-term seizure freedom (13.3% at T5). Overall, 65.2% of patients evidenced improved quality of life at last follow-up. However, 12.4% had adverse events, but most were mild and disappeared after 3-4 months. CONCLUSIONS: Early vagus nerve stimulator implantation within 5 years of seizure onset was the only predictor of favorable clinical outcome in pediatric patients. Improved quality of life and a low incidence of significant adverse events were observed.
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Epilepsia Resistente a Medicamentos/terapia , Estimulação do Nervo Vago/métodos , Estimulação do Nervo Vago/estatística & dados numéricos , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Prrt2 is a neuron-specific protein expressed at axonal and pre-synaptic domains, involved in synaptic neurotransmitter release and modulation of intrinsic excitability. Mutations in PRRT2 cause a spectrum of autosomal dominant paroxysmal neurological disorders including epilepsy, movement disorders, and hemiplegic migraine and show incomplete penetrance and variable expressivity. We assessed the diagnostic rate of PRRT2 in a cohort of Italian patients with epilepsy and/or paroxysmal kinesigenic dyskinesia (PKD) and evaluated genotype-phenotype correlations. Clinical data were collected using a structured questionnaire. Twenty-seven out of 55 (49.1%) probands carried PRRT2 heterozygous pathogenic variants, including six previously known genotypes and one novel missense mutation. A family history of epilepsy starting in the first year of life and/or PKD was strongly suggestive of a PRRT2 pathogenic variant. Epilepsy patients harbouring PRRT2 pathogenic variants showed earlier seizure onset and more frequent clusters compared with PRRT2-negative individuals with epilepsy. Moreover, we did also identify individuals with PRRT2 pathogenic variants with atypical age at onset, i.e. childhood-onset epilepsy and infantile-onset PKD. However, the lack of a clear correlation between specific PRRT2 genotypes and clinical manifestations and the high incidence of asymptomatic carriers suggest the involvement of additional factors in modulating expressivity of PRRT2-related disorders. Finally, our study supports the pleiotropic and multifaceted physiological role of PRRT2 gene which is emerging from experimental neuroscience.
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Distonia/genética , Epilepsia/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Itália , Masculino , Mutação , Convulsões/genética , Adulto JovemRESUMO
PURPOSE: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations. METHODS: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel. RESULTS: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044). CONCLUSION: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.
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Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Lisencefalia , Malformações do Desenvolvimento Cortical , Estudos de Associação Genética , Humanos , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , MutaçãoRESUMO
OBJECTIVE: The Renin-Angiotensin-Aldosterone System (RAAS) plays a major role in the regulation of cardiovascular functions, water and electrolytic balance, and hormonal responses. We perform a review of the literature, aiming at providing the current concepts regarding the angiotensin interaction with the immune system in the brain and the related implications for cardiovascular and neuroendocrine responses. METHODS: Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined. RESULTS: Angiotensin II (ANG II), beside stimulating aldosterone, vasopressin and CRH-ACTH release, sodium and water retention, thirst, and sympathetic nerve activity, exerts its effects on the immune system via the Angiotensin Type 1 Receptor (AT 1R) that is located in the brain, pituitary, adrenal gland, and kidney. Several actions are triggered by the binding of circulating ANG II to AT 1R into the circumventricular organs that lack the Blood-Brain-Barrier (BBB). Furthermore, the BBB becomes permeable during chronic hypertension thereby ANG II may also access brain nuclei controlling cardiovascular functions. Subfornical organ, organum vasculosum lamina terminalis, area postrema, paraventricular nucleus, septal nuclei, amygdala, nucleus of the solitary tract and retroventral lateral medulla oblongata are the brain structures that mediate the actions of ANG II since they are provided with a high concentration of AT 1R. ANG II induces also T-lymphocyte activation and vascular infiltration of leukocytes and, moreover, oxidative stress stimulating inflammatory responses via inhibition of endothelial progenitor cells and stimulation of inflammatory and microglial cells facilitating the development of hypertension. CONCLUSION: Besides the well-known mechanisms by which RAAS activation can lead to the development of hypertension, the interactions between ANG II and the immune system at the brain level can play a significant role.
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Encéfalo/fisiopatologia , Sistema Cardiovascular/inervação , Hipertensão/fisiopatologia , Sistema Imunitário/inervação , Neuroimunomodulação , Sistemas Neurossecretores/fisiopatologia , Sistema Renina-Angiotensina , Animais , Pressão Arterial , Encéfalo/imunologia , Encéfalo/metabolismo , Sistema Cardiovascular/imunologia , Ingestão de Líquidos , Humanos , Hipertensão/imunologia , Hipertensão/metabolismo , Sistema Imunitário/imunologia , Sistemas Neurossecretores/imunologia , Sistemas Neurossecretores/metabolismo , Estresse Oxidativo , Transdução de Sinais , Equilíbrio HidroeletrolíticoRESUMO
PURPOSE: Gluten-related disorders (GRDs) are a group of immune-mediated diseases often associated to neurologic manifestations. Epilepsies with cerebral calcifications, with or without coeliac disease (CD), are rare neurological disorders characterized by childhood-onset focal seizures, often refractory to antiepileptic drugs. Transglutaminase 6 antibodies (anti-TG6) have been considered a biomarker for gluten-related ataxia and neuropathy, but their prevalence in epilepsies with cerebral calcifications is unknown. The aim of this study is to evaluate anti-TG6 prevalence in patients with epilepsies and cerebral calcifications. METHOD: this was a cross-sectional study conducted at five Italian epilepsy centres. The following groups were included. Group 1: nine patients with CD, posterior cerebral calcifications and epilepsy (CEC); group 2: nine patients with epilepsy and posterior cerebral calcifications, without CD; group 3: twenty patients with focal epilepsy of unknown etiology; group 4: twenty-two healthy controls (HC). All subjects were tested for serological evidence of anti-TG6 IgA and IgG. Differences among groups were analysed using χ ² test. RESULTS: anti-TG6 were present in 1/9 subjects (11%) of group 1, 2/9 subjects (22%) of group 2, 0/20 subjects in group 3, 3/22 (13.6%) of HC. No significant difference was found among the 4 groups. CONCLUSIONS: Anti-TG6 do not seem to be associated to epilepsies with cerebral calcifications.
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Autoanticorpos/sangue , Encefalopatias/imunologia , Doença Celíaca/imunologia , Epilepsia/imunologia , Transglutaminases/imunologia , Adulto , Autoantígenos/imunologia , Encéfalo/patologia , Encefalopatias/complicações , Calcinose/complicações , Calcinose/imunologia , Doença Celíaca/complicações , Estudos Transversais , Epilepsia/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes (TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1) have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in RNASEH2B, SAMHD1 and IFIH1 gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in RNASEH2B and a lower frequency of mutations in TREX1 than those seen in international series. RNASEH2B mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.
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OBJECTIVE: The aim of this narrative review was to analyze the role played by brain areas, neurohormones and neurotransmitters in the regulation of emotional and sexual behavior in the male. METHODS: We analyzed the currently available literature dealing with brain structures, neurotransmitters and neurohormones involved in the regulation of emotional and sexual behavior in the male. RESULTS: A common brain pathway is involved in these two aspects. The Hippocampus seems to control the signals coming from the external environment, while the amygdala and the hypothalamus control the response to social stimuli. Stimulation of amygdala in the animal models increases sexual performance, while it triggers violent emotional responses. Stimulation of the hypothalamus causes reactions of violent anger and increases sexual activity. Catecholaminergic stimulation of the amygdala and hypothalamus increases emotional and sexual behavior, while serotonin plays an inhibitory role. Cholinergic inhibition leads to a suppression of copulatory activity, while the animal becomes hyperemotive. Opioids, such as ß-endorphin and met-enkephalin, reduce copulatory activity and induce impotence. Gonadal steroid hormones, such as estrogen in female and testosterone in male, which play a major role in the control of sexual behavior and gender difference have been highlighted in this review. Vasopressin, oxytocin and their receptors are expressed in high density in the "social behavior neural network" and play a role as signal system controlling social behavior. Finally, the neuropeptide kisspeptin and its receptors, located in the limbic structures, mediate olfactory control of the gonadotropic axis. CONCLUSION: Further studies are needed to evaluate possible implications in the treatment of psychosexual and reproductive disorders.
Assuntos
Emoções/fisiologia , Hormônios Esteroides Gonadais/metabolismo , Neuropeptídeos/metabolismo , Sistemas Neurossecretores/metabolismo , Comportamento Sexual/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/metabolismo , Humanos , Masculino , Comportamento Sexual/psicologiaRESUMO
BACKGROUND AND OBJECTIVE: The sleep-wake cycle is characterized by a circadian rhythm involving neurotransmitters and neurohormones that are released from brainstem nuclei and hypothalamus. The aim of this review is to analyze the role played by central neural pathways, neurotransmitters and neurohormones in the regulation of vigilance states. METHOD: We analyzed the literature identifying relevant articles dealing with central neural pathways, neurotransmitters and neurohormones involved in the control of wakefulness and sleep. RESULTS: The reticular activating system is the key center in the control of the states of wakefulness and sleep via alertness and hypnogenic centers. Neurotransmitters and neurohormones interplay during the dark-light cycle in order to maintain a normal plasmatic concentration of ions, proteins and peripheral hormones, and behavioral state control. CONCLUSION: An updated description of pathways, neurotransmitters and neurohormones involved in the regulation of vigilance states has been depicted.