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2.
Ann Neurol ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31618474

RESUMO

OBJECTIVE: Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort. METHODS: Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. RESULTS: We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. INTERPRETATION: We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. This article is protected by copyright. All rights reserved.

3.
Paediatr Drugs ; 21(4): 283-290, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179531

RESUMO

BACKGROUND: A pharmaceutical grade formulation of cannabidiol (CBD) has been approved for the treatment of Dravet syndrome and Lennox-Gastaut syndrome; however, this formulation is not yet available to patients outside the USA. In addition, CBD is thought to have broad anti-seizure properties that may be beneficial for other types of intractable epilepsy. OBJECTIVE: The aim of this study was to evaluate the efficacy, safety and tolerability of artisanal medical CBD oil in patients with developmental and epileptic encephalopathy (DEE) at the tertiary epilepsy center of Bambino Gesù Children's Hospital in Rome, Italy. METHODS: This was a single-center, prospective, open-label study. Patients aged from 1 to 18 years with DEE and seizures refractory to appropriate antiepileptic drugs (AEDs) and other alternative treatments (i.e., vagal nerve stimulator and ketogenic diet) were included. Crystalline extract CBD powder (98-99% pure) in an oil artisanal formulation was added to the baseline AED regimen at a dosage of 2-5 mg/kg/day divided for twice-daily administration, then up-titrated until intolerance or a maximum dosage of 25 mg/kg/day was reached. Patients were treated for at least 6 months. Efficacy, safety and tolerability of CBD treatment were assessed through the evaluation of seizure frequency and reports of adverse effects. RESULTS: Twenty-nine patients were enrolled in this study (41.4% male). The mean duration of exposure to artisanal CBD was 11.2 months [range 6-25 months; standard deviation (SD) ± 4.4 months]. Mean age at study enrollment was 9.3 years (range 1.9-16.3 years; SD ± 4.7 years). Eleven out of 29 patients (37.9%) had a ≥ 50% improvement in seizure frequency; one patient became seizure free. None of the patients reported worsening seizure frequency; however, 18 patients (62.1%) experienced no beneficial effect regarding seizure frequency. Adverse effects were reported in seven patients (24.14%), most commonly somnolence, decreased appetite and diarrhea. Adverse events were mild and transient, and no dose modification of CBD or other AEDs was required. CONCLUSIONS: These data suggest that CBD may have beneficial effects in patients with DEE and an acceptable safety profile. Placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in patients with DEE.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Adolescente , Anticonvulsivantes/farmacologia , Canabidiol/farmacologia , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/patologia , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
4.
Epilepsy Behav ; 96: 219-223, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31174070

RESUMO

Developmental and epileptic encephalopathy (DEE) due to SCN8A gene variants is characterized by drug-resistant early onset epilepsy associated with severe intellectual disability. Different seizure types have been reported, and a sequence of autonomic manifestations such as brady-/tachycardia, irregular breathing, and cyanosis. Nevertheless, an exhaustive video-polygraphic documentation is still lacking. In this study, we reviewed the ictal electroencephalograms (EEGs) of five patients with SCN8A-DEE followed-up at the Neuroscience Department at Bambino Gesù Children's Hospital in Rome. We identified generalized tonic seizure as the major seizure type at epilepsy onset. Seizure severity could vary from subtle to marked clinical manifestations, depending from the extent and groups of muscles involved and association with autonomic modifications. We found autonomic signs in 80% of seizures in our cases, and we were able to identify a stereotyped sequence of ictal events for most of seizures. Autonomic signs occurred in rapid sequence: flushing of the face, sometimes associated with sialorrhea, bradycardia, and hypopnea appeared within the first 1-2 s. Tachycardia, polypnea, perioral cyanosis, and pallor occurred later in the course of the seizure. Generalized tonic seizures are rarely described in other genetic epileptic conditions of early infancy because of ion channel mutations, such as in DEE due to KCNQ2 or SCN2A gene mutations, where seizures are most frequently reported as focal to bilateral tonic. Therefore, generalized symmetric tonic seizures with autonomic signs can be considered a clinical hallmark for diagnosis of SCN8A-related DEE and relevant for therapeutic implications.

5.
Am J Med Genet A ; 179(8): 1631-1636, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31136090

RESUMO

POGZ (# 614787) encodes a multidomain nuclear protein involved in transcriptional regulation and its defective function has been recently associated with a syndromic neurodevelopmental disorder, known as White-Sutton syndrome (# 616364). While originally epileptic seizures were unreported, it seems that epilepsy represents a recurrent feature in affected subjects. Few data, however, are available on electroclinical features of POGZ-related epilepsy. We report a 5-year-old girl with a de novo inactivating POGZ mutation with a complex neurological phenotype characterized by hypotonia, severe developmental delay, and paroxysmal epileptic and nonepileptic events. Comparing this patient with the previously reported nine cases exhibiting epilepsy as associated feature, we detected that epilepsy onset is mostly during infancy (1-4 years of age), with both focal and generalized seizures. EEGs reveal that epileptic abnormalities mainly are localized in the frontal regions, and seizure control might be reached with one or multiple antiepileptic drugs. Besides dysmorphic features and other comorbidities (microcephaly, intellectual disability, absent speech, sensorineural hearing loss, and autistic spectrum disorder) major brain MR features include cortical and cerebellar atrophy, delayed myelination, and brainstem hypoplasia. Although the small number of patients reported, we were able to delineate primary electroclinical epileptic phenotype related to POGZ mutations. This would be crucial for an early identification and management of the condition.

6.
Clin Genet ; 95(4): 525-531, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30684285

RESUMO

Whole exome sequencing (WES) has led to the understanding of the molecular events affecting neurodevelopment in an extremely diverse clinical context, including diseases with intellectual disability (ID) associated with variable central nervous system (CNS) malformations, and developmental and epileptic encephalopathies (DEEs). Recently, PACS2 mutations have been causally linked to a DEE with cerebellar dysgenesis and facial dysmorphism. All known patients presented with a recurrent de novo missense mutation, c.625G>A (p.Glu209Lys). Here, we report on a 7-year-old boy with DEE, cerebellar dysgenesis, facial dysmorphism and postnatal growth delay, apparently not fitting with any recognized disorder. WES disclosed a de novo novel missense PACS2 variant, c.631G>A (p.Glu211Lys), as the molecular cause of this complex phenotype. We provide a detailed clinical characterization of this patient, and analyse the available clinical data of individuals with PACS2 mutations to delineate more accurately the clinical spectrum associated with this recently described syndrome. Our study expands the clinical and molecular spectrum of PACS2 mutations. Overview of the available clinical data allow to delineate the condition associated with PACS2 mutations as a variable trait, in which the key features are represented by moderate to severe ID, cerebellar dysgenesis and other CNS malformations, reduced growth, and facial dysmorphism.

7.
Epilepsia ; 59(12): 2260-2271, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30451291

RESUMO

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.

8.
Neurology ; 91(12): e1112-e1124, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30171078

RESUMO

OBJECTIVE: To delineate the electroclinical features of SCN8A infantile developmental and epileptic encephalopathy (EIEE13, OMIM #614558). METHODS: Twenty-two patients, aged 19 months to 22 years, underwent electroclinical assessment. RESULTS: Sixteen of 22 patients had mildly delayed development since birth. Drug-resistant epilepsy started at a median age of 4 months, followed by developmental slowing, pyramidal/extrapyramidal signs (22/22), movement disorders (12/22), cortical blindness (17/22), sialorrhea, and severe gastrointestinal symptoms (15/22), worsening during early childhood and plateauing at age 5 to 9 years. Death occurred in 4 children, following extreme neurologic deterioration, at 22 months to 5.5 years. Nonconvulsive status epilepticus recurred in 14 of 22 patients. The most effective antiepileptic drugs were oxcarbazepine, carbamazepine, phenytoin, and benzodiazepines. EEG showed background deterioration, epileptiform abnormalities with a temporo-occipital predominance, and posterior delta/beta activity correlating with visual impairment. Video-EEG documented focal seizures (FS) (22/22), spasm-like episodes (8/22), cortical myoclonus (8/22), and myoclonic absences (1/22). FS typically clustered and were prolonged (<20 minutes) with (1) cyanosis, hypomotor, and vegetative semiology, sometimes unnoticed, followed by (2) tonic-vibratory and (3) (hemi)-clonic manifestations ± evolution to a bilateral tonic-clonic seizure. FS had posterior-temporal/occipital onset, slowly spreading and sometimes migrating between hemispheres. Brain MRI showed progressive parenchymal atrophy and restriction of the optic radiations. CONCLUSIONS: SCN8A developmental and epileptic encephalopathy has strikingly consistent electroclinical features, suggesting a global progressive brain dysfunction primarily affecting the temporo-occipital regions. Both uncontrolled epilepsy and developmental compromise contribute to the profound impairment (increasing risk of death) during early childhood, but stabilization occurs in late childhood.

9.
Hum Mutat ; 39(12): 1885-1900, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30161288

RESUMO

Cerebral cavernous malformation (CCM) is a capillary malformation arising in the central nervous system. CCM may occur sporadically or cluster in families with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Three genes are associated with CCM KRIT1, CCM2, and PDCD10. This work is a retrospective single-center molecular study on samples from multiple Italian clinical providers. From a pool of 317 CCM index patients, we found germline variants in either of the three genes in 80 (25.2%) probands, for a total of 55 different variants. In available families, extended molecular analysis found segregation in 60 additional subjects, for a total of 140 mutated individuals. From the 55 variants, 39 occurred in KRIT1 (20 novel), 8 in CCM2 (4 novel), and 8 in PDCD10 (4 novel). Effects of the three novel KRIT1 missense variants were characterized in silico. We also investigated a novel PDCD10 deletion spanning exon 4-10, on patient's fibroblasts, which showed significant reduction of interactions between KRIT1 and CCM2 encoded proteins and impaired autophagy process. This is the largest study in Italian CCM patients and expands the known mutational spectrum of KRIT1, CCM2, and PDCD10. Our approach highlights the relevance of seeking supporting information to pathogenicity of new variants for the improvement of management of CCM.

10.
Seizure ; 57: 8-10, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29529558

RESUMO

CHD2 gene has been described in association with different types of childhood myoclonic epilepsy and is emerging as a gene involved in photosensitivity alone or combined with epilepsy. Recent studies suggest that CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity and in particular with self-induced seizures. We report the case of a child with CHD2 mutation and mild developmental impairment that since the age of 3 years started with myoclonic seizures apparently well responding to antiepileptic drugs and that subsequently developed intractable self-induced seizures. Through an accurate Video-EEG polygraphic analysis, we demonstrated that seizures are related to an abnormal increase of epileptiform activity after eye-closure or loss of fixation as observed in the Fixation-Off Sensitivity (FOS) phenomenon. In conclusion our study adds relevant features of the CHD2-epilepsy phenotype and confirms that CHD2 mutations produce a distinctive form of myoclonic epilepsy with visual-sensitive seizures.


Assuntos
Encéfalo/fisiopatologia , Proteínas de Ligação a DNA/genética , Epilepsia Mioclônica Juvenil/genética , Epilepsia Mioclônica Juvenil/fisiopatologia , Criança , Eletroencefalografia , Fixação Ocular , Humanos , Masculino , Mutação , Epilepsia Mioclônica Juvenil/diagnóstico , Epilepsia Mioclônica Juvenil/tratamento farmacológico , Fenótipo , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/fisiopatologia , Percepção Visual
11.
Epilepsia ; 59(2): 389-402, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29315614

RESUMO

OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.


Assuntos
Epilepsias Mioclônicas/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/complicações , Ataxia/genética , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Epilepsias Parciais/complicações , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Resultado do Tratamento , Ácido Valproico/uso terapêutico , Adulto Jovem
13.
Brain ; 140(11): 2879-2894, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29053855

RESUMO

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.


Assuntos
Encefalopatias/genética , Fissura Palatina/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Facies , Deficiência Intelectual/genética , Nistagmo Patológico/genética , Receptores de GABA-A/genética , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Feminino , Variação Genética , Humanos , Masculino , Microcefalia/genética , Mutagênese Sítio-Dirigida , Oócitos/metabolismo , Técnicas de Patch-Clamp , Linhagem , Receptores de GABA-A/metabolismo , Síndrome , Xenopus laevis , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
14.
Epilepsia ; 58(8): 1380-1388, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28632327

RESUMO

OBJECTIVE: This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes. METHODS: Retrospective clinical chart review of a series of patients diagnosed with CLN2 disease from 2005 to 2015 at a single center in Italy. Clinical, MRI, and EEG findings were reviewed. RESULTS: A total of 14 patients were included. For the whole group, median (range) age at disease onset was 3.0 (2.0-3.8) years. Epilepsy was the most commonly reported presenting symptom (in 50% [seven of 14] of patients), occurring at the age of 3.2 (2.6-3.8) years. First seizure was myoclonic in 36% (five of 14) of patients, followed by generalized tonic-clonic in 29% (4 of 14), atonic in 22% (three of 14), and focal with motor signs in 14% (two of 14). All patients walked independently at the age of 12.0 (11.0-18.0) months, but delayed speech or regression of acquired verbal skills was present in 100% of patients at 3 years. EEGs revealed a photoparoxysmal response (PPR) on intermittent photic stimulation in 93% (13 of 14) of patients. PPR was present from the first EEG, which was performed at 3.6 (3.1-4.0) years, in 43% (six of 14) of patients; it was documented at low (1-3 Hz) stimulation frequencies in 69% (nine of 13) and took the form of a flash-per-flash response in 69% (nine of 13). First brain MRI at the age of 3.8 (3.0-5.1) years revealed cerebellar atrophy in 100% (14 of 14) of patients and alteration of the periventricular white matter signal in the posterior hemispheric region in 79% (11 of 14). SIGNIFICANCE: Early photosensitivity (typically PPR at low stimulation frequencies of 1-3 Hz) is a hallmark of CLN2 disease. This diagnosis should be considered in a child presenting with any type of seizure, and particularly if it is accompanied by delayed speech and/or ataxia or MRI abnormalities (posterior white matter signal alteration or cerebellar atrophy).


Assuntos
Lipofuscinoses Ceroides Neuronais/complicações , Lipofuscinoses Ceroides Neuronais/diagnóstico , Transtornos de Fotossensibilidade/etiologia , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Transtornos de Fotossensibilidade/diagnóstico por imagem , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença
15.
Epilepsia ; 58(6): e91-e95, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28471529

RESUMO

Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays. Apart from estradiol and progesterone, all the considered hormones were evaluated in basal condition and after stimulation with adrenocorticotropic hormone (ACTH). A generalized decrease in blood levels of almost all measured neuroactive steroids was found. When considering sexual development, cortisol and pregnenolone sulfate basal levels were significantly reduced in postpubertal girls affected by PCDH19-FE. Of interest, ACTH administration did not recover pregnenolone sulfate serum levels but restored cortisol to control levels. In prepubertal girls with PCDH19-FE, by challenging adrenal function with ACTH we disclosed defects in the production of cortisol, pregnenolone sulfate, and 17OH-progesterone, which were not apparent in basal condition. These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity.


Assuntos
Caderinas/genética , Epilepsia/sangue , Epilepsia/genética , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hormônios Esteroides Gonadais/sangue , Deficiência Intelectual/sangue , Deficiência Intelectual/genética , Pregnanolona/sangue , Pregnanolona/deficiência , Pregnenolona/sangue , 17-alfa-Hidroxiprogesterona/sangue , Adolescente , Hormônio Adrenocorticotrópico/farmacologia , Síndrome Adrenogenital/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Estradiol/sangue , Feminino , Humanos , Hidrocortisona/sangue , Progesterona/sangue , Estudos Prospectivos , Puberdade Precoce/sangue , Puberdade Precoce/genética , Valores de Referência
16.
Neurology ; 88(11): 1037-1044, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28202706

RESUMO

OBJECTIVE: To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations. METHODS: Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients. RESULTS: Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85% in the 0- to 6-month group, 51% in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity = 83.3%, specificity = 76.6%). CONCLUSIONS: In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.


Assuntos
Epilepsias Mioclônicas/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Curva ROC , Estatísticas não Paramétricas , Adulto Jovem
17.
Eur J Paediatr Neurol ; 21(3): 450-456, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28007337

RESUMO

BACKGROUND: Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA). METHODS: We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy. RESULTS: De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases. CONCLUSION: Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias.


Assuntos
Ataxia/genética , Canais de Cálcio Tipo N/genética , Cerebelo/anormalidades , Mutação de Sentido Incorreto , Ataxia/complicações , Atrofia/patologia , Criança , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/genética , Neuroimagem , Linhagem , Fenótipo
18.
Seizure ; 42: 20-28, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27693808

RESUMO

PURPOSE: to evaluate the efficacy and safety of intravenous (IV) lacosamide (LCM) in the treatment of seizure clusters (SC) and status epilepticus (SE) in hospitalized adult patients. METHODS: we prospectively analyzed treatment response, seizure outcome, and adverse effects of IV LCM in 38 patients with seizure emergencies (15 with SC, 23 with SE) during a hospital stay. The loading dose of IV LCM was 200-400mg and the maintenance dose was 200-400mg daily. Response to IV LCM was evaluated within 20min, 4h and 24h of LCM infusion. RESULTS: an acute anti-seizure effect after IV LCM was especially evident when it was first used - (SC) or second line (established SE) treatment. In particular, 87% of SC patients (13/15) and 80% of established SE (8/10) demonstrated response to LCM treatment, while no patients with super-refractory SE (0/8) responded to IV LCM according to our criteria. The loading of IV LCM was well tolerated, with mild adverse effects (2/38 temporary dizziness). In most patients, during and after administration of the loading dose of IV LCM a temporary (30min-1h) sedation was observed. No ECG and laboratory values-changes were documented in any of the patients. CONCLUSIONS: LCM is an effective and well-tolerated treatment when used to treat SC in hospitalized adult patients. As add-on therapy, it may be useful to stop seizure activity in patients with focal SE not responding to first/second-line intravenous AEDs.


Assuntos
Acetamidas/administração & dosagem , Anticonvulsivantes/administração & dosagem , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Acetamidas/efeitos adversos , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/efeitos adversos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Eletroencefalografia , Feminino , Hospitalização , Humanos , Pacientes Internados , Lacosamida , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/fisiopatologia , Resultado do Tratamento
20.
Epilepsy Res ; 125: 32-6, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27371789

RESUMO

Aim of this study is to compare PCDH19-related epilepsy and Dravet Syndrome (DS) in order to find out differences between these two infantile epilepsies with fever sensitivity. We retrospectively reviewed the medical records of 15 patients with PCDH19-related epilepsy and 19 with DS. Comparisons were performed with Fisher's exact test or Student's t-test. Females prevailed in PCDH19-related epilepsy. Epilepsy onset was earlier in DS (5.0+2.1 vs 11.2+7.0months; p<0.05). The second seizure/cluster occurred after a longer latency in PCDH19-related epilepsy rather than in DS (10.1±13.6 vs 2.2±2.1months; p<0.05). Seizures were mainly single and prolonged seizures in DS, and brief and clustered in PCDH19-related epilepsy. Myoclonic and clonic seizures have been found only in DS. Other types of seizures were found in both epilepsies with a prevalence of GTCS and atypical absences in DS, and focal motor and hypomotor seizures in PCDH19-related epilepsy. Seizures with affective symptoms have been confirmed to be typical of PCDH19-related epilepsy. Status Epilepticus equally occurred in both groups. Photosensitivity was detected only in DS. No differences were found about the presence of intellectual disabilities and behavioral disturbances. We were able to find out some distinctive features, which could address the diagnosis towards DS or PCDH19-related epilepsy, since first manifestation. These considerations suggest to definitively considering PCDH19 gene as cause of a proper epileptic phenotype.


Assuntos
Caderinas/genética , Síndromes Epilépticas/genética , Síndromes Epilépticas/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Idade de Início , Criança , Diagnóstico Diferencial , Síndromes Epilépticas/classificação , Síndromes Epilépticas/diagnóstico , Feminino , Seguimentos , Humanos , Testes de Inteligência , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , Caracteres Sexuais
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