RESUMO
OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.
Assuntos
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
Familial adult myoclonus epilepsy (FAME) is an autosomal dominant condition characterized by the association of myoclonic tremor and epilepsy mainly with onset in adulthood. The clinical course is non-progressive or slowly progressive, as epilepsy is commonly controlled with appropriate antiseizure medication and individuals have a normal life expectancy. However, the myoclonus severity increases with age and leads to some degree of disability in the elderly. Because the non-coding repeat expansions responsible for FAME are not detected by routine genetic tests being used at this time, a clinical diagnosis accompanied by neurophysiological testing remains essential to guide the geneticist on the selection of the specific genetic technique.
Assuntos
Epilepsias Mioclônicas , Mioclonia , Humanos , Adulto , Idoso , Mioclonia/diagnóstico , Mioclonia/genética , Mioclonia/complicações , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/complicações , Linhagem , Progressão da DoençaRESUMO
OBJECTIVE: The objective of the study was to describe the electroclinical features, seizure semiology, and the long-term evolution of gelastic seizures (GS) not associated with hypothalamic hamartoma (HH). METHODS: We reviewed video-electroencephalogram (video-EEG) recordings from pediatric patients with GS without HH admitted to 14 Italian epilepsy centers from 1994 to 2013. We collected information about age at onset, seizures semiology, EEG and magnetic resonance imaging (MRI) findings, treatment, and clinical outcome in terms of seizure control after a long-term follow-up. RESULTS: A total of 30 pediatric patients were stratified into two groups according to neuroimaging findings: group 1 including 19 children (63.3%) with unremarkable neuroimaging and group 2 including 11 children with structural brain abnormalities (36.7%). At the follow-up, patients of group 1 showed better clinical outcome both in terms of seizure control and use of AED polytherapy. Our patients showed remarkable clinical heterogeneity, including seizure semiology and epilepsy severity. Electroencephalogram recordings showed abnormalities mainly in the frontal, temporal, and frontotemporal regions without relevant differences between the two groups. Overall, carbamazepine showed good efficacy to control GS. CONCLUSIONS: Patients with nonlesional GS have a more favorable outcome with better drug response, less need of polytherapy, and good long-term prognosis, both in terms of seizure control and EEG findings.
Assuntos
Eletroencefalografia , Epilepsias Parciais/etiologia , Hamartoma/complicações , Doenças Hipotalâmicas/complicações , Convulsões/etiologia , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Epilepsias Parciais/diagnóstico , Feminino , Seguimentos , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Convulsões/diagnóstico , Gravação em VídeoRESUMO
OBJECTIVE: Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder. METHODS: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis. RESULTS: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics. INTERPRETATION: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. Ann Neurol 2018;83:483-493.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/genética , Variação Genética/genética , Proteínas com Domínio LIM/genética , Mutação/genética , Adulto , Sequência de Aminoácidos , Animais , Células COS , Chlorocebus aethiops , Estudos de Coortes , Feminino , Humanos , Itália , Masculino , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Oxigenases de Função Mista , Linhagem , Proteína Reelina , Adulto JovemRESUMO
OBJECTIVE: Although many studies have attempted to describe treatment outcomes in patients with drug-resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug-resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. METHODS: This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug-resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). RESULTS: A seizure-free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a "treatment failure" as compared to the judgment of the investigator (46.7% vs 62.9%, P < 0.001), because many more patients were rated as "undetermined outcome" (45.6% vs 27.7%, P < 0.001); 19.3% of the recruited patients were not considered drug-resistant by the EP. SIGNIFICANCE: This study validates the use of ILAE treatment outcome criteria in a real-life setting, providing validated estimates of seizure freedom in patients with drug-resistant focal epilepsy in relation to the number of previously failed AEDs. Fewer than one in 10 patients achieved seizure freedom on a newly introduced AED over the study period. Pseudo drug resistance could be identified in one of five cases.
Assuntos
Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsias Parciais/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Resultado do Tratamento , Adulto JovemRESUMO
Many neuropsychiatric phenotypes have been reported in association with rearrangements in the 15q11-q13 region. Clinical presentations can include hypotonia, developmental delay, severe/moderate intellectual disabilities, poor expressive language, difficult to treat epilepsy, and autism spectrum disorders. Here we report an additional case of a girl with inversion duplication on chromosome 15 (Inv-Dup 15) showing a peculiar and milder clinical phenotype, including atypical high-functioning autism disorder, late onset and drug-responsive epilepsy, and a relatively good language development . This report suggests that a diagnosis of Inv-Dup (15) can be suspected during more benign atypical condition with a better outcome than usually reported.
Assuntos
Transtorno do Espectro Autista/fisiopatologia , Epilepsia/fisiopatologia , Deficiência Intelectual/fisiopatologia , Adulto , Transtorno do Espectro Autista/etiologia , Aberrações Cromossômicas , Cromossomos Humanos Par 15 , Epilepsia/etiologia , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/etiologiaRESUMO
Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.
Assuntos
Moléculas de Adesão Celular Neuronais/genética , Epilepsia do Lobo Frontal/genética , Epilepsia do Lobo Frontal/patologia , Proteínas da Matriz Extracelular/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Proteínas do Tecido Nervoso/genética , Serina Endopeptidases/genética , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/patologia , Animais , Sequência de Bases , Moléculas de Adesão Celular Neuronais/sangue , Moléculas de Adesão Celular Neuronais/química , Moléculas de Adesão Celular Neuronais/metabolismo , Mapeamento Cromossômico , Exoma , Proteínas da Matriz Extracelular/sangue , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/metabolismo , Imunofluorescência , Componentes do Gene , Humanos , Immunoblotting , Peptídeos e Proteínas de Sinalização Intercelular , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Conformação Proteica , Dobramento de Proteína , Proteínas/metabolismo , Ratos , Proteína Reelina , Análise de Sequência de DNA , Serina Endopeptidases/sangue , Serina Endopeptidases/química , Serina Endopeptidases/metabolismoRESUMO
Gelastic seizures, usually with onset in early infancy, are the hallmark manifestation of hypothalamic hamartoma. This seizure type is directly generated by hamartoma itself, intrinsically epileptogenic because of its anatomofunctional organization. Other types of seizures, focal or generalized, may appear during the evolution, probably resulting from mechanisms of secondary epileptogenesis. Nevertheless, the clinical expression and the severity of the syndrome, ranging from a focal drug-resistant epilepsy to a catastrophic generalized encephalopathy with severe cognitive and behavioral impairments, depends on the size and the site of attachment of the hamartoma. Early suspicion, timely diagnosis, and appropriate treatment are mandatory to reverse a potential catastrophic evolution of this condition.
Assuntos
Epilepsias Parciais/diagnóstico , Hamartoma/diagnóstico , Doenças Hipotalâmicas/diagnóstico , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/fisiopatologia , Transtornos do Comportamento Infantil/cirurgia , Pré-Escolar , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/cirurgia , Progressão da Doença , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia Resistente a Medicamentos/cirurgia , Diagnóstico Precoce , Intervenção Médica Precoce , Eletroencefalografia , Epilepsias Parciais/fisiopatologia , Epilepsias Parciais/cirurgia , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/fisiopatologia , Epilepsia Generalizada/cirurgia , Hamartoma/fisiopatologia , Hamartoma/cirurgia , Humanos , Doenças Hipotalâmicas/fisiopatologia , Doenças Hipotalâmicas/cirurgia , Hipotálamo/fisiopatologia , Hipotálamo/cirurgia , Lactente , Excitação Neurológica/fisiologia , Tomografia por Emissão de Pósitrons , Prognóstico , Radiocirurgia , Processamento de Sinais Assistido por Computador , SíndromeRESUMO
OBJECTIVE: To describe the clinical phenotype of 7 families with Autosomal Dominant Lateral Temporal Lobe Epilepsy (ADLTE) related to Reelin (RELN) mutations comparing the data with those observed in 12 LGI1-mutated pedigrees belonging to our series. METHODS: Out of 40 Italian families with ADLTE, collected by epileptologists participating in a collaborative study of the Commission for Genetics of the Italian League against Epilepsy encompassing a 14-year period (2000-2014), 7 (17.5%) were found to harbor heterozygous RELN mutations. The whole series also included 12 (30%) LGI1 mutated families and 21 (52.5%) non-mutated pedigrees. The clinical, neurophysiological, and neuroradiological findings of RELN and LGI1 mutated families were analyzed. RESULTS: Out of 28 affected individuals belonging to 7 RELN mutated families, 24 had sufficient clinical data available for the study. In these patients, the epilepsy onset occurred at a mean age of 20years, with focal seizures characterized by auditory auras in about 71% of the cases, associated in one-third of patients with aphasia, visual disturbances or other less common symptoms (vertigo or déjà-vu). Tonic-clonic seizures were reported by almost all patients (88%), preceded by typical aura in 67% of cases. Seizures were precipitated by environmental noises in 8% of patients and were completely or almost completely controlled by antiepileptic treatment in the vast majority of cases (96%). The interictal EEG recordings showed epileptiform abnormalities or focal slow waves in 80% of patients, localized over the temporal regions, with marked left predominance and conventional 1,5T MRI scans were not contributory. By comparing these findings with those observed in families with LGI1 mutations, we did not observe significant differences except for a higher rate of left-sided EEG abnormalities in the RELN group. SIGNIFICANCE: Heterozygous RELN mutations cause a typical ADLTE syndrome, indistinguishable from that associated with LGI1 mutations.
Assuntos
Moléculas de Adesão Celular Neuronais/genética , Epilepsia do Lobo Frontal/genética , Proteínas da Matriz Extracelular/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Serina Endopeptidases/genética , Transtornos do Sono-Vigília/genética , Adulto , Epilepsia do Lobo Frontal/diagnóstico , Feminino , Humanos , Itália , Masculino , Linhagem , Proteína Reelina , Transtornos do Sono-Vigília/diagnóstico , Adulto JovemRESUMO
Nowadays a substantial armamentarium of antiepileptic drugs (AEDs) is available, including drugs with different mechanisms of action, pharmacokinetics, efficacy and tolerability; therefore the choice for the right treatment is often challenging. The specific characteristic of the drug, the epileptic syndrome, seizure types and the patient's features need to be taken into consideration driving the choice through available evidence-based studies, which are often lacking for older AEDs. Besides, study conditions in registered clinical trials (RCTs) are quite different from daily clinical practice, which is more complex and various. When dealing with first diagnosed epilepsy, monotherapy is widely accepted as the gold standard option. Likewise, alternative monotherapy should be considered when the first drug treatment fails. However, the association of different AEDs in polytherapy is a common practice. The choice of AEDs used in association is often based on clinical experience or anecdotal observations or small clinical studies. Polytherapy should be as "rational" as possible and consider the mechanism of action, the pharmacokinetic characteristics and the safety of each drug. When dealing with drug resistant patients, clinicians should never give up and consider the use of AEDs acting on new targets. An attempt to come back to a monotherapy or simpler therapeutic regimen should be pursued even in patients who were previously drug resistant. This review will focus on the strategies to treat epilepsy by choosing among 25 available drugs.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Animais , Humanos , Convulsões/tratamento farmacológicoRESUMO
Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.
Assuntos
Proteínas de Ligação a DNA/genética , Epilepsia Reflexa/genética , Predisposição Genética para Doença , Mutação/genética , Animais , Eletroencefalografia , Técnicas de Silenciamento de Genes/métodos , Humanos , Estimulação Luminosa/métodos , Fatores de Risco , Peixe-ZebraRESUMO
OBJECTIVE: The objective of this report was to assess the psychiatric comorbidity in a group of patients affected by autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME). METHODS: Reliable and validated psychodiagnostic scales including the BDI (Beck Depression Inventory), STAI-Y1 and 2 (State-Trait Anxiety Inventory - Y; 1 and 2), MMPI-2 (Minnesota Multiphasic Personality Inventory - 2), and QoLIE-31 (Quality of Life in Epilepsy Inventory - 31) were administered to 20 patients with ADCME, 20 patients with juvenile myoclonic epilepsy (JME), and 20 healthy controls. RESULTS: There was a higher prevalence of mood disorders in patients with ADCME compared to patients with JME and healthy controls, particularly depression (p=0.035 and p=0.017, respectively) and state anxiety (p=0.024 and p=0.019, respectively). Trait anxiety was not different from JME (p=0.102) but higher than healthy controls (p=0.017). The myoclonus score positively correlated with both state (rho: 0.58, p=0.042) and trait anxiety (rho: 0.65, p=0.011). These psychiatric features were also often associated with pathological traits of personality: paranoid (OR: 25.7, p=0.003), psychasthenia (OR: 7.0, p=0.023), schizophrenia (OR: 8.5, p=0.011), and hypomania (OR: 5.5, p=0.022). Finally, in patients with ADCME, decreased quality of life correlated with these psychiatric symptoms. SIGNIFICANCE: Patients with ADCME show a significant psychiatric burden that impairs their quality of life. A comprehensive psychiatric evaluation should be offered at the time of diagnosis to detect these comorbidities and to treat them.
Assuntos
Epilepsia/psicologia , Transtornos Mentais/psicologia , Mioclonia/psicologia , Tremor/psicologia , Adulto , Ansiedade/epidemiologia , Ansiedade/psicologia , Depressão/epidemiologia , Depressão/psicologia , Epilepsia/complicações , Epilepsia/epidemiologia , Feminino , Humanos , Itália/epidemiologia , Masculino , Transtornos Mentais/complicações , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Transtornos do Humor/epidemiologia , Epilepsia Mioclônica Juvenil/complicações , Epilepsia Mioclônica Juvenil/psicologia , Mioclonia/complicações , Mioclonia/epidemiologia , Transtornos da Personalidade/epidemiologia , Transtornos da Personalidade/psicologia , Prevalência , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/complicações , Transtornos Psicóticos/epidemiologia , Qualidade de Vida , Tremor/complicações , Tremor/epidemiologia , Adulto JovemAssuntos
Epilepsia , Deficiência Intelectual , Criança , Epilepsia/diagnóstico , Epilepsia/genética , GTP Fosfo-Hidrolases/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Convulsões , Deleção de SequênciaRESUMO
Mutations in the DEPDC5 (DEP domain-containing protein 5) gene are a major cause of familial focal epilepsy with variable foci (FFEVF) and are predicted to account for 12-37% of families with inherited focal epilepsies. To assess the clinical impact of DEPDC5 mutations in familial temporal lobe epilepsy, we screened a collection of Italian families with either autosomal dominant lateral temporal epilepsy (ADLTE) or familial mesial temporal lobe epilepsy (FMTLE). The probands of 28 families classified as ADLTE and 17 families as FMTLE were screened for DEPDC5 mutations by whole exome or targeted massive parallel sequencing. Putative mutations were validated by Sanger sequencing. We identified a DEPDC5 nonsense mutation (c.918C>G; p.Tyr306*) in a family with two affected members, clinically classified as FMTLE. The proband had temporal lobe seizures with prominent psychic symptoms (déjà vu, derealization, and forced thoughts); her mother had temporal lobe seizures, mainly featuring visceral epigastric auras and anxiety. In total, we found a single DEPDC5 mutation in one of (2.2%) 45 families with genetic temporal lobe epilepsy, a proportion much lower than that reported in other inherited focal epilepsies.
Assuntos
Epilepsia do Lobo Temporal/genética , Saúde da Família , Mutação/genética , Proteínas Repressoras/genética , Adulto , Análise Mutacional de DNA , Feminino , Proteínas Ativadoras de GTPase , Humanos , Itália , MasculinoRESUMO
OBJECTIVE: To evaluate direct medical costs and their predictors in patients with refractory epilepsy enrolled into the SOPHIE study (Study of Outcomes of PHarmacoresistance In Epilepsy) in Italy. METHODS: Adults and children with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers and followed for 18 months. At entry, all subjects underwent a structured interview and a medical examination, and were asked to keep records of diagnostic examinations, laboratory tests, specialist consultations, treatments, hospital admissions, and day-hospital days during follow-up. Study visits included assessments every 6 months of seizure frequency, health-related quality of life (Quality of Life in Epilepsy Inventory 31), medication-related adverse events (Adverse Event Profile) and mood state (Beck Depression Inventory-II). Cost items were priced by applying Italian tariffs. Cost estimates were adjusted to 2013 values. RESULTS: Of 1,124 enrolled individuals, 1,040 completed follow-up. Average annual cost per patient was 4,677. The highest cost was for antiepileptic drug (AED) treatment (50%), followed by hospital admissions (29% of overall costs). AED polytherapy, seizure frequency during follow-up, grade III pharmacoresistance, medical and psychiatric comorbidities, and occurrence of status epilepticus during follow-up were identified as significant predictors of higher costs. Age between 6 and 11 years, and genetic (idiopathic) generalized epilepsies were associated with the lowest costs. Costs showed prominent variation across centers, largely due to differences in the clinical characteristics of cohorts enrolled at each center and the prescribing of second-generation AEDs. Individual outliers associated with high costs related to hospital admissions had a major influence on costs in many centers. SIGNIFICANCE: Refractory epilepsy is associated with high costs that affect individuals and society. Costs differ across centers in relation to the characteristics of patients and the extent of use of more expensive, second-generation AEDs. Epilepsy-specific costs cannot be easily differentiated from costs related to comorbidities.
Assuntos
Epilepsia/economia , Epilepsia/epidemiologia , Custos de Cuidados de Saúde , Qualidade de Vida , Adolescente , Adulto , Estudos de Coortes , Epilepsia/terapia , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Epilepsy affects approximately 3% of the world's population, and sudden death is a significant cause of death in this population. Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of all these cases, which increases the rate of sudden death by 24-fold as compared to the general population. The underlying mechanisms are still not elucidated, but recent studies suggest the possibility that a common genetic channelopathy might contribute to both epilepsy and cardiac disease to increase the incidence of death via a lethal cardiac arrhythmia. We performed genetic testing in a large cohort of individuals with epilepsy and cardiac conduction disorders in order to identify genetic mutations that could play a role in the mechanism of sudden death. Putative pathogenic disease-causing mutations in genes encoding cardiac ion channel were detected in 24% of unrelated individuals with epilepsy. Segregation analysis through genetic screening of the available family members and functional studies are crucial tasks to understand and to prove the possible pathogenicity of the variant, but in our cohort, only two families were available. Despite further research should be performed to clarify the mechanism of coexistence of both clinical conditions, genetic analysis, applied also in post-mortem setting, could be very useful to identify genetic factors that predispose epileptic patients to sudden death, helping to prevent sudden death in patients with epilepsy.
Assuntos
Arritmias Cardíacas/genética , Arritmias Cardíacas/mortalidade , Morte Súbita/epidemiologia , Morte Súbita/etiologia , Epilepsia/genética , Epilepsia/mortalidade , Genética Forense , Alelos , Síndrome de Brugada/genética , Síndrome de Brugada/mortalidade , Canalopatias/genética , Canalopatias/mortalidade , Códon sem Sentido/genética , Estudos de Coortes , Estudos Transversais , Análise Mutacional de DNA , Triagem de Portadores Genéticos , Testes Genéticos , Variação Genética/genética , Humanos , Incidência , Síndrome do QT Longo/genética , Síndrome do QT Longo/mortalidade , Mutação de Sentido Incorreto/genética , Análise de Sequência de DNARESUMO
Epilepsy is one of the most common presentations associated with chromosome aberrations. Detailed descriptions of some aberration-specific epileptic and electroencephalographic (EEG) phenotypes have been reported (i.e., Angelman syndrome, ring 20 etc.). However there is limited and mixed information about the characteristics of epilepsy related to trisomy 18. Thus a common seizure phenotype has not been characterized yet. Here we describe in detail a patient with refractory epilepsy and partial 18q trisomy.
Assuntos
Epilepsia/genética , Epilepsia/patologia , Trissomia/patologia , Adulto , Cromossomos Humanos Par 18/genética , Hibridização Genômica Comparativa , Eletroencefalografia , Humanos , Masculino , Trissomia/genéticaRESUMO
OBJECTIVE: Autosomal dominant lateral temporal epilepsy (ADLTE) is a focal epileptic syndrome characterized by auditory or aphasic auras. Mutations in the LGI1 gene account for <50% of ADLTE families. To identify copy number variants (CNVs) related to ADLTE, we examined a collection of ADLTE families without LGI1 mutations. METHODS: Twenty-one families were included based on a history of focal seizures with auditory and/or receptive aphasic symptoms in two or more individuals, absence of brain abnormalities, and negative LGI1 test. DNA suitable for single nucleotide polymorphism-array analysis was genotyped using the high-density HumanOmni1-Quad v1.0 beadchip (Illumina). CNVs were inferred using the PennCNV algorithm. Selected CNVs were validated by real-time quantitative polymerase chain reaction (qPCR). RESULTS: We analyzed 62 affected and 114 unaffected members of our study families and identified a total of 11,214 CNVs, corresponding to 1,890 unique regions with an average size of 67.3 kb. Most CNVs were <50 kb, whereas a small proportion (1.2%) exceeded 500 kb. We identified 12 rare CNVs that segregated with lateral temporal epilepsy in single families. Particularly, we found rare microdeletions within or near two genes, RBFOX1 and NRXN1, previously shown to harbor deletions associated with idiopathic generalized epilepsy, and a microduplication in the proximal region of chromosome 1q21.1, where duplications have been associated with various neurodevelopmental disorders and epilepsy. We also found numerous polymorphic CNVs in the affected members of one or more families, including a deletion of the PCDHA8/10 genes, which was enriched in the patients of our family cohort. SIGNIFICANCE: Our results provide clues on genes for susceptibility to ADLTE, particularly in those families where the inheritance pattern is less compatible with autosomal dominance. Some of these genes also confer risk for other epilepsy syndromes.
Assuntos
Variações do Número de Cópias de DNA/genética , Epilepsia do Lobo Temporal/genética , Predisposição Genética para Doença/genética , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
We report the case of 62-year-old woman referred to our department because of a clinical suspicion of tonic-clonic seizures. Clinical examination revealed an exaggerated startle reflex, EEG showed a photomyoclonic response, and blood tests indicated severe hypocalcaemia. Additional clinical data, treatment strategies, and long-term follow-up visits were reported. The present report discusses the difficulties in distinguishing between epileptic and non-epileptic startles, and shows, for the first time, exaggerated startle reflex and extreme photomyoclonic response due to severe hypocalcaemia.
Assuntos
Hipocalcemia/complicações , Reflexo de Sobressalto/fisiologia , Convulsões/etiologia , Eletroencefalografia/métodos , Feminino , Seguimentos , Humanos , Hipocalcemia/diagnóstico , Hipocalcemia/fisiopatologia , Pessoa de Meia-Idade , Convulsões/tratamento farmacológico , Gravação em Vídeo/métodos , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
There has been increased interest in a possible association between epilepsy channelopathies and cardiac arrhythmias, such as long QT syndrome (LQTS). We report a kindred that features LQTS, idiopathic epilepsy, and increased risk of sudden death. Genetic study showed a previously unreported heterozygous point mutation (c.246T>C) in the KCNH2 gene. Functional studies showed that the mutation induces severe loss of function. This observation provides further evidence for a possible link between idiopathic epilepsy and LQTS.