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1.
Am J Hum Genet ; 110(1): 146-160, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36608681

RESUMO

Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132-requiring upregulation of neddylation to restore proteasomal function and proteasomal stress-led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature-delayed closure of the ischiopubic rami-correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.


Assuntos
Deficiência Intelectual , Linfopenia , Humanos , Proteína NEDD8/genética , Proteína NEDD8/metabolismo , Transdução de Sinais/genética , Deficiência Intelectual/genética , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Linfopenia/genética
2.
Epilepsia ; 62(7): e103-e109, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34041744

RESUMO

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia Generalizada/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/genética , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/etiologia , Exoma/genética , Feminino , Variação Genética , Humanos , Lactente , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Masculino , Mutação/genética , Fenótipo , Estado Epiléptico/diagnóstico , Estado Epiléptico/etiologia , Estado Epiléptico/genética , Adulto Jovem
3.
Epilepsia ; 58(12): 2098-2103, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29105055

RESUMO

OBJECTIVE: The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia. METHODS: Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation. RESULTS: Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) . SIGNIFICANCE: First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.


Assuntos
Espasmos Infantis/terapia , Hormônio Adrenocorticotrópico/uso terapêutico , Idade de Início , Anticonvulsivantes/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Prednisolona/uso terapêutico , Cobertura de Condição Pré-Existente , Estudos Prospectivos , Fatores Sexuais , Espasmos Infantis/fisiopatologia , Resultado do Tratamento , Vigabatrina/uso terapêutico
5.
Clin Trials ; 10(4): 568-86, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23818435

RESUMO

BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.


Assuntos
Epilepsia/genética , Genótipo , Fenótipo , Pesquisa em Genética , Humanos , Gestão da Informação , Análise de Sequência com Séries de Oligonucleotídeos , Projetos de Pesquisa , Estudos Retrospectivos
6.
Neurol Ther ; 12(2): 343-350, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36795289

RESUMO

Dravet syndrome (DS) is a severe genetic epilepsy characterized by early-life onset, seizures, and neurodevelopmental delays that have major impacts on affected children. DS is an incurable condition that requires a lifelong multidisciplinary approach involving both clinical and caregiver support. A better understanding of the multiple perspectives involved in the care of patients is necessary for supporting the diagnosis, management, and treatment of DS. Here we describe the personal experiences of a caregiver and a clinician facing the challenges of diagnosing and treating a patient throughout the three phases of DS. During the initial phase, the main goals include establishing an accurate diagnosis, coordination of care, and communication between clinicians and caregivers. After a diagnosis is established, frequent seizures and developmental delays are a major concern in the second phase, which is very taxing on children and their caregivers, so caregivers require support and resources to advocate for safe and effective care. Seizures may improve in the third phase, but developmental, communication, and behavioral symptoms persist as caregivers navigate the eventual transition from pediatric to adult care. Optimal care for patients is provided when clinicians are well educated on the syndrome and collaboration is established between members of the medical team and family.

7.
Epilepsia ; 52(6): 1071-5, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21671922

RESUMO

PURPOSE: Epilepsy and electroencephalographic abnormalities are frequent in idiopathic autism, but there is little information regarding treatment-resistant epilepsy (TRE) in this group. We sought to define the clinical and electrophysiologic characteristics and treatment outcomes in these patients. METHODS: We retrospectively reviewed clinical and laboratory data of patients with idiopathic autism evaluated at NYU Epilepsy Center during a 20-year period. KEY FINDINGS: One hundred twenty-seven patients had idiopathic autism and at least one epileptic seizure; 33.9% had TRE and 27.5% were seizure free. The remaining 38.6% of patients had infrequent seizures or insufficient data to categorize. Patients with TRE had a significantly earlier onset of seizures than seizure-free patients, and a trend for more developmental regression and motor and language delays. Three patients had surgical resection (two had limited improvement and one had no improvement) and one had an anterior callosotomy (no improvement). Vagus nerve stimulator (VNS) implantation provided limited improvement (2 patients) and no improvement (7). SIGNIFICANCE: This study found that TRE is common in idiopathic autism and more common with early age of seizure onset. Relatively few patients underwent surgical resection due to multifocal partial epilepsy, comorbid generalized epilepsy, or limited impact of ongoing partial seizures given other problems related to autism. Our small sample suggests that surgical and VNS outcomes in this group are less favorable than in other TRE populations.


Assuntos
Transtorno Autístico/complicações , Transtorno Autístico/fisiopatologia , Epilepsia/complicações , Epilepsia/fisiopatologia , Adolescente , Adulto , Transtorno Autístico/cirurgia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsia/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
8.
Ann Clin Transl Neurol ; 8(3): 639-644, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33538404

RESUMO

OBJECTIVE: Ataluren is a compound that reads through premature stop codons and increases protein expression by increasing translation without modifying transcription or mRNA stability. We investigated the safety and efficacy of ataluren in children with nonsense variants causing Dravet Syndrome (DS) and CDKL5 Deficiency Syndrome (CDD). METHODS: This single-center double-blind, placebo-controlled crossover trial randomized subjects to receive ataluren or placebo for 12 weeks (period 1), a 4-week washout, then another 12-week treatment (period 2). The primary outcome was ataluren's safety profile. The secondary outcome measures were (1) changes in convulsive and/or drop seizure frequency and (2) changes in minor seizure types during ataluren treatment compared to placebo. Exploratory objectives assessed changes in cognitive, motor, and behavioral function as well as quality of life during ataluren therapy. RESULTS: We enrolled seven subjects with DS and eight subjects with CDD. Three treatment-related adverse events (AE) occurred during the blinded phases. Two subjects withdrew due to AE. Ataluren was not effective in reducing seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with either DS or CDD due to nonsense variants. Limitations included a small sample size and 12-week treatment phase, possibly too short to identify a disease-modifying effect. SIGNIFICANCE: There was no difference between ataluren and placebo; ataluren is not an effective therapy for seizures or other disorders in children with DS or CDD due to nonsense variants. There were no drug-related serious AE during the double-blind period, consistent with ataluren's favorable safety profile in larger studies. (Funded by Epilepsy Foundation, Dravet Syndrome Foundation, Finding A Cure for Seizures and Epilepsy and PTC Therapeutics, Inc.; ClinicalTrials.gov number, NCT02758626).


Assuntos
Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Síndromes Epilépticas/tratamento farmacológico , Oxidiazóis/farmacologia , Espasmos Infantis/tratamento farmacológico , Criança , Pré-Escolar , Códon sem Sentido , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Oxidiazóis/administração & dosagem , Oxidiazóis/efeitos adversos , Falha de Tratamento
9.
J Child Neurol ; 32(1): 35-40, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27655472

RESUMO

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting cannabidiol, 6 of 7 patients' seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add cannabidiol as a possible treatment for FIRES.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Síndromes Epilépticas/tratamento farmacológico , Febre/complicações , Estado Epiléptico/tratamento farmacológico , Doença Aguda , Criança , Doença Crônica , Epilepsia Resistente a Medicamentos/etiologia , Síndromes Epilépticas/etiologia , Humanos , Infecções/complicações , Masculino , Estado Epiléptico/etiologia , Resultado do Tratamento
10.
Autism Res ; 9(2): 311-20, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26112160

RESUMO

The male:female ratio in autism spectrum disorder (ASD) averages greater than 4:1 while the male:female ratio of ASD with epilepsy averages less than 3:1. This indicates an elevated risk of epilepsy in females with ASD; yet, it is unknown whether phenotypic features of epilepsy and ASD differ between males and females with this comorbidity. The goal of this study is to investigate sex differences in phenotypic features of epilepsy and ASD in a prospective sample of 130 children and young adults with an initial ASD diagnosis and subsequent epilepsy diagnosis. All participants were characterized by standardized diagnostic inventories, parent/caregiver completed questionnaires, and medical/academic record review. Diagnostic classifications of epilepsy, ASD, and intellectual disability were performed by board certified neurologists and a pediatric neuropsychologist. Results demonstrated a lower male:female ratio (1.8:1) in individuals with ASD and treatment-resistant epilepsy relative to those with ASD and treatment-responsive epilepsy (4.9:1), indicating a higher risk of treatment-resistant epilepsy in females. Mild neuroimaging abnormalities were more common in females than males and this was associated with increased risk of treatment-resistance. In contrast, ASD symptom severity was lower in females compared with males. Findings distinguish females with ASD and epilepsy as a distinct subgroup at higher risk for a more severe epilepsy phenotype in the context of a less severe ASD phenotype. Increased risk of anti-epileptic treatment resistance in females with ASD and epilepsy suggests that comprehensive genetic, imaging, and neurologic screening and enhanced treatment monitoring may be indicated for this subgroup. Autism Res 2016, 9: 311-320. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Epilepsia/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Comorbidade , Feminino , Humanos , Masculino , Estudos Prospectivos , Risco , Distribuição por Sexo , Adulto Jovem
11.
Lancet Neurol ; 15(3): 270-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26724101

RESUMO

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. FUNDING: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.


Assuntos
Anticonvulsivantes/farmacologia , Canabidiol/farmacologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Convulsões/tratamento farmacológico , Adolescente , Adulto , Idade de Início , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Lactente , Masculino , Adulto Jovem
13.
Neurology ; 83(16): 1444-9, 2014 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-25230998

RESUMO

OBJECTIVE: We studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview. METHODS: In this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic-clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their "grand mal seizures." Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions. RESULTS: Seven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura. CONCLUSIONS: Auras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.


Assuntos
Epilepsia Generalizada/epidemiologia , Adulto , Fatores Etários , Idade de Início , Estudos Transversais , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/fisiopatologia , Feminino , Humanos , Entrevistas como Assunto , Masculino , Prevalência , Convulsões/epidemiologia , Convulsões/fisiopatologia , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem
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