RESUMO
OBJECTIVE: Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening. METHODS: We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH). RESULTS: We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. SIGNIFICANCE: Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.
Assuntos
Epilepsia/genética , Proteínas Munc18/genética , Idade de Início , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Eletroencefalografia , Epilepsias Mioclônicas/genética , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação , Estudos Retrospectivos , Deleção de Sequência , Espasmos Infantis/genéticaRESUMO
BACKGROUND: Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials. OBJECTIVE: We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients. METHODS: We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2). RESULTS: Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups. CONCLUSION: We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.
Assuntos
Deficiência Intelectual/psicologia , Pensamento , Adolescente , Adulto , Estudos de Casos e Controles , Cognição , Síndrome de Down/fisiopatologia , Síndrome de Down/psicologia , Feminino , Síndrome do Cromossomo X Frágil/fisiopatologia , Síndrome do Cromossomo X Frágil/psicologia , Proteínas de Homeodomínio/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Fatores de Transcrição/genética , Adulto JovemRESUMO
BACKGROUND: For 60% of acute febrile encephalitis cases, the cause is unknown. Autoantibodies directed against different synaptic proteins or receptors in patients with autoimmune encephalitis have recently been described and could indicate a differential diagnosis of infectious encephalitis. OBJECTIVE: The aim of this study was to retrospectively investigate the presence of autoantibodies directed against synaptic proteins or receptors in patients with acute febrile encephalitis. Samples were collected in France in 2007 during a national prospective study. METHODS: A total of 253 patients with acute febrile encephalitis were enrolled in 2007. Clinical data were collected with a standardized questionnaire. When possible, cerebrospinal fluid CSF was collected and stored at -80 °C. A total of 108 CSF samples were available for retrospective autoantibody screening. Among the 108 patients, infectious etiology had been detected in 38 cases (35%); of these 38 patients, 29 (27%) had viral encephalitis, and 9 (8%) had bacterial encephalitis. No specific diagnosis was indicated for the other 70 patients (65%). Autoantibodies were detected using a cell-based assay in which HEK293 cells were transfected with plasmids coding for different synaptic proteins or receptors. RESULTS: Two patients had anti-NMDA receptor antibodies (NMDAR-Abs), and all patients were negative for anti-Lgi1, CASPR2, GABABR, AMPAR, and mGluR5 antibodies. The two patients with NMDAR-Abs presented neurological and psychiatric symptoms typical of NMDAR-Abs encephalitis. CONCLUSIONS: Autoimmune etiology seems to be rare (less than 2%) in patients with acute febrile encephalitis. However, patients should be systematically screened for the presence of NMDAR-Abs, particularly patients presenting with psychiatric symptoms.
Assuntos
Encefalopatias/diagnóstico , Encefalopatias/patologia , Encefalite por Arbovirus/diagnóstico , Encefalite por Arbovirus/patologia , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/patologia , Receptores de N-Metil-D-Aspartato/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/líquido cefalorraquidiano , Encefalopatias/epidemiologia , Líquido Cefalorraquidiano/química , Criança , Pré-Escolar , Diagnóstico Diferencial , Encefalite , Encefalite por Arbovirus/epidemiologia , Estudos Epidemiológicos , Feminino , França/epidemiologia , Doença de Hashimoto/epidemiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation. METHODS: We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control. RESULTS: Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. CONCLUSION: These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.
Assuntos
Apraxias/genética , Extremidades/fisiopatologia , Duplicação Gênica , Proteínas de Homeodomínio/genética , Modelos Biológicos , Fatores de Transcrição/genética , Adolescente , Adulto , Fenômenos Biomecânicos , Estudos de Casos e Controles , Criança , Síndrome de Down/fisiopatologia , Humanos , Mutação , Adulto JovemRESUMO
Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive metabolic disease. A delay of treatment may affect outcome and early initiation of pyridoxine based on effective diagnosis is crucial to ensure good cognitive outcome in neonates. A consensus for the diagnosis of PDE is based on refractive seizures and responsiveness to pyridoxine, however, a growing body of evidence suggests that additional elements should be considered which include biochemical data, genetic screening, and EEG monitoring. We present a case study of a neonate with PDE, who presented with misleading clinical presentation and a novel mutation in the antiquitin (ALDH7A1) gene (A294V), and highlight important aspects in order to consider the definition of diagnosis and management of PDE in the light of more recent data.
Assuntos
Aldeído Desidrogenase/genética , Eletroencefalografia , Epilepsia , Mutação/genética , Piridoxina/uso terapêutico , Gravação em Vídeo , Complexo Vitamínico B/uso terapêutico , Criança , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/metabolismo , Feminino , HumanosRESUMO
We report an 11-year-old girl for whom the diagnosis of cri du chat syndrome (CdCS) was made during a genetic investigation of childhood apraxia of speech. The patient presented with the classic chromosome 5 short arm deletion found in CdCS. The microdeletion, characterised using aCGH (array Comparative Genomic Hybridisation), was 12.85 Mb, overlapping the 5p15.2 and 5p15.3 critical regions. CdCS is typically associated with severe mental retardation while this patient had normal intellectual performance, confirmed by normal results from categorisation tasks. This mild phenotype was assessed using a comprehensive cognitive battery. Language evaluation showed normal receptive vocabulary scores, in contrast with obvious oro-facial dyspraxia. Disabled fine motor skills were confirmed as well as weak visuo-spatial reasoning abilities. In conclusion, fine cognitive assessment may be worthwhile for patients with CdCS since good intellectual functioning may be masked by severe speech and gestural dyspraxia, thus requiring specific teaching and rehabilitation strategies.