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1.
Front Pediatr ; 9: 621200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33748042

RESUMO

Objective: To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as de novo West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms. Methods: We analyzed data from an unpublished cohort of 28 genetically confirmed cases of PDE with antiquitine (ATQ) deficiency and performed a review of the literature looking for description of West syndrome in patients with either PDE with ATQ deficiency or PLP-dependent epilepsy with Pyridox(am)ine phosphate oxidase (PNPO) deficiency. Results: Of the 28 cases from the ATQ deficiency French cohort, 5 had spasms. In four cases, spasms were associated with other types of seizures (myoclonus, focal seizures). In the last case, seizures started on the day of birth. None of these cases corresponded to de novo West syndrome. The review of the literature found only one case of PNPO deficiency presenting as de novo West syndrome and no case of ATQ deficiency. Significance: The presentation of PDE- and PLP-dependent epilepsy as de novo West syndrome is so exceptional that it probably does not justify a systematic trial of pyridoxine or PLP. We propose considering a therapeutic trial with these vitamins in West syndrome if spasms are associated with other seizure types or start before the age of 2 months.

2.
Eur J Med Genet ; 63(12): 104063, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32947049

RESUMO

OBJECTIVE: To perform genotype-phenotype, clinical and molecular analysis in a large 3-generation family with autosomal dominant congenital spinal muscular atrophy. METHODS: Using a combined genetic approach including whole genome scanning, next generation sequencing-based multigene panel, whole genome sequencing, and targeted variant Sanger sequencing, we studied the proband and multiple affected individuals of this family who presented bilateral proximal lower limb muscle weakness and atrophy. RESULTS: We identified a novel heterozygous variant, c.1826T > C; p.Ile609Thr, in the DYNC1H1 gene localized within the common haplotype in the 14q32.3 chromosomal region which cosegregated with disease in this large family. Within the family, affected individuals were found to have a wide array of clinical variability. Although some individuals presented the typical lower motor neuron phenotype with areflexia and denervation, others presented with muscle weakness and atrophy, hyperreflexia, and absence of denervation suggesting a predominant upper motor neuron disease. In addition, some affected individuals presented with an intermediate phenotype characterized by hyperreflexia and denervation, expressing a combination of lower and upper motor neuron defects. CONCLUSION: Our study demonstrates the wide clinical variability associated with a single disease causing variant in DYNC1H1 gene and this variant demonstrated a high penetrance within this large family.


Assuntos
Dineínas do Citoplasma/genética , Atrofia Muscular Espinal/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neurônios Motores/fisiologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular Espinal/patologia , Linhagem , Fenótipo , Reflexo , Extremidade Superior/fisiopatologia
3.
Neurology ; 94(13): e1378-e1385, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32123049

RESUMO

OBJECTIVE: To assess nonparoxysmal movement disorders in ATP1A3 mutation-positive patients with alternating hemiplegia of childhood (AHC). METHODS: Twenty-eight patients underwent neurologic examination with particular focus on movement phenomenology by a specialist in movement disorders. Video recordings were reviewed by another movement disorders specialist and data were correlated with patients' characteristics. RESULTS: Ten patients were diagnosed with chorea, 16 with dystonia (nonparoxysmal), 4 with myoclonus, and 2 with ataxia. Nine patients had more than one movement disorder and 8 patients had none. The degree of movement disorder was moderate to severe in 12/28 patients. At inclusion, dystonic patients (n = 16) were older (p = 0.007) than nondystonic patients. Moreover, patients (n = 18) with dystonia or chorea, or both, had earlier disease onset (p = 0.042) and more severe neurologic impairment (p = 0.012), but this did not correlate with genotype. All patients presented with hypotonia, which was characterized as moderate or severe in 16/28. Patients with dystonia or chorea (n = 18) had more pronounced hypotonia (p = 0.011). Bradykinesia (n = 16) was associated with an early age at assessment (p < 0.01). Significant dysarthria was diagnosed in 11/25 cases. A history of acute neurologic deterioration and further regression of motor function, typically after a stressful event, was reported in 7 patients. CONCLUSIONS: Despite the relatively limited number of patients and the cross-sectional nature of the study, this detailed categorization of movement disorders in patients with AHC offers valuable insight into their precise characterization. Further longitudinal studies on this topic are needed.


Assuntos
Hemiplegia/complicações , Transtornos dos Movimentos/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Mutação , ATPase Trocadora de Sódio-Potássio/genética , Adulto Jovem
4.
Neurol Genet ; 5(6): e363, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31872048

RESUMO

OBJECTIVE: To report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine. METHODS: We reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and KCNT1 mutations, in collaboration with the network of the French reference center for rare epilepsies. RESULTS: The mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified KCNT1 variants clustered as "hot spots" on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency. CONCLUSIONS: The majority of the KCNT1 mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients.

5.
Brain ; 142(10): 2996-3008, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532509

RESUMO

Epilepsy of infancy with migrating focal seizures was first described in 1995. Fifteen years later, KCNT1 gene mutations were identified as the major disease-causing gene of this disease. Currently, the data on epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations are heterogeneous and many questions remain unanswered including the prognosis and the long-term outcome especially regarding epilepsy, neurological and developmental status and the presence of microcephaly. The aim of this study was to assess data from patients with epilepsy in infancy with migrating focal seizures with KCNT1 mutations to refine the phenotype spectrum and the outcome. We used mind maps based on medical reports of children followed in the network of the French reference centre for rare epilepsies and we developed family surveys to assess the long-term outcome. Seventeen patients were included [age: median (25th-75th percentile): 4 (2-15) years, sex ratio: 1.4, length of follow-up: 4 (2-15) years]. Seventy-one per cent started at 6 (1-52) days with sporadic motor seizures (n = 12), increasing up to a stormy phase with long lasting migrating seizures at 57 (30-89) days. The others entered this stormy phase directly at 1 (1-23) day. Ten patients entered a consecutive phase at 1.3 (1-2.8) years where seizures persisted at least daily (n = 8), but presented different semiology: brief and hypertonic with a nocturnal (n = 6) and clustered (n = 6) aspects. Suppression interictal patterns were identified on the EEG in 71% of patients (n = 12) sometimes from the first EEG (n = 6). Three patients received quinidine without reported efficacy. Long-term outcome was poor with neurological sequelae and active epilepsy except for one patient who had an early and long-lasting seizure-free period. Extracerebral symptoms probably linked with KCNT1 mutation were present, including arteriovenous fistula, dilated cardiomyopathy and precocious puberty. Eight patients (47%) had died at 3 (1.5-15.4) years including three from suspected sudden unexpected death in epilepsy. Refining the electro-clinical characteristics and the temporal sequence of epilepsy in infancy with migrating focal seizures should help diagnosis of this epilepsy. A better knowledge of the outcome allows one to advise families and to define the appropriate follow-up and therapies. Extracerebral involvement should be investigated, in particular the cardiac system, as it may be involved in the high prevalence of sudden unexpected death in epilepsy in these cases.


Assuntos
Epilepsias Parciais/genética , Mutação , Proteínas do Tecido Nervoso/genética , Canais de Potássio Ativados por Sódio/genética , Morte Súbita Inesperada na Epilepsia , Adolescente , Mapeamento Encefálico/métodos , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsias Parciais/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Canais de Potássio/genética , Canais de Potássio/metabolismo , Canais de Potássio Ativados por Sódio/metabolismo
6.
Genet Med ; 21(3): 553-563, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29997391

RESUMO

PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).


Assuntos
Ataxia/genética , Ataxia Cerebelar/genética , Espasmos Infantis/genética , Adolescente , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Exoma/genética , Feminino , França , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Mutação/genética , Fenótipo , Sequenciamento do Exoma/métodos , Adulto Jovem
7.
Epilepsia ; 57(6): 956-66, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27106864

RESUMO

OBJECTIVE: Rasmussen's encephalitis (RE) is a severe chronic inflammatory brain disease affecting one cerebral hemisphere and leading to drug-resistant epilepsy, progressive neurologic deficit, and unilateral brain atrophy. Hemispherotomy remains the gold standard treatment but causes permanent functional impairment. No standardized medical treatment protocol currently exists for patients prior to indication of hemispherotomy, although some immunotherapies have shown partial efficacy with functional preservation but poor antiseizure effect. Some studies suggest a role for tumor necrosis factor alpha (TNF-α) in RE pathophysiology. METHODS: We report an open-label study evaluating the efficacy and the safety of anti-TNF-α therapy (adalimumab) in 11 patients with RE. The primary outcome criterion was the decrease of seizure frequency. The secondary outcome criteria were neurologic and cognitive outcomes and existence of side effects. RESULTS: Adalimumab was introduced with a median delay of 31 months after seizure onset (range 1 month to 16 years), and follow-up was for a median period of 18 months (range 9-54 months). There was a significant seizure frequency decrease after adalimumab administration (from a median of 360 to a median of 32 seizures per quarter, p ≤ 0.01). Statistical analysis showed that adalimumab had a significant intrinsic effect (p < 0.005) independent from disease fluctuations. Five patients (45%) were found to have sustained improvement over consecutive quarters in seizure frequency (decrease of 50%) on adalimumab. Three of these five patients also had no further neurocognitive deterioration. Adalimumab was well tolerated. SIGNIFICANCE: Our study reports efficacy of adalimumab in terms of seizure frequency control. In addition, stabilization of functional decline occurred in three patients. This efficacy might be particularly relevant for atypical slowly progressive forms of RE, in which hemispherotomy is not clearly indicated. Due to our study limitations, further studies are mandatory to confirm these preliminary results.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Encefalite/tratamento farmacológico , Fator de Necrose Tumoral alfa/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Testes Neuropsicológicos , Projetos Piloto , Estatísticas não Paramétricas , Resultado do Tratamento , Gravação em Vídeo , Adulto Jovem
8.
Pediatr Blood Cancer ; 61(6): 1041-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24482108

RESUMO

OBJECTIVES: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. STUDY DESIGN: Two pedigrees were identified from the French registry. RESULTS: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. CONCLUSIONS: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neutropenia/congênito , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Atrofia , Infecções Bacterianas/etiologia , Encéfalo/patologia , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Consanguinidade , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Etnicidade/genética , Éxons/genética , Feminino , França , Genes Recessivos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Hospedeiro Imunocomprometido , Lactente , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto , Mielopoese/genética , Mielopoese/fisiologia , Neutropenia/sangue , Neutropenia/genética , Neutropenia/patologia , Neutropenia/cirurgia , Paquistão/etnologia , Linhagem , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Deleção de Sequência
9.
Epilepsia ; 54(9): 1571-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23815601

RESUMO

PURPOSE: To determine what epilepsy types occur after herpetic encephalitis and what are the determinant factors for subsequent infantile spasms. METHODS: We analyzed retrospectively the clinical history of 22 patients, referred to Necker and Saint Vincent de Paul Hospitals (Paris) through the French pediatric epilepsy network from March 1986 to April 2010 and who developed epilepsy some months after herpetic encephalitis. We focused on seizure semiology with video-electroencephalography (EEG) recording, and on neuroradiology and epilepsy follow-up. KEY FINDINGS: Fourteen patients developed pharmacoresistant spasms, and eight developed focal epilepsy, but none had both. The patients who developed spasms were more frequently younger than 30 months at age of onset of epilepsy and had herpetic encephalitis earlier (mean 10.6 months of age) than those who developed focal epilepsy (mean 59.7 and 39.6 months, respectively). Epilepsy follow-up was similar in both groups (8.5 and 11 years, respectively). We found 26 affected cerebral areas; none alone was related to the development of epileptic spasms. SIGNIFICANCE: Risk factors to develop epileptic spasms were to have had herpetic encephalitis early (mean 10 months); to be significantly younger at onset of epilepsy (mean 22.1 months); and to have cerebral lesions involving the insula, the hippocampus, and the temporal pole.


Assuntos
Encefalite por Herpes Simples/metabolismo , Espasmos Infantis/metabolismo , Fatores Etários , Córtex Cerebral/metabolismo , Criança , Pré-Escolar , Encefalite por Herpes Simples/complicações , Humanos , Lactente , Recém-Nascido , Estudos Retrospectivos , Espasmos Infantis/etiologia
10.
Orphanet J Rare Dis ; 8: 80, 2013 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-23692823

RESUMO

BACKGROUND: Early onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients. METHODS: We have screened KCNQ2 in a cohort of 71 patients with an EOEE, without any brain structural abnormality. To be included in the cohort, patient's epilepsy should begin before three months of age and be associated with abnormal interictal EEG and neurological impairment. Brain MRI should not show any structural abnormality that could account for the epilepsy. RESULTS: Out of those 71 patients, 16 had a de novo mutation in KCNQ2 (23%). Interestingly, in the majority of the cases, the initial epileptic features of these patients were comparable to those previously described in the case of benign familial neonatal epilepsy (BFNE) also caused by KCNQ2 mutations. However, in contrast to BFNE, the interictal background EEG was altered and displayed multifocal spikes or a suppression-burst pattern. The ongoing epilepsy and development were highly variable but overall severe: 15/16 had obvious cognitive impairment, half of the patients became seizure-free, 5/16 could walk before the age of 3 and only 2/16 patient acquired the ability to speak. CONCLUSION: This study confirms that KCNQ2 is frequently mutated de novo in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the neurological and epileptic evolution is variable.


Assuntos
Epilepsia Neonatal Benigna/genética , Epilepsia Neonatal Benigna/patologia , Canal de Potássio KCNQ2/genética , Mutação , Encéfalo/diagnóstico por imagem , Eletroencefalografia , Epilepsia/genética , Epilepsia Neonatal Benigna/diagnóstico , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Fenótipo , Radiografia
11.
Am J Hum Genet ; 91(2): 372-8, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-22883145

RESUMO

Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.


Assuntos
Fissura Palatina/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Síndromes Orofaciodigitais/genética , Fenótipo , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Proteínas Reguladoras de Apoptose , Sequência de Bases , Cerebelo/anormalidades , Cerebelo/patologia , Criança , Fissura Palatina/patologia , Exoma/genética , Feto/patologia , Deformidades Congênitas do Pé/patologia , Deformidades Congênitas da Mão/patologia , Proteínas Hedgehog/metabolismo , Homozigoto , Humanos , Dados de Sequência Molecular , Mutação/genética , Síndromes Orofaciodigitais/patologia , Análise de Sequência de DNA , Transdução de Sinais/genética , Adulto Jovem
12.
Orphanet J Rare Dis ; 6: 83, 2011 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-22151964

RESUMO

BACKGROUND: Vinblastine (VBL) is the standard treatment for systemic Langerhans cell histiocytosis (LCH), but little is known about its efficacy in central nervous system (CNS) mass lesions. METHODS: A retrospective chart review was conducted. Twenty patients from the French LCH Study Group register met the inclusion criteria. In brief, they had CNS mass lesions, had been treated with VBL, and were evaluable for radiologic response. RESULTS: The median age at diagnosis of LCH was 11.5 years (range: 1-50). Intravenous VBL 6 mg/m2 was given in a 6-week induction treatment, followed by a maintenance treatment. The median total duration was 12 months (range: 3-30). Eleven patients received steroids concomitantly. Fifteen patients achieved an objective response; five had a complete response (CR: 25%), ten had a partial response (PR: 50%), four had stable disease (SD: 20%) and one patient progressed (PD: 5%). Of interest, four out of the six patients who received VBL without concomitant steroids achieved an objective response. With a median follow-up of 6.8 years, the 5-year event-free and overall survival was 61% and 84%, respectively. VBL was well-tolerated and there were no patient withdrawals due to adverse events. CONCLUSION: VBL, with or without steroids, could potentially be a useful therapeutic option in LCH with CNS mass lesions, especially for those with inoperable lesions or multiple lesions. Prospective clinical trials are warranted for the evaluation of VBL in this indication.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Sistema Nervoso Central/patologia , Histiocitose de Células de Langerhans/tratamento farmacológico , Vimblastina/uso terapêutico , Adolescente , Adulto , Sistema Nervoso Central/efeitos dos fármacos , Doenças do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/mortalidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Esteroides/uso terapêutico , Resultado do Tratamento , Adulto Jovem
13.
Emerg Infect Dis ; 17(8): 1436-44, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21801621

RESUMO

For many encephalitis cases, the cause remains unidentified. After 2 children (from the same family) received a diagnosis of acute necrotizing encephalopathy at Centre Hospitalier Universitaire (Tours, France), we attempted to identify the etiologic agent. Because clinical samples from the 2 patients were negative for all pathogens tested, urine and throat swab specimens were added to epithelial cells, and virus isolates detected were characterized by molecular analysis and electron microscopy. We identified a novel reovirus strain (serotype 2), MRV2Tou05, which seems to be closely related to porcine and human strains. A specific antibody response directed against this new reovirus strain was observed in convalescent-phase serum specimens from the patients, whereas no response was observed in 38 serum specimens from 38 healthy adults. This novel reovirus is a new etiologic agent of encephalitis.


Assuntos
Encefalite Viral/virologia , Leucoencefalite Hemorrágica Aguda/virologia , Orthoreovirus de Mamíferos/classificação , Orthoreovirus de Mamíferos/isolamento & purificação , Infecções por Reoviridae/virologia , Adulto , Animais , Anticorpos Antivirais/sangue , Linhagem Celular , Criança , Chlorocebus aethiops , Feminino , França/epidemiologia , Hospitais Universitários , Humanos , Lactente , Masculino , Orthoreovirus de Mamíferos/genética , Orthoreovirus de Mamíferos/imunologia , Filogenia , Análise de Sequência de DNA , Sorotipagem , Células Vero
14.
Epilepsia ; 52(10): 1828-34, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21770924

RESUMO

PURPOSE: STXBP1 (MUNC18-1) mutations have been associated with various types of epilepsies, mostly beginning early in life. To refine the phenotype associated with STXBP1 aberrations in early onset epileptic syndromes, we studied this gene in a cohort of patients with early onset epileptic encephalopathy. METHODS: STXBP1 was screened in a multicenter cohort of 52 patients with early onset epilepsy (first seizure observed before the age of 3 months), no cortical malformation on brain magnetic resonance imaging (MRI), and negative metabolic screening. Three groups of patients could be distinguished in this cohort: (1) Ohtahara syndromes (n = 38); (2) early myoclonic encephalopathies (n = 7); and (3) early onset epileptic encephalopathies that did not match any familiar syndrome (n = 7). None of the patients displayed any cortical malformation on brain MRI and all were screened through multiple video-electroencephalography (EEG) recordings for a time period spanning from birth to their sixth postnatal month. Subsequently, patients had standard EEG or video-EEG recordings. KEY FINDINGS: We found five novel STXBP1 mutations in patients for whom video-EEG recordings could be sampled from the beginning of the disease. All patients with a mutation displayed Ohtahara syndrome, since most early seizures could be classified as epileptic spasms and since the silent EEG periods were on average shorter than bursts. However, each patient in addition displayed a particular clinical and EEG feature: In two patients, early seizures were clonic, with very early EEG studies exhibiting relatively low amplitude bursts of activity before progressing into a typical suppression-burst pattern, whereas the three other patients displayed epileptic spasms associated with typical suppression-burst patterns starting from the early recordings. Epilepsy dramatically improved after 6 months and finally disappeared before the end of the first year of life for four patients; the remaining one patient had few seizures until 18 months of age. In parallel, EEG paroxysmal abnormalities disappeared in three patients and decreased in two, giving place to continuous activity with fast rhythms. Each patient displayed frequent nonepileptic movement disorders that could easily be mistaken for epileptic seizures. These movements could be observed as early as the neonatal period and, unlike seizures, persisted during all the follow-up period. SIGNIFICANCE: We confirm that STXBP1 is a major gene to screen in cases of Ohtahara syndrome, since it is mutated in >10% of the Ohtahara patients within our cohort. This gene should particularly be tested in the case of a surprising evolution of the patient condition if epileptic seizures and EEG paroxysmal activity disappear and are replaced by fast rhythms after the end of the first postnatal year.


Assuntos
Epilepsia/genética , Proteínas Munc18/genética , Idade de Início , Anticonvulsivantes/uso terapêutico , Encéfalo/patologia , Encéfalo/fisiopatologia , Eletroencefalografia , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Epilepsia/fisiopatologia , Genótipo , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Síndrome , Gravação em Vídeo
15.
Am J Med Genet A ; 152A(5): 1244-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20425829

RESUMO

Myoclonus dystonia (M-D) is a rare genetic movement disorder characterized by a combination of myoclonic jerks and dystonia. It is usually due to mutations in the SGCE gene. We report on a patient with a typical M-D syndrome, but also short stature, microcephaly, and mental retardation. Molecular analysis showed no mutations within the SGCE gene but a microdeletion encompassing the SGCE gene in chromosome region 7q21. Array-CGH analysis showed that the deletion spanned approximately 1.88 Mb. We suggest that M-D plus patients with mental retardation, microcephaly, dysmorphism, or short stature, all frequently associated disorders, should be screened for 7q21 microdeletion. By examining previously published cases of mental retardation associated with pure 7q21 deletions, we identified two distinct regions of respectively 455 and 496 kb that are critical for mental retardation and growth retardation. Among the genes located within these regions, LOC253012, also known as HEPACAM2, is a good candidate for both mental retardation and microcephaly.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Distonia/complicações , Distonia/genética , Mioclonia/complicações , Mioclonia/genética , Adolescente , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase , Gravidez , Síndrome
16.
Arch Neurol ; 66(8): 1007-15, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19667223

RESUMO

OBJECTIVE: With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype. DESIGN: Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly. INTERVENTIONS: Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined. RESULTS: Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly. CONCLUSION: Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Encéfalo/patologia , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Análise Mutacional de DNA , Genótipo , Imageamento por Ressonância Magnética , Proteínas Associadas aos Microtúbulos/genética , Exame Neurológico , Adolescente , Adulto , Criança , Pré-Escolar , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/classificação , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/diagnóstico , Feminino , Humanos , Lactente , Masculino , Fenótipo , Adulto Jovem
17.
Neuropsychologia ; 47(3): 761-70, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19126410

RESUMO

INTRODUCTION: Developmental dyslexia (DD) is a frequent language-based learning disorder. The predominant etiological view postulates that reading problems originate from a phonological impairment. METHOD: We studied mismatch negativity (MMN) and Late Discriminative Negativity (LDN) to syllables change in both children (n=12; 8-12 years) and young adults (n=15; 14-23 years) with DD compared with controls. RESULTS/DISCUSSION: The present study confirmed abnormal automatic discrimination of syllable changes in both children and adults with developmental dyslexia. MMN topographic, amplitude and latency group differences were evidenced, suggesting different brain mechanisms involved in elementary auditory stimulus change-detection in DD, especially in the left hemisphere. The LDN results demonstrated that the auditory disorder of temporal processing in DD children becomes more serious at late stages of information processing and that the apparent cerebral hypo reactivity to speech changes in DD actually may correspond to additional processes. The age-related differences observed in both MMN and LDN topographies, amplitudes and latency between subjects with DD and controls could indicate different developmental courses in the neural representation of basic speech sounds in good and poor readers, with a tendency to normalization with increasing age. CONCLUSION: Our results showing atypical electrophysiological concomitants of speech auditory perception in DD strongly support the hypothesis of deviant cortical organization in DD.


Assuntos
Percepção Auditiva , Transtornos da Percepção Auditiva/fisiopatologia , Discriminação Psicológica , Dislexia/fisiopatologia , Potenciais Evocados Auditivos , Percepção da Fala , Adolescente , Fatores Etários , Análise de Variância , Transtornos da Percepção Auditiva/diagnóstico , Transtornos da Percepção Auditiva/psicologia , Estudos de Casos e Controles , Criança , Dislexia/diagnóstico , Dislexia/psicologia , Eletroencefalografia , Eletrofisiologia , Feminino , Humanos , Masculino , Adulto Jovem
18.
Dev Neuropsychol ; 34(6): 736-48, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20183730

RESUMO

Learning disabilities represent the main childhood complication in neurofibromatosis type 1 (NF1). Patients frequently exhibit T2-weighted hyperintensities called unidentified bright objects (UBOs) on brain magnetic resonance imaging (MRI), with unclear relationship to such cognitive disabilities. This study aimed to determine whether thalamo-striatal UBOs correlate with cognitive disturbances. Thirty-seven NF1 children were studied: 24 with UBOs (18 of which were thalamo-striatal UBOs), and 13 without UBOs. NF1 subjects carrying thalamo-striatal UBOs had significantly lower IQs and visuospatial performances than those without UBOs in this location. These results suggest that UBOs may contribute to NF1 cognitive impairments through thalamo-cortical dysfunction.


Assuntos
Transtornos Cognitivos/diagnóstico , Corpo Estriado/patologia , Imageamento por Ressonância Magnética , Neurofibromatose 1/epidemiologia , Tálamo/patologia , Adolescente , Criança , Transtornos Cognitivos/epidemiologia , Feminino , Humanos , Masculino , Percepção Espacial , Percepção Visual
19.
Epilepsia ; 48(6): 1104-10, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17430407

RESUMO

BACKGROUND: Continuous spike-waves during slow sleep syndrome (CSWSS) is a rare epileptic syndrome occurring in children, which is characterized by the association of epilepsy, neuropsychological disorders, and abnormal paroxysmal electroencephalographic (EEG) discharges activated by sleep. Language can be affected but, to date, language disorders and their long-term outcome have been documented only rarely. PURPOSES: Description of language impairment in patients with the CSWSS. METHODS: We performed a detailed language testing in 10 right-handed children and adolescents with the CSWSS. Their pragmatic performance was compared to that of a control population of 36 children aged 6-10 years. RESULTS: Patients with CSWSS had lower scores in tests measuring their lexical, morphosyntactic, and pragmatic skills compared to controls. Comprehension remains unaffected. In addition, language impairment was found to be just as severe in patients in remission as those still in an active phase. CONCLUSIONS: We found severe language impairments in lexical and syntactic skills. The language profile is different from that observed in the Landau-Kleffner syndrome. Moreover patients in remission and those in an active phase of the CSWSS have the same language impairment profiles. This confirms the poor long-term neuropsychological prognosis. Our results raise points about the relationship between epileptic activity and language development. This pilot study underscores the need to assess language, and especially pragmatic skills, and to study long-term outcome in such childhood epileptic syndromes.


Assuntos
Eletroencefalografia/estatística & dados numéricos , Epilepsia/diagnóstico , Desenvolvimento da Linguagem , Transtornos da Linguagem/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Transtornos do Sono-Vigília/diagnóstico , Adolescente , Adulto , Córtex Cerebral/fisiopatologia , Criança , Comorbidade , Epilepsia/epidemiologia , Epilepsia/fisiopatologia , Feminino , Humanos , Testes de Inteligência , Transtornos da Linguagem/epidemiologia , Transtornos da Linguagem/fisiopatologia , Masculino , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/fisiopatologia , Síndrome
20.
J Neurol Sci ; 249(2): 166-71, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16859712

RESUMO

We report the case of a young girl who presented severe learning disabilities in oral and written language related to a continuous spike-waves during slow sleep (CSWS) syndrome. A sleep EEG recording obtained in her younger brother, who presented a clinical pattern suggesting developmental dysphasia, also showed a CSWS syndrome. These two clinical cases underscore the need to look for this syndrome in the siblings of an affected child when learning difficulties appear in a child who previously had normal psychomotor development.


Assuntos
Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Transtornos Intrínsecos do Sono/fisiopatologia , Sono/fisiologia , Estado Epiléptico/fisiopatologia , Criança , Pré-Escolar , Dislexia/genética , Dislexia/fisiopatologia , Eletroencefalografia , Epilepsia Tônico-Clônica/genética , Epilepsia Tônico-Clônica/fisiopatologia , Feminino , Humanos , Transtornos do Desenvolvimento da Linguagem/genética , Deficiências da Aprendizagem/etiologia , Masculino , Testes Neuropsicológicos , Orientação , Transtornos Psicomotores/genética , Transtornos Psicomotores/fisiopatologia , Irmãos , Transtornos Intrínsecos do Sono/genética , Distúrbios da Fala/genética , Distúrbios da Fala/fisiopatologia , Estado Epiléptico/genética , Lobo Temporal/fisiopatologia , Percepção Visual , Redação
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