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Neurology ; 92(11): e1238-e1249, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737342


OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Clin EEG Neurosci ; : 1550059418794347, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30117335


Patients with temporal lobe epilepsy (TLE) due to mesial temporal sclerosis (MTS) are eligible candidates for resective epilepsy surgery. We report on 2 male patients aged 4 years with suspected TLE due to MTS who were referred for presurgical evaluation. Both patients came to medical attention within the first year of life suffering from febrile status epileptici and subsequent unprovoked seizures. The following years, moderate developmental delay was present. High-resolution magnetic resonance imaging confirmed hippocampal sclerosis. Continuous EEG video monitoring revealed seizure patterns contralateral to the MTS in both patients. Genetic analysis was performed as both the clinical presentation of the patients and EEG video monitoring findings were not consistent with the presence of the hippocampal sclerosis alone and revealed de novo mutations within exon of the SCN1A gene. Resective surgical strategies were omitted due to the genetic findings. In conclusion, both patients suffered from a dual pathology syndrome with ( a) TLE related to MTS resulting most likely from recurrent febrile status in early childhood and ( b) Dravet syndrome, which is most likely the cause of the febrile convulsions leading to the MTS in these 2 patients.

Neurology ; 86(10): 954-62, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26865513


OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Encefalopatias/genética , Epilepsia/genética , Proteínas Munc18/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Encefalopatias/diagnóstico , Encefalopatias/epidemiologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Adulto Jovem
Dev Neurorehabil ; 17(6): 420-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25057804


OBJECTIVE: To evaluate the association of hip lateralisation with health-related quality of life (HRQL) in children with cerebral palsy (CP) using the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD(®)) questionnaire. METHODS: We assessed n = 34 patients (mean age: 10.2 years, SD: 4.7 years; female: n = 16) with bilateral CP and Gross Motor Function Classification System (GMFCS) Level III-V using the CPCHILD(®) questionnaire. Hip lateralisation was measured by Reimer`s migration percentage (MP). RESULTS: There was an association between both, MP and GMFCS with CPCHILD(®) total score. Stratified analyses did not suggest interaction of the association between MP and CPCHILD(®) total score by GMFCS level. After adjustment for GMFCS level, we found a significant linear decrease of CPCHILD(®) total score of -0.188 points by 1% increment in MP. CONCLUSIONS: There was an association between MP and HRQL, which could not be explained by the GMFCS level.

Paralisia Cerebral/fisiopatologia , Luxação do Quadril , Qualidade de Vida , Adolescente , Cuidadores , Paralisia Cerebral/psicologia , Criança , Pré-Escolar , Crianças com Deficiência , Feminino , Quadril/fisiopatologia , Humanos , Masculino , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
Neuropediatrics ; 45(5): 289-93, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24700153


We aimed to translate the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire into German and to evaluate its reliability and validity by studying the association between CPCHILD scores and gross motor function as measured by the gross motor function classification system (GMFCS) in children with cerebral palsy (CP). The original CPCHILD questionnaire and manual were translated and back translated. It was administered to primary caregivers of persons with CP (GMFCS levels III-V) and was completed a second time 2 weeks after the first to measure test-retest reliability (n = 17). Primary caregivers of 68 children with CP; GMFCS level III (n = 14), level IV (n = 28), and level V (n = 26) completed the questionnaire. Mean total CPCHILD scores across GMFCS levels were 67.1 ± 14.9 for GMFCS level III, 56.6 ± 11.8 for level IV, and 44.3 ± 12.9 for level V. Good correlation (r = - 0.56) was observed between GMFCS and total scores test-retest reliability showed intraclass correlation coefficients between 0.4 and 0.9. The German CPCHILD yielded similar test-retest reliability and score distributions across the GMFCS level as the original version. The best correlations were observed for domains that are close to the functional deficits.

Atividades Cotidianas/psicologia , Cuidadores/psicologia , Paralisia Cerebral , Deficiências do Desenvolvimento/etiologia , Inquéritos e Questionários , Traduções , Adolescente , Adulto , Paralisia Cerebral/complicações , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/enfermagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Adulto Jovem