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Epilepsia ; 59(2): 389-402, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29315614


OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.

Epilepsias Mioclônicas/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/complicações , Ataxia/genética , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Epilepsias Parciais/complicações , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Resultado do Tratamento , Ácido Valproico/uso terapêutico , Adulto Jovem
Am J Med Genet A ; 167A(4): 862-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25706929


9q22.3 microdeletion syndrome is a well-described contiguous deletion syndrome with features of Gorlin syndrome and other manifestations. Commonly reported findings in addition to those of Gorlin syndrome include metopic craniosynostosis, hydrocephalus, intellectual disability, and minor facial anomalies. The critical region for this condition was found to include the PTCH1 and FANCC genes; however, other genes are often deleted in affected individuals but their role in the observed phenotype is not understood. Fewer than 50 individuals with 9q22.3 microdeletion have been reported, all diagnosed postnatally on the basis of the phenotype. A confirmed prenatal diagnosis and accompanying fetal imaging has not been reported to date. We describe a patient with prenatally diagnosed 9q22.3 microdeletion syndrome following the ultrasonographic identification of trigonocephaly, macrosomia, organomegaly, ventriculomegaly, and anomalous vertebrae.

Anormalidades Múltiplas/diagnóstico por imagem , Deleção Cromossômica , Craniossinostoses/diagnóstico por imagem , Hidrocefalia/diagnóstico por imagem , Poli-Hidrâmnios/diagnóstico por imagem , Anormalidades Múltiplas/genética , Transtornos Cromossômicos/diagnóstico por imagem , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 9/genética , Craniossinostoses/genética , Feminino , Humanos , Hidrocefalia/genética , Lactente , Poli-Hidrâmnios/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Ultrassonografia Pré-Natal