RESUMO
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
Assuntos
Mutação com Ganho de Função , Estudos de Associação Genética , Genótipo , Helicase IFIH1 Induzida por Interferon/genética , Fenótipo , Alelos , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Helicase IFIH1 Induzida por Interferon/química , Masculino , Modelos Moleculares , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
We prospectively analyzed EEGs from participants in the ongoing NIH Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study. Of the one-hundred-sixty enrolled patients (2006-2010), 115 had complete data (58 boys, median age 3.6 years). Distinct EEG findings were intermittent rhythmic delta waves (83.5%), interictal epileptiform discharges (74.2%), intermittent rhythmic theta waves (43.5%), and posterior rhythm slowing (43.5%). Centro-occipital and centro-temporal delta waves decreased with age (p=0.01, p=0.03). There were no specific correlations between EEG patterns and genotypes. A classification tree allowed the prediction of deletions class-1 (5.9 Mb) in patients with intermittent theta waves in <50% of EEG and interictal epileptiform abnormalities; UPD, UBE3A mutation or imprinting defects in patients with intermittent theta in <50% of EEG without interictal epileptiform abnormalities; deletions class-2 (5.0 Mb) in patients with >50% theta and normal posterior rhythm; atypical deletions in patients with >50% theta but abnormal posterior rhythm. EEG patterns are important biomarkers in Angelman syndrome and may suggest the underlying genetic etiology.
Assuntos
Síndrome de Angelman , Ondas Encefálicas/fisiologia , Eletroencefalografia , Genótipo , Deleção de Sequência/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Fatores Etários , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/genética , Síndrome de Angelman/fisiopatologia , Ondas Encefálicas/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Análise de Regressão , Estudos Retrospectivos , Processamento de Sinais Assistido por Computador , Adulto JovemRESUMO
We compared three-channel montage with 21-channel neonatal minimal placement montage for the detection of neonatal seizures and quantification of seizure burden. Thirty-five neonatal electroencephalograms were retrospectively and blindly reviewed by two independent readers. Tracings were analyzed in the three-channel montage for seizure number, duration, and quantification of seizure burden before reanalysis with the full 21-channel neonatal minimal placement montage. Seizures were identified using standard definitions of electroencephalographic seizure. Sensitivity, specificity, and interrater reliability were calculated. The sensitivity and specificity of three-channel montage for detecting seizures > 10 seconds were 91% and 100% for reader 1, respectively, and 82% and 96% for reader 2, respectively. The interrater agreement for detection of seizures was excellent (κ = 0.86, 94% percent overall agreement). For quantification of seizure burden, strong, positive correlation existed between assessments by full montage and three-channel montage (for reader 1, r = 0.945, n = 11, P < 0.0001; for reader 2, r = 0.902, n = 11, P < 0.0001), and strong correlation existed between the readers for three-channel montage (r = 0.879, n = 11, P < 0.0001). Despite its limitations, three-channel montage is useful in the detection of neonatal seizures and quantification of seizure burden.