RESUMO
Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
Assuntos
Ataxia/genética , Encéfalo/patologia , Síndrome do Cromossomo X Frágil/genética , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Distrofias Musculares/genética , Doenças Neurodegenerativas/genética , Tremor/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Ataxia/patologia , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/patologia , Estudo de Associação Genômica Ampla , Humanos , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/patologia , Desequilíbrio de Ligação , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/patologia , Mutação , Doenças Neurodegenerativas/patologia , Neuroimagem/métodos , Linhagem , Tremor/patologiaRESUMO
Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.
Assuntos
Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Repetições de Microssatélites , Proteínas do Tecido Nervoso/genética , Motivo Estéril alfa/genética , Adulto , Idade de Início , Autoantígenos/genética , Sequência de Bases , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/patologia , Feminino , Instabilidade Genômica , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Íntrons , Masculino , Linhagem , Células de Purkinje/patologia , Proteínas de Ligação a RNA/genética , Análise de Sequência de DNARESUMO
Objective To identify the prehospital factors predicting the performance of tracheal intubation (TI) at the emergency department (ED) in patients with convulsive seizure or epilepsy. Methods We performed a retrospective analysis of seizure patients who underwent TI at the ED soon after arrival. The clinical variables obtained in the prehospital setting were reviewed. Patients The study population included consecutive adult patients who were transported to an urban tertiary care ED due to convulsive seizure between August 2010 and September 2015. Results Among the 822 eligible patients, 59 patients (7.2%) underwent TI at the ED. Four independent prehospital predictors were identified using multivariate analysis: age ≥50 years (+1 point), meeting the definition of convulsive status epilepticus (+4 points), and an on-scene heart rate of ≥120 bpm (+1 point) led to a higher likelihood of TI, while a higher on-scene (alert or confused) level of consciousness (-3 points) led to a lower likelihood of TI. The derived prediction rule (the sum of all points) had good predictive performance with an area under the curve of 0.88 (95% confidence interval: 0.79-0.97), a sensitivity of 0.62, a specificity of 0.91, and a positive likelihood ratio of 10.6, when the cut-off value was set to 5 points. Conclusion We constructed a simple prehospital prediction rule to help predict the need for TI in seizure patients, even in the prehospital phase. This may possibly lead to the more effective management of seizure patients in the ED.
