RESUMO
Essential tremor (ET) is a common neurodegenerative disorder that is characterized by a postural or motion tremor. Despite a strong genetic basis, a gene with rare pathogenic mutations that cause ET has not yet been reported. We used exome sequencing to implement a simple approach to control for misdiagnosis of ET, as well as phenocopies involving sporadic and senile ET cases. We studied a large ET-affected family and identified a FUS p.Gln290(∗) mutation as the cause of ET in this family. Further screening of 270 ET cases identified two additional rare missense FUS variants. Functional considerations suggest that the pathogenic effects of ET-specific FUS mutations are different from the effects observed when FUS is mutated in amyotrophic lateral sclerosis cases; we have shown that the ET FUS nonsense mutation is degraded by the nonsense-mediated-decay pathway, whereas amyotrophic lateral sclerosis FUS mutant transcripts are not.
Assuntos
Tremor Essencial/genética , Exoma/genética , Predisposição Genética para Doença/genética , Proteína FUS de Ligação a RNA/genética , Sequência de Bases , Humanos , Dados de Sequência Molecular , Mutação Puntual/genética , Quebeque , Análise de Sequência de DNARESUMO
Difficulty producing intelligible speech is a debilitating symptom of Parkinson's disease (PD). Yet, both the robust evaluation of speech impairments and the identification of the affected brain systems are challenging. Using task-free magnetoencephalography, we examine the spectral and spatial definitions of the functional neuropathology underlying reduced speech quality in patients with PD using a new approach to characterize speech impairments and a novel brain-imaging marker. We found that the interactive scoring of speech impairments in PD (N = 59) is reliable across non-expert raters, and better related to the hallmark motor and cognitive impairments of PD than automatically-extracted acoustical features. By relating these speech impairment ratings to neurophysiological deviations from healthy adults (N = 65), we show that articulation impairments in patients with PD are associated with aberrant activity in the left inferior frontal cortex, and that functional connectivity of this region with somatomotor cortices mediates the influence of cognitive decline on speech deficits.
Assuntos
Predisposição Genética para Doença/genética , Glucosilceramidase/genética , Mutação/genética , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/etnologia , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Gilles de la Tourette syndrome (TS) and chronic tic disorder (CT) are often associated with a variety of behavioral comorbidities including attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive behavior (OCB), oppositional-defiant disorder (ODD) and temper outbursts. ODD is often associated with ADHD but its links to other symptoms of TS/CT is not as clear. This study examined whether the various symptoms of ODD were differentially linked to the various comorbidities in TS. A clinical sample of 135 children diagnosed with TS was evaluated through parent questionnaires and semi-structured interviews. Regressions and structural equation modeling confirmed that ODD is multidimensional in a TS/CT sample and showed that OCB was associated with the irritability symptoms of ODD whereas ADHD was associated with the Headstrong symptoms of ODD. Results suggest that increased attention to the different facets of ODD may help improve our understanding of emotional symptoms in TS/CT.
Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo/diagnóstico , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/epidemiologia , Síndrome de Tourette/diagnóstico , Síndrome de Tourette/epidemiologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/psicologia , Criança , Doença Crônica , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/psicologia , Pais/psicologia , Inquéritos e Questionários , Síndrome de Tourette/psicologiaRESUMO
Essential tremor (ET) is a complex genetic disorder for which no causative gene has been found. Recently, a genome-wide association study reported that two variants in the LINGO1 locus were associated to this disease. The aim of the present study was to test if this specific association could be replicated using a French-Canadian cohort of 259 ET patients and 479 ethnically matched controls. Our genotyping results lead us to conclude that no association exists between the key variant rs9652490 and ET (P(corr)â=â1.00).
Assuntos
Tremor Essencial/genética , Estudo de Associação Genômica Ampla , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Canadá/etnologia , Estudos de Casos e Controles , Tremor Essencial/etnologia , Predisposição Genética para Doença , Genótipo , Humanos , População BrancaRESUMO
Mirror movements are involuntary contralateral movements that mirror voluntary ones and are often associated with defects in midline crossing of the developing central nervous system. We studied two large families, one French Canadian and one Iranian, in which isolated congenital mirror movements were inherited as an autosomal dominant trait. We found that affected individuals carried protein-truncating mutations in DCC (deleted in colorectal carcinoma), a gene on chromosome 18q21.2 that encodes a receptor for netrin-1, a diffusible protein that helps guide axon growth across the midline. Functional analysis of the mutant DCC protein from the French Canadian family revealed a defect in netrin-1 binding. Thus, DCC has an important role in lateralization of the human nervous system.