RESUMO
Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.
Assuntos
Encefalopatias/genética , Exodesoxirribonucleases/genética , Mutação , Fosfoproteínas/genética , Doenças Retinianas/genética , Sequência de Aminoácidos , Encefalopatias/enzimologia , Linhagem Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Genes Dominantes , Predisposição Genética para Doença , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Microscopia Confocal , Dados de Sequência Molecular , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Doenças Retinianas/enzimologia , Homologia de Sequência de Aminoácidos , TransfecçãoAssuntos
CADASIL/diagnóstico por imagem , CADASIL/epidemiologia , Vasculite Retiniana/diagnóstico por imagem , Vasculite Retiniana/epidemiologia , Adulto , CADASIL/genética , Feminino , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/epidemiologia , Leucoencefalopatias/genética , Masculino , Pessoa de Meia-Idade , Vasculite Retiniana/genéticaRESUMO
PURPOSE: Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders. METHODS: Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism. RESULTS: The premutation + gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson's Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke's Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood. CONCLUSION: Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration.
Assuntos
DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Transtornos Parkinsonianos/genética , Transcrição Gênica/genética , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Medical conditions with effective therapies are usually managed with objective measurement and therapeutic targets. Parkinson's disease has effective therapies, but continuous objective measurement has only recently become available. This blinded, controlled study examined whether management of Parkinson's disease was improved when clinical assessment and therapeutic decisions were aided by objective measurement. The primary endpoint was improvement in the Movement Disorder Society-United Parkinson's Disease Rating Scale's (MDS-UPDRS) Total Score. In one arm, objective measurement assisted doctors to alter therapy over successive visits until objective measurement scores were in target. Patients in the other arm were conventionally assessed and therapies were changed until judged optimal. There were 75 subjects in the objective measurement arm and 79 in the arm with conventional assessment and treatment. There were statistically significant improvements in the moderate clinically meaningful range in the MDS-UPDRS Total, III, IV scales in the arm using objective measurement, but not in the conventionally treated arm. These findings show that global motor and non-motor disability is improved when management of Parkinson's disease is assisted by objective measurement.
RESUMO
INTRODUCTION: Evaluation of people with Parkinson's disease (PD) is often complex due to heterogeneity of symptoms and disease course, including the variability of motor fluctuations and dyskinesia. Routine clinical evaluations may be incomplete, may not accurately capture important symptoms, and may not reflect day-to-day variability. While significant advances have been made in wearable ambulatory continuous objective monitoring (COM) technologies, many clinicians remain uncertain of how to incorporate them in clinical practice, including the value to clinical decision-making. The Personal KinetiGraph™ (PKG) has FDA clearance in the United States, and has recently been used in several clinical studies. Areas covered: An expert group of movement disorders neurologists convened to discuss the clinical utility of the PKG in the routine assessment of people with PD. Based on their experience, the group identified clinical scenarios where objective information gained from review of PKG reports can provide useful information to improve clinical management. Expert commentary: PKG provides clinically meaningful data in patients with PD that can aid the clinician in evaluating patients and optimizing their pharmacologic therapy. Early clinical experience and expert opinion suggest that utilization of COM technologies such as the PKG have the potential to improve medical care in people with PD.