RESUMO
The risk for carriers of repeat expansion mutations in C9orf72 to develop amyotrophic lateral sclerosis and frontotemporal dementia increases with age. Functional magnetic resonance imaging studies have shown reduced connectivity in symptomatic carriers, but it is not known whether connectivity declines throughout life as an acceleration of the normal aging pattern. In this study, we examined intra-network homogeneity (NeHo) in 5 functional networks in 15 presymptomatic C9+ carriers over an 18-month period and compared to repeated scans in 34 healthy controls and 27 symptomatic C9+ carriers. The longitudinal trajectory of NeHo in the somatomotor, dorsal attention, and default mode networks in presymptomatic carriers differed from aging controls and symptomatic carriers. In somatomotor networks, NeHo increased over time in regions adjacent to regions where symptomatic carriers had reduced NeHo. In the default network, the posterior cingulate exhibited age-dependent increases in NeHo. These findings are evidence against the proposal that the decline in functional connectivity seen in symptomatic carriers represents a lifelong acceleration of the healthy aging process.
Assuntos
Proteína C9orf72/genética , Expansão das Repetições de DNA , Envelhecimento Saudável/genética , Envelhecimento Saudável/fisiologia , Heterozigoto , Mutação/genética , Rede Nervosa/patologia , Rede Nervosa/fisiologia , Esclerose Lateral Amiotrófica/genética , Feminino , Demência Frontotemporal/genética , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/patologia , Giro do Cíngulo/fisiologia , Envelhecimento Saudável/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagemRESUMO
BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) has long been characterized by a combination of bilateral ptosis and dysphagia and subsequent limb girdle weakness. The role of the typical intranuclear inclusion in the pathophysiology is unresolved. OBJECTIVE: The aim of this study was to describe the clinical and histopathological features of oculopharyngeal muscular dystrophy (OPMD). We examined this in a Dutch cohort including presymptomatic Ala-expanded-PABPN1 carriers and late symptomatic patients. METHODS: We performed a prospective, observational study in OPMD patients and adult children of genetically confirmed OPMD patients. The study includes a structured history, a detailed neurological examination, muscle histology and biochemical analysis. Forty patients and 18 adult children participated in this study, among whom were six presymptomatic mutation carriers. One patient died during the study and had given permission to autopsy. RESULTS: In addition to the characteristic OPMD symptoms including ptosis and dysphagia, other symptoms such as limb girdle and axial weakness, and external ophthalmoplegia were frequently observed. Intranuclear aggregates were observed in the biopsies of presymptomatic carriers. Biochemical analysis of the biopsies of the presymptomatic carriers showed no mitochondrial dysfunction. The autopsy showed that muscle weakness correlated with histopathological findings in five different muscles in an individual patient. CONCLUSIONS: The main findings of this nationwide study are the presence of intranuclear aggregates before clinical onset and the absence of mitochondrial changes in Ala-expanded-PABPN1 carriers. This indicates that the expression of Ala-expanded-PABPN1 causes the formation of nuclear aggregates before the onset of muscle weakness. Normal results of biochemical analysis in presymptomatic carriers suggest that possible mitochondrial dysfunction occurs later. Furthermore we confirmed that limb girdle weakness occurs frequently in Dutch OPMD patients. This study thus expands the OPMD research towards characterization of presymptomatic carriers.
Assuntos
Blefaroptose/fisiopatologia , Transtornos de Deglutição/fisiopatologia , Corpos de Inclusão Intranuclear/metabolismo , Debilidade Muscular/fisiopatologia , Distrofia Muscular Oculofaríngea , Oftalmoplegia/fisiopatologia , Proteína I de Ligação a Poli(A)/genética , Sintomas Prodrômicos , Adulto , Filhos Adultos , Idoso , Idoso de 80 Anos ou mais , Blefaroptose/etiologia , Transtornos de Deglutição/etiologia , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Distrofia Muscular Oculofaríngea/complicações , Distrofia Muscular Oculofaríngea/genética , Distrofia Muscular Oculofaríngea/metabolismo , Distrofia Muscular Oculofaríngea/fisiopatologia , Oftalmoplegia/etiologia , Estudos ProspectivosRESUMO
A characteristic feature of spinocerebellar ataxia type 2 (SCA2) is saccadic slowing at early disease stages. We sought to determine whether this sign is detectable before clinical manifestation and quantifies the disease progression throughout life in linear fashion. In a specialized ataxia clinic, 54 presymptomatic carriers of SCA2 polyglutamine expansions and 56 relatives without mutation were documented with regard to their maximal saccade velocit Spinocerebellar ataxia type 2 Among the control individuals, a significant effect of aging on MSV was observed. After elimination of this age influence through a matched-pair approach, a presymptomatic decrease of MSV could be shown. The MSV reduction was stronger in carriers of large expansions. In the years before calculated disease manifestation, the MSV impairment advanced insidiously.Saccade velocity is a sensitive SCA2 endophenotype that reflects early pontine degenerationPolyglutamine expansion and may be a useful diagnostic parameter before the onset of ataxia. Significance: Future neuroprotective therapies of polyglutamine neurodegeneration may be assessed by MSV from earliest to prefinal disease stages...(AU)
