Frontotemporal Dementia: SQSTM1 Exon 5 Mutation
Ficheiros
Data
2015
Título da revista
ISSN da revista
Título do Volume
Editora
Resumo
O termo demência descreve um conjunto de sintomas que podem ser causados por diversas doenças que afetam o cérebro.
Com uma prevalência de aproximadamente 15-22/100.000 na população entre os 45 e 65 anos de idade a Demência Frontotemporal (DFT) é a segunda doença neurodegenerativa mais comum em pessoas com idades inferiores a 65 anos, sendo ultrapassada apenas pela Doença de Alzheimer (DA). A DFT implica uma perda de função cognitiva grave o suficiente para afetar as atividades do dia a dia. É caracterizada por uma alteração progressiva de comportamento, linguagem e conduta social relacionadas com a degeneração dos lobos frontal e temporal anterior (de um ou dos dois hemisférios cerebrais).
Os sintomas geralmente começam entre os 50 e 60 anos e idade e afetam igualmente homens e mulheres.
Demência Frontotemporal é um grupo heterogéneo de desordens neurodegenerativas, sendo que DFT é utilizado para descrever o síndrome clinico enquanto que Degeneração Lobar Frontotemporal (DLFT) é utilizado para descrever o diagnostico patológico.
Atualmente a terminologia mais aceite passa por dividir a DFT em dois grupos : a variante comportamental da DFT, caracterizada por alterações na personalidade e comportamento social (disfunção do córtex pré-frontal e do lobo anterior temporal) e a Afasia Primária Progressiva (APP) caracterizada por capacidades linguísticas diminuídas (disfunção do hemisfério cerebral esquerdo).
A APP pode ser subdividida em três subtipos clínicos: a Demência Semântica (DS), Afasia Progressiva Não Fluente (APNF) e a variante Logopénica da APP (APL).
Entre um terço e metade dos doentes com DFT apresentam uma historia familiar positiva de transmissão autossómica dominante. Assim sendo, esta porção é geneticamente determinada enquanto que os casos restantes são esporádicos não tendo uma causa definida conhecida. É importante diagnosticar as formas genéticas destas doenças uma vez que um diagnóstico
precoce influencia o plano de tratamento. É portanto importante perceber como e por que processos a genética influencia estas doenças.
Os genes mais comummente associados com a DFT são: MAPT, GRN, C9orf72, CHMP2B, e VCP.
O objetivo deste estudo foi sequenciar e analisar amostras de DNA (extraído a partir de sangue periférico) de dois irmãos de uma paciente que havia sido previamente diagnosticada com DFT , possuindo uma mutação no quinto exão do gene SQSTM1 (p.Pro232Thr). Este estudo pretendia portanto avaliar a conexão entre esta mutação e a DFT uma vez que ambos os irmãos demonstravam evidencias de um diagnostico de DFT.
Após terminar a análise genética não foi, no entanto, possível tirar conclusões acerca da relação entre a Demência Frontotemporal e a mutação encontrada no caso index uma vez que não foi encontrada qualquer mutação em nenhum dos dois irmão.
The term dementia describes a number of symptoms that can be caused by several diseases affecting the brain. With a prevalence of 15-22/100.000 in the population between 45 and 65 years, Frontotemporal Dementia (FTD) is the second most common neurodegenerative disease (in patients with age of onset before 65 years old), following Alzheimer Disease (AD). FTD implies the loss of cognitive functions severe enough to affect activities of daily living. It is characterized by a progressive alteration in behaviour, language and social conduct linked to frontal and anterior temporal lobe degeneration (unilateral or on both sides of the brain). The symptoms usually start between 50 and 60 years of age and affect both men and women equally. Frontotemporal Dementia comprises an heterogeneous group of neurodegenerative disorders. FTD is used to describe the clinical syndrome while Frontotemporal Lobar Degeneration (FTLD) is used to describe the pathological diagnosis. Nowadays the most accepted terminology is dividing FTD into two main groups: behavioural variant of FTD (bvFTD), characterized by progressive impairment of personality and social behaviour (prefrontal and anterior temporal lobe dysfunction) and Primary Progressive Aphasia (PPA), characterized by diminished linguistic skills (left side dysfunction). PPA can be subdivided into three clinical subtypes: Semantic Dementia (SD), Progressive Nonfluent Aphasia (PNFA) and Logopenic Variant of PPA (LPA). A third to a half of the FTD patients shows a positive family history of autossomal dominant transmission. Therefore, this portion is genetically determined while the remaining cases are sporadic without having a known definitive cause. It is important to diagnose the genetic forms of these diseases because the early diagnosis influences the best course of treatment. Besides it is important to understand how and through which pathways genetic alterations influence these diseases. So far, the genes most commonly associated with FTD are: MAPT, GRN, C9orf72, CHMP2B, and VCP. The aim of this study was to sequence and analyse DNA samples (extracted from peripheral blood) from two siblings of a patient who had previously been diagnosed with FTD, carrying a novel mutation on the fifth exon of the SQSTM1 gene (p.Pro232Thr). This study intended to evaluate the connection between this mutation and FTD once the two siblings also showed evidence of the disease. After finishing the genetic analysis was, however, impossible to take any conclusion about the relation between the mutation found in the index case and Dementia Frontotemporal once no mutation was found on the two siblings.
The term dementia describes a number of symptoms that can be caused by several diseases affecting the brain. With a prevalence of 15-22/100.000 in the population between 45 and 65 years, Frontotemporal Dementia (FTD) is the second most common neurodegenerative disease (in patients with age of onset before 65 years old), following Alzheimer Disease (AD). FTD implies the loss of cognitive functions severe enough to affect activities of daily living. It is characterized by a progressive alteration in behaviour, language and social conduct linked to frontal and anterior temporal lobe degeneration (unilateral or on both sides of the brain). The symptoms usually start between 50 and 60 years of age and affect both men and women equally. Frontotemporal Dementia comprises an heterogeneous group of neurodegenerative disorders. FTD is used to describe the clinical syndrome while Frontotemporal Lobar Degeneration (FTLD) is used to describe the pathological diagnosis. Nowadays the most accepted terminology is dividing FTD into two main groups: behavioural variant of FTD (bvFTD), characterized by progressive impairment of personality and social behaviour (prefrontal and anterior temporal lobe dysfunction) and Primary Progressive Aphasia (PPA), characterized by diminished linguistic skills (left side dysfunction). PPA can be subdivided into three clinical subtypes: Semantic Dementia (SD), Progressive Nonfluent Aphasia (PNFA) and Logopenic Variant of PPA (LPA). A third to a half of the FTD patients shows a positive family history of autossomal dominant transmission. Therefore, this portion is genetically determined while the remaining cases are sporadic without having a known definitive cause. It is important to diagnose the genetic forms of these diseases because the early diagnosis influences the best course of treatment. Besides it is important to understand how and through which pathways genetic alterations influence these diseases. So far, the genes most commonly associated with FTD are: MAPT, GRN, C9orf72, CHMP2B, and VCP. The aim of this study was to sequence and analyse DNA samples (extracted from peripheral blood) from two siblings of a patient who had previously been diagnosed with FTD, carrying a novel mutation on the fifth exon of the SQSTM1 gene (p.Pro232Thr). This study intended to evaluate the connection between this mutation and FTD once the two siblings also showed evidence of the disease. After finishing the genetic analysis was, however, impossible to take any conclusion about the relation between the mutation found in the index case and Dementia Frontotemporal once no mutation was found on the two siblings.
Descrição
Dissertação de Mestrado em Biologia Clínica Laboratorial
Palavras-chave
Demência frontotemporal , Degeneração lobar frontotemporal