C9orf72 Hexanucleotide Repeat Expansions in Clinical Alzheimer Disease

Harms, Matthew B.; Benitez, Bruno A.; Cairns, Nigel J.; Cooper, Barry; Cooper, Paul; Mayo, Kevin H.; Carrell, David; Faber, Kelley; Williamson, Jennifer; Bird, T.; Diaz‐Arrastia, Ramon; Foroud, Tatiana; Boeve, Bradley F.; Graff‐Radford, Neill R.; Mayeux, Richard; Chakraverty, Sumi; Goate, Alison M.; Cruchaga, Carlos

doi:10.1001/2013.jamaneurol.537

Cited by 93 publications

(78 citation statements)

References 33 publications

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“…Mutations have been identified, at low frequencies (less than 1%-2%), in genes causing frontotemporal lobar degeneration (FTLD), that is, mutations in MAPT [83,84] and in granulin (GRN) [80][81][82], and the repeat expansion in C9orf72 [85][86][87] (Table 3). The genetic heterogeneity of the phenotypic presentation of AD supports that both diseases form part of an AD-FTLD disease continuum [100,101].…”

Section: The Role Of Other Neurodegenerative Brain Diseases Genes In mentioning

confidence: 99%

Molecular genetics of early‐onset Alzheimer's disease revisited

Cacace

Sleegers

Broeckhoven

2016

Alzheimer's & Dementia

486

404

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As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

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Section: The Role Of Other Neurodegenerative Brain Diseases Genes In mentioning

confidence: 99%

Molecular genetics of early‐onset Alzheimer's disease revisited

Cacace

Sleegers

Broeckhoven

2016

Alzheimer's & Dementia

486

404

View full text Add to dashboard Cite

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“…Neuropsychiatric profile involves early disinhibition (up to 85%), lack of insight (up to 78%), hallucinations (up to 50%), delusion (up to 50%), anxiety (up to 52%), hyperorality (up to 100%), early apathy (up to 100%), loss of empathy (up to 77%) and obsessive-compulsive symptoms (up to 12%) 5,42,43 . There is an important clinical overlap with probable Alzheimer's disease in the early-onset cases, mainly in Caucasian patients 45,46 , making it difficult to promote a proper genetic evaluation in association with classical genes (APP, PSEN1, PSEN2) 47,48 , although such cases generally present with an older age than with the FTD clinical spectrum 26 . UBQLN2 gene mutations are great mimickers frequently differentiated in clinical means by the absence of psychiatric features (not behavioural symptoms) and lower motor neuron involvement 14 .…”

Section: Clinical and Laboratory Characterizationmentioning

confidence: 99%

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

Souza

Pinto

Oliveira

2015

Arq. Neuro-Psiquiatr.

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Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC) of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.Keywords: neurodegenerative diseases, motor neuron disease, frontotemporal dementia, parkinsonism, C9orf72. RESUMOAs doenças neurodegenerativas representam um grupo heterogêneo de condições neurológicas envolvendo fundamentalmente síndromes demenciais, doenças do neurônio motor e distúrbios de movimento. Relacionam-se, em sua maioria, a processos fisiopatológicos distintos, destacadamente nas formas familiares em que a heterogeneidade clínica e genética são exuberantes. Na última década, muito conhecimento se acumulou a respeito da genética das doenças neurodegenerativas, tornando-se bastante importante nos casos de doenças do neurônio motor e de demência frontotemporal as expansões de repetições do gene C9orf72. Esta revisão aborda os principais aspectos clínicos, radiológicos e genéticos relativos aos fenótipos relacionados à expansão de repetição do hexanucleotídeo (GGGGCC) no gene C9orf72. Estudos futuros vão objetivar a caracterização dos aspectos neuropsicológicos, de imagem e patológicos dos achados extra-motores da doença do neurônio motor e ajudarão a fornecer um novo sistema de classificação relevante em termos clínicos e biológicos.Palavras-chave: doenças neurodegenerativas, doença do neurônio motor, demência frontotemporal, parkinsonismo, C9orf72.

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“…23,24 The C9orf72 HRE also represents the most common genetic cause of frontotemporal dementia (FTD), which is characterized by degeneration of the frontal and temporal lobes of the brain and is the second most common type of dementia in people younger than 65. 25 Furthermore, the C9orf72 HRE is linked to rare cases of other neurological conditions, including Alzheimer's disease, [26][27][28][29] Huntington's disease, 30 multiple system atrophy, 31 depressive pseudodementia, 32 bipolar disorder, [33][34][35] and schizophrenia. 36 Given these wide-ranging implications, understanding the molecular mechanisms of C9orf72 HRE-associated diseases has become a significant challenge in the study of neurodegeneration.…”

Section: C9orf72 Repeat Expansion Diseasesmentioning

confidence: 99%