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

Souza, Paulo Victor Sgobbi de; Pinto, Wladimir Bocca Vieira de Rezende; Oliveira, Acary Souza Bullé

doi:10.1590/0004-282x20140229

Cited by 24 publications

(23 citation statements)

References 57 publications

(98 reference statements)

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“…It occurs in an autosomal dominant inherited pattern in association with FTD and is associated with hexanucleotide repeat expansion (GGGGCC) in the non-conding intronic region of 5' regulatory region of C9orf72 gene (chromosome 9 open reading frame 72; 9p21.2), coding the C9orf72 protein, involved in multiple intracellular mechanisms 45,46 . Loss of function by happloinsufficiency and toxic gain-of-function mechanisms are both present.…”

Section: Ftd-als Typementioning

confidence: 99%

Clinical and genetic basis of familial amyotrophic lateral sclerosis

Souza

Pinto

Chieia

et al. 2015

Arq. Neuro-Psiquiatr.

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Amyotrophic lateral sclerosis represents the most common neurodegenerative disease leading to upper and lower motor neuron compromise. Although the vast majority of cases are sporadic, substantial gain has been observed in the knowledge of the genetic forms of the disease, especially of familial forms. There is a direct correlation between the profile of the mutated genes in sporadic and familial forms, highlighting the main role ofC9orf72 gene in the clinical forms associated with frontotemporal dementia spectrum. The different genes related to familial and sporadic forms represent an important advance on the pathophysiology of the disease and genetic therapeutic perspectives, such as antisense therapy. The objective of this review is to signal and summarize clinical and genetic data related to familial forms of amyotrophic lateral sclerosis.

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Section: Ftd-als Typementioning

confidence: 99%

Clinical and genetic basis of familial amyotrophic lateral sclerosis

Souza

Pinto

Chieia

et al. 2015

Arq. Neuro-Psiquiatr.

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“…The first causative genetic mutations were described in Cu-Zn superoxide dismutase 1 (SOD1) gene in 1993 [3], and due to several genome sequencing projects, many of the genes responsible for ALS (>30 genes so far) have been described [4]. The identification of a hexanucleotide repeat expansion (HRE) GGGGCC (G4C2 > 30) in the non-coding region of the human chromosome 9 open reading frame 72 (C9ORF72) gene as the most frequent genetic cause of both ALS and frontotemporal dementia (FTD), and which is also present in other neurodegenerative diseases, has represented one of the major breakthroughs in the last 20 years of research in this field [5,6]. In fact, the G4C2 HRE in the C9ORF72 gene is detected in as many as 40 % of fALS and FTD and in approximately 9 % of sALS cases, with further descriptions in other neurodegenerative disorders [5,[7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

et al. 2016

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The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we Maria Sara Cipolat Mis and Simona Brajkovic contributed equally to this work.

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“…While the C9orf72 mutations are more common in populations of European ancestry, it can be found in East Asian populations as well [15]. Specifically, in a cohort of ALS and FTD Caucasian patients from USA, Europe, Middle East, and Australia, the mutation was present in 7 % of sALS, 39.3 % of fALS, 6 % sFTD, and 24.8 % of fFTD [12].…”

Section: Demographics Of C9orf72 In Ftd and Alsmentioning

confidence: 94%

“…ALS is familial in approximately 5 to 10 % of cases [13,14]. Of these, approximately one third or more of familial ALS (fALS) can be attributed to the C9orf72 mutation [15]; SOD1 mutation accounts for 20 % of fALS, while mutations of TAR DNA-binding protein (TARDBP) (5-10 %), FUS RNA-binding protein (FUS) (5 %), are less frequent [14]. In one cohort of ALS-FTD patients, 26 % were found to be C9orf72 positive (6 out of 23 subjects) [16].…”

Section: Diagnosis and Geneticsmentioning

confidence: 99%

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Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Patel

Sampson

2015

Curr Neurol Neurosci Rep

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This review article focuses on the cognitive profile associated with the C9orf72 gene with GGGGCC (G4C2) hexanucleotide repeat expansions that is commonly found in both familial and sporadic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in order to aid clinicians in the screening process. In this growing clinical continuum between FTD and ALS, understanding and recognizing a neurocognitive profile is important for diagnosis. Key features of this profile include executive dysfunction with memory impairment and language deficits as the disease progresses. Behaviorally, patients are prone to disinhibition, apathy, and psychosis. With the discovery of this mutation, studies have begun to characterize the different phenotypes associated with this mutation in terms of epidemiology, clinical presentation, imaging, and pathology. Greater awareness and increased surveillance for this mutation will benefit patients and their families in terms of access to genetic counseling, research studies, and improved understanding of the disease process.

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

Cited by 24 publications

References 57 publications

Clinical and genetic basis of familial amyotrophic lateral sclerosis

Clinical and genetic basis of familial amyotrophic lateral sclerosis

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

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