C9ORF72 Intermediate Repeat Expansion in a Patient With Psychiatric Disorders and Progressive Cerebellar Ataxia

Meloni, Mario; Farris, Rita; Solla, Paolo; Mascia, Marcello Mario; Marrosu, Francesco; Cannas, Antonino

doi:10.1097/nrl.0000000000000147

Cited by 7 publications

(11 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The uniform association of disruptive sleep events with C9orf72 mutations (but not with other FTD mutations or AD syndromes) was a striking feature of this cohort. This observation is in line with previous reports of disordered REM behaviour in association with C9orf72 mutations [[54], [55], [56]] and accords with the neuroanatomical signature of this genetic FTD subtype, which characteristically involves a thalamo-parietal network implicated in the generation of REM sleep [57,58]. It is clear, however, that any genetic basis for sleep symptomatology is likely to be complex: sleep symptoms were reported by all patients with FTD mutations here and severe sleep phenotypes have also been previously reported with MAPT mutations, in human patients and in animal models [[59], [60], [61], [62]].…”

Section: Discussionsupporting

confidence: 93%

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer’s disease: A proof-of-principle behavioural study

et al. 2019

View full text Add to dashboard Cite

HighlightsSleep is a key concern in dementias but their sleep phenotypes are not well defined.We addressed this issue in major FTD and AD syndromes versus healthy older controls.We surveyed sleep duration, quality and disruptive events, and daytime somnolence.Sleep symptoms were frequent in FTD and AD and distinguished these diseases.Sleep disturbance is an important clinical issue across major FTD and AD syndromes.

show abstract

Section: Discussionsupporting

confidence: 93%

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer’s disease: A proof-of-principle behavioural study

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Many studies report an intermediate range of repeats in patients with different phenotypes that include: typical PD, atypical parkinsonism, including PSP, MSA, and PD complicated by psychosis, ET plus parkinsonism, or even cerebellar ataxia . Previous studies have reported the presence of patients with an intermediate size of repeats in cases with FTD/ALS phenotypes .…”

Section: Resultsmentioning

confidence: 99%

“…Additional ataxia case reports include a patient with pure cerebellar ataxia and a large C9orf72 expansion, and a patient with progressive cerebellar ataxia and psychiatric symptoms, who was reported to carry an intermediate expansion of 21 repeat units …”

Section: Resultsmentioning

confidence: 99%

“…41 Many studies report an intermediate range of repeats in patients with different phenotypes that include: typical PD, 40,42,44,46,52 atypical parkinsonism, including PSP, MSA, and PD complicated by psychosis, 41,47,58 ET plus parkinsonism, 44 or even cerebellar ataxia. 84 Previous studies have reported the presence of patients with an intermediate size of repeats in cases with FTD/ALS phenotypes. 20,27,90,91 The exact definition of intermediate repeat expansion size is not firmly established though, and its possible role in disease is still being questioned, but cannot be completely disregarded with the current data.…”

Section: Clinical Significance Of C9orf72 In Parkinsonism and Movemenmentioning

confidence: 99%

See 1 more Smart Citation

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

Bourinaris

Houlden

2018

Movement Disord Clin Pract

View full text Add to dashboard Cite

Background The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined. Methods A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed. Results and Discussion In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD‐phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72‐related neurodegeneration that could explain the wide phenotypic variation.

show abstract

“…A large non-coding hexanucleotide repeat expansion (HRE) in the C9orf72 gene (>30 up to 1000 units) is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) [1,2], both characterized by neuroinflammation and high systemic levels of interleukin-6, interleukin-1β and tumor necrosis factor-α [3]. Healthy people harbor alleles ranging from 2 to 30 repeat units, but a real cut-off has not been determined and HREs of intermediate length (9-30 units), although rare, seem to be more frequent in neurodegenerative, neuropsychiatric and autoimmune disorders [4][5][6][7][8][9][10][11][12]. Gain of functions linked to the presence of the large HRE, resulting in nuclear RNA foci and cytoplasmic aggregation of dipeptide repeat proteins, are the main pathogenic mechanisms of neurodegeneration in FTD and ALS, but C9orf72 haploinsufficiency is assumed to play a role in the underlying neuroinflammation [13].…”

Section: Introductionmentioning

confidence: 99%

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

Zanella

Zacchi

Piva

et al. 2021

IJMS

View full text Add to dashboard Cite

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

show abstract

C9ORF72 Intermediate Repeat Expansion in a Patient With Psychiatric Disorders and Progressive Cerebellar Ataxia

Cited by 7 publications

References 14 publications

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer’s disease: A proof-of-principle behavioural study

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer’s disease: A proof-of-principle behavioural study

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

Contact Info

Product

Resources

About