C9ORF72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or Parkinson’s disease complicated by psychosis or dementia in a Sardinian population

Cannas, Antonino; Solla, Paolo; Borghero, Giuseppe; Floris, Gianluca; Chiò, Adriano; Mascia, Marcello Mario; Modugno, Nicola; Muroni, Antonella; Orofino, Gianni; Stefano, Francesca Di; Calvo, Andrea; Moglia, Cristina; Restagno, Gabriella; Meloni, Mario; Farris, Rita; Ciaccio, Daniela; Puddu, Roberta; Vacca, Melisa Iris Sabina; Melis, Rosanna; Murru, Maria Rita; Tranquilli, Stefania; Corongiu, Daniela; Rolesu, Marcella; Cuccu, Stefania; Marrosu, Maria Giovanna; Marrosu, Francesco

doi:10.1007/s00415-015-7873-6

Cited by 23 publications

(20 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A couple of studies that have been carried in mostly Caucasian populations from Europe and North America reported small frequencies of C9orf72 in PD cohorts, smaller than 1% . All other studies in Caucasian populations, including European and North American patients, did not report any positive C9orf72 expansion carriers . Finally, many studies that have been carried out in populations of Asian origin were also negative for the presence of expansion carriers, a fact that is coherent with the small frequency of the expansion in Asian populations.…”

Section: Resultsmentioning

confidence: 73%

“…These include a prevalence of 2% in a cohort of 102 DLB patients, and some positive cases of CBS and PSP in small cohorts of patients . The rest of the studies did not report the presence of large C9orf72 expansions in clinically diagnosed patients . Finally, a study that failed to identify large expansions in a cohort of patients with atypical parkinsonism, reported a significant frequency of intermediate sizes of 20 to 29 repeats (n = 4/92) .…”

Section: Resultsmentioning

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

Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

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

show abstract

“…In atypical PD or PD with psychosis, intermediate expansions (20)(21)(22)(23)(24)(25)(26)(27)(28)(29) were detected in three female cases with atypical parkinsonian syndromes (severe rigid akinetic parkinsonism) and neuropsychiatric symptoms including schizoaffective psychosis and an FTD-like dementia. 42 Unfortunately, these cases did not have pathological diagnosis. In schizophrenia, the pathogenic repeat expansion was detected in only two patients (0.67%), but the estimated number of repeats in controls appeared lower (2-5 units) than in schizophrenic patients without the expansion (2-30 units).…”

Section: Original Articlementioning

confidence: 95%

“…41 Intermediate repeats (20-29 units) were significantly more frequent in atypical parkinsonism cases than controls (p<0.034) and were seen in four (4.3%) female patients (with 20, 22, 23 and 28 repeats), three of whom had non-classical atypical parkinsonism. 42 PSP patients with intermediate repeat lengths of 26 and 30 were reported, but it is unclear if the repeat expansions and clinical symptoms are related. 33 Five studies of Alzheimer's disease (AD), including one study with 80% of subjects under age 65, 43 were included.…”

Section: Original Articlementioning

confidence: 99%

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

Tan

2017

J Med Genet

View full text Add to dashboard Cite

C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of <20 hexanucleotide repeats are observed in controls, while up to thousands associate with disease. Intermediate C9orf72 repeat lengths, however, remain uncertain. We systematically reviewed the role of intermediate C9orf72 alleles in C9orf72-related neurological disorders. We identified 49 studies with adequate available data on normal or intermediate C9orf72 repeat length, involving subjects with FTD, ALS, Parkinson’s disease (PD), atypical parkinsonism, Alzheimer’s disease (AD) and other aetiologies. We found that, overall, normal or intermediate C9orf72 repeat lengths are not associated with higher disease risk across these disorders, but intermediate allele sizes appear to associate more frequently with neuropsychiatric phenotypes. Intermediate sizes were detected in subjects with personal or family history of FTD and/or psychiatric illness, parkinsonism complicated by psychosis and rarely in psychiatric cohorts. Length of the hexanucleotide repeat may be influenced by ethnicity (with Asian controls displaying shorter normal repeat lengths compared with Caucasians) and underlying haplotype, with more patients and controls carrying the ‘risk’ haplotype rs3849942 displaying intermediate alleles. There is some evidence that intermediate alleles display increased methylation levels and affect normal transcriptional activity of the C9orf72 promoter, but the ‘critical’ repeat size required for initiation of neurodegeneration remains unknown and requires further study. In common neurological diseases, intermediate C9orf72 repeats do not influence disease risk but may associate with higher frequency of neuropsychiatric symptoms. This has important clinical relevance as intermediate carriers pose a challenge for genetic counselling.

show abstract

“…[6-8] Psychosis is a common symptom in DLB, raising the question of whether the C9orf72 hexanucleotide expansion is a genetic factor in DLB. Previous clinical studies have considered this question[9-12], with one study reporting two out of 102 clinically diagnosed DLB patients having a pathogenic repeat expansion. [10] However, the clinical diagnosis of DLB is challenging with a high false positive rate due to mimic syndromes.…”

Section: Introductionmentioning

confidence: 99%

<b><i>C9orf72</i></b> Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Geiger

Arthur

Dawson³

et al. 2016

Neurodegener Dis

View full text Add to dashboard Cite

Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. Objective: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. Methods: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. Results: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. Conclusion: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

show abstract

C9ORF72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or Parkinson’s disease complicated by psychosis or dementia in a Sardinian population

Cited by 23 publications

References 37 publications

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

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

Intermediate C9orf72 alleles in neurological disorders: does size really matter?

<b><i>C9orf72</i></b> Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Contact Info

Product

Resources

About