Distinct Clinical Characteristics of C9orf72 Expansion Carriers Compared With GRN, MAPT, and Nonmutation Carriers in a Flanders-Belgian FTLD Cohort

Langenhove, Tim Van; Zee, Julie van der; Gijselinck, Ilse; Engelborghs, Sebastiaan; Vandenberghe, Rik; Vandenbulcke, Mathieu; Bleecker, Jan De; Sieben, Anne; Versijpt, Jan; Ivanoiu, Adrian; Deryck, Olivier; Willems, Christiana; Dillen, Lubina; Philtjens, Stéphanie; Maes, Githa; Bäumer, Veerle; Broeck, Marleen Van den; Mattheijssens, Maria; Peeters, Karin; Martin, Jean‐Jacques; Michotte, Alex; Santens, Patrick; Jonghe, Peter De; Cras, Patrick; Deyn, Peter Paul De; Cruts, Marc; Broeckhoven, Christine Van

doi:10.1001/2013.jamaneurol.181

Cited by 84 publications

(85 citation statements)

References 33 publications

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“…Inappropriate behavior associated with apathy, loss of interest and empathy characterized early phases of the disease in 3 of our 4 patients, while only patient 4 with bvFTD-MND overlap expressed early visual hallucinations and agitation. These findings contradicted the previous observation that C9 + carriers with bvFTD often presented with inappropriate behavior and agitation, in contrast to patients with bvFTD due to GRN mutation in whom apathy dominated [26]. In accordance with previous studies [27], we did not identify any C9orf72 hexanucleotide expansions in the patients with other forms of dementia included in this study (PPA, FTD-PSP, DLB or AD).…”

Section: Discussioncontrasting

confidence: 71%

Screening for C9orf72 Expansion Mutation in Serbian Patients with Early-Onset Dementia

Mandic-Stojmenovic

Stefanova²,

Dobričić³

et al. 2015

Dement Geriatr Cogn Disord

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Background: Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia (EOD), characterized by behavioral changes (behavioral variant; bvFTD) or language deficits. A hexanucleotide repeat expansion in a noncoding region of chromosome 9 open reading frame 72 (C9orf72) has been proved to be a major cause of both familial and sporadic amyotrophic lateral sclerosis or FTD, with or without concomitant motor neuron disease (MND). Methods: The aim of this study was to assess the frequency of the C9orf72 hexanucleotide expansion in a cohort of 117 Serbian patients with EOD and to report phenotypic features of identified carriers. Results: We identified 4 of 117 (3.4%) patients with EOD to have C9orf72 hexanucleotide expansions. All patients were classified in the FTD disease spectrum group (8.2%): 3 patients fulfilled the criteria for bvFTD, and 1 patient had FTD-MND. None of the patients with the C9orf72 hexanucleotide expansion fulfilled the diagnostic criteria for language variants of FTD, FTD-progressive supranuclear palsy overlap syndrome, dementia with Lewy bodies or Alzheimer's dementia. Conclusion: In a cohort of consecutive patients with EOD, 3.4% had the C9orf72 hexanucleotide expansion with clinical phenotypes of bvFTD or an overlap of bvFTD and MND.

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Section: Discussioncontrasting

confidence: 71%

Screening for C9orf72 Expansion Mutation in Serbian Patients with Early-Onset Dementia

Mandic-Stojmenovic

Stefanova²,

Dobričić³

et al. 2015

Dement Geriatr Cogn Disord

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“…Phenotypes of C9ORF72 repeat expansion carriers, in general, appear to differ from patients with mutations in GRN or MAPT. [26][27][28][29][30] It was shown that age at onset is earlier in patients with C9ORF72 expansions compared to patients with GRN mutations, [26][27][28][29] but later compared to patients with MAPT mutations. [27][28][29] Moreover, MND is frequently detected in patients with C9ORF72 expansions, whereas signs of MND are scarce in patients with GRN or MAPT mutations.…”

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confidence: 99%

“…[27][28][29] Moreover, MND is frequently detected in patients with C9ORF72 expansions, whereas signs of MND are scarce in patients with GRN or MAPT mutations. 26,[28][29][30] Behavioral variant FTD is the predominant phenotype of all 3 groups; primary progressive aphasia and corticobasal syndrome phenotypes are rare in patients with C9ORF72 expansions, and are more frequently detected in patients with GRN or MAPT mutations. 26,29 The co-occurrence of C9ORF72 expansions and mutations in GRN or MAPT in patients with FTD could have several explanations.…”

mentioning

confidence: 99%

“…26,[28][29][30] Behavioral variant FTD is the predominant phenotype of all 3 groups; primary progressive aphasia and corticobasal syndrome phenotypes are rare in patients with C9ORF72 expansions, and are more frequently detected in patients with GRN or MAPT mutations. 26,29 The co-occurrence of C9ORF72 expansions and mutations in GRN or MAPT in patients with FTD could have several explanations. First, it could be argued that only C9ORF72 expansions are pathogenic, and that the GRN or MAPT mutations are rare benign variants or mere risk factors.…”

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confidence: 99%

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C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

et al. 2013

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Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (.3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions:Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members. Neurology

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“…These characteristic neuronal inclusions can be found in several neuroanatomical sites, but the hippocampal pyramidal neurons and cerebellar granule cell layer seem to be the most affected (Al-Sarraj et al, 2011). Clinically, the predominant phenotype in these patients is bvFTD associated with ALS, although the presentation may vary widely even within the same family (bvFTD or ALS or a combination of both diseases) (Murray et al, 2011;Van Langenhove et al, 2013). Considering the FTLD spectrum, the most represented subtype is bvFTD, whereas PNFA is the least frequent.…”

Section: Rainero Et Almentioning

confidence: 99%

Recent advances in the molecular genetics of frontotemporal lobar degeneration

Rainero¹

2017

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SummaryThe term frontotemporal lobar degeneration (FTLD) describes a spectrum of neurodegenerative disorders associated with deposition of misfolded proteins in the frontal and temporal lobes. Up to 40% of FTLD patients reports a family history of neurodegeneration, and approximately 1/3 of familial cases shows an autosomal dominant pattern of inheritance of the phenotype. Over the past two decades, several causative and susceptibility genes for FTLD have been discovered, supporting the notion that genetic factors are important contributors to the disease processes. Genetic variants in three genes, MAPT, GRN and C9orf72, account for about half of familial FTLD cases. In addition, rare defects in the CHMP2B, VCP, TARDBP, SQSTM1, FUS, UBQLN, OPTN, TREM2, CHCHD10 and TBK1 genes have been described. Additional genes are expected to be found in near future. The purpose of this review is to describe recent advances in the molecular genetics of the FTLD spectrum and to discuss implications for genetic counseling.

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Distinct Clinical Characteristics of C9orf72 Expansion Carriers Compared With GRN, MAPT, and Nonmutation Carriers in a Flanders-Belgian FTLD Cohort

Cited by 84 publications

References 33 publications

Screening for <b><i>C9orf72</i></b> Expansion Mutation in Serbian Patients with Early-Onset Dementia

Screening for <b><i>C9orf72</i></b> Expansion Mutation in Serbian Patients with Early-Onset Dementia

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Recent advances in the molecular genetics of frontotemporal lobar degeneration

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