Psychiatric Presentations of <i>C9orf72</i> Mutation: What Are the Diagnostic Implications for Clinicians?

Ducharme, Simon; Bajestan, Sepideh N.; Dickerson, Bradford C.; Voon, Valerie

doi:10.1176/appi.neuropsych.16090168

Cited by 67 publications

(72 citation statements)

References 95 publications

(172 reference statements)

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“…Atrophy in this nucleus can lead to altered processing of pain, hallucinations, and both affective and psychotic symptoms. This is in line with frequently reported clinical symptoms in C9orf72 carriers that tend not to be found in other forms of FTD (Ducharme, Bajestan, Dickerson, & Voon, 2017;Fletcher et al, 2015). We also found that the LGN was particularly affected in C9orf72, an area previously linked to visual hallucinations which are a common feature of this genetic group (Ducharme et al, 2017;Kertesz et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

“…The pulvinar is a key region for limbic functions and intramodality integration of sensory information (Schmahmann, 2003) ( Table 1). This is in line with frequently reported clinical symptoms in C9orf72 carriers that tend not to be found in other forms of FTD (Ducharme, Bajestan, Dickerson, & Voon, 2017;Fletcher et al, 2015). This is in line with frequently reported clinical symptoms in C9orf72 carriers that tend not to be found in other forms of FTD (Ducharme, Bajestan, Dickerson, & Voon, 2017;Fletcher et al, 2015).…”

Section: Discussionsupporting

confidence: 90%

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Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72

Bocchetta

Iglesias

Neason

et al. 2019

Human Brain Mapping

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Thalamic atrophy is a common feature across all forms of FTD but little is known about specific nuclei involvement. We aimed to investigate in vivo atrophy of the thalamic nuclei across the FTD spectrum. A cohort of 402 FTD patients (age: mean(SD) 64.3 (8.2) years; disease duration: 4.8(2.8) years) was compared with 104 age-matched controls (age: 62.5(10.4) years), using an automated segmentation of T1-weighted MRIs to extract volumes of 14 thalamic nuclei. Stratification was performed by clinical diagnosis (180 behavioural variant FTD (bvFTD), 85 semantic variant primary progressive aphasia (svPPA), 114 nonfluent variant PPA (nfvPPA), 15 PPA not otherwise specified (PPA-NOS), and 8 with associated motor neurone disease (FTD-MND), genetic diagnosis (27 MAPT, 28 C9orf72, 18 GRN), and pathological confirmation (37 tauopathy, 38 TDP-43opathy, 4 FUSopathy). The mediodorsal nucleus (MD) was the only nucleus affectedin all FTD subgroups (16-33% smaller than controls). The laterodorsal nucleus was also particularly affected in genetic cases (28-38%), TDP-43 type A (47%), tau-CBD (44%), and FTD-MND (53%). The pulvinar was affected only in the C9orf72 group (16%). Both the lateral and medial geniculate nuclei were also affected in the genetic cases (10-20%), particularly the LGN in C9orf72 expansion carriers. Use of individual thalamic nuclei volumes provided higher accuracy in discriminating between FTD groups than the whole thalamic volume. The MD is the only structure affected across all FTD groups. Differential involvement of the thalamic nuclei among FTD forms is seen, with a unique pattern of atrophy in the pulvinar in C9orf72 expansion carriers. K E Y W O R D Sfrontotemporal dementia, magnetic resonance imaging, thalamic nuclei

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72

Bocchetta

Iglesias

Neason

et al. 2019

Human Brain Mapping

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“…because the hexanucleotide repeat is reported to have a frequency less than 0.1% in those with schizophrenia. 32 We found increased rates of recorded cardiovascular disease (CVD) before diagnosis of ALS (RR = 1.21; 95% CI, 1.15-1.27), as previously reported. 16 This association, however, was not detected in the narrow definition of heart disease; MI.…”

Section: Discussionsupporting

confidence: 84%

ALS in Danish Registries

et al. 2020

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ObjectiveTo investigate the genetic contribution to amyotrophic lateral sclerosis (ALS) and the phenotypic and genetic associations between ALS and psychiatric and cardiovascular disorders (CVD) we used the national registry data from Denmark linked to first-degree relatives to estimate heritability and cross-trait parameters.MethodsALS cases and 100 sex and birth-matched controls per case from the Danish Civil Registration System were linked to their records in the Danish National Patient Registry. Cases and controls were compared for (1) risk of ALS in first-degree relatives, used to estimate heritability, (2) comorbidity with psychiatric disorders and CVD, and (3) risk of psychiatric disorders and CVD in first-degree relatives.Results5,808 ALS cases and 580,800 controls were identified. Fifteen percent of cases and controls could be linked to both parents and full siblings, whereas 70% could be linked to children. (1) We estimated the heritability of ALS to be 0.43 (95% CI, 0.34–0.53). (2) We found increased rates of diagnosis of mental disorders (risk ratio = 1.18; 95% CI, 1.09–1.29) and CVD in those later diagnosed with ALS. (3) In first-degree relatives of those with ALS, we found increased rate of schizophrenia (1.17; 95% CI, 0.96–1.42), but no evidence for increased risk CVD.ConclusionsHeritability of ALS is lower than commonly reported. There is likely a genetic relationship between ALS and schizophrenia, and a nongenetic relationship between ALS and CVD.

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“…An increased prevalence of psychotic symptoms in FTD patients with C9orf72 expansion has been reported. However, a recent comprehensive review concluded that the prevalence of C9orf in primary psychiatric presentations is estimated to be around 0.1% 15 and not larger than its prevalence in healthy controls. A possible association with Alzheimer's disease (AD) has also been examined.…”

Section: Background Discovery and Clinical Significance Of C9orf72mentioning

confidence: 99%

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

Bourinaris

Houlden

2018

Movement Disord Clin Pract

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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.

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Psychiatric Presentations of C9orf72 Mutation: What Are the Diagnostic Implications for Clinicians?

Cited by 67 publications

References 95 publications

Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72

Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72

ALS in Danish Registries

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

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