Early life involvement in C9orf72 repeat expansion carriers

Abstract

ObjectivesThe chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72RE-associated disease is sometimes hard to define, we hypothesise that C9orf72RE may cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72RE. Second, we aimed to describe distinctive characteristics of C9orf72RE during disease course.MethodsOut of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72RE bvFTD patients and 23 C9orf72RE negative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses.ResultsEducation, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having ‘fixed behavioural patterns in daily life’ and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers.ConclusionThis is the first study thoroughly exploring biographies of bvFTD patients with C9orf72RE, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72RE exerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72RE -associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.

Psychopathology in premanifest C9orf72 repeat expansion carriers

“…Interestingly, this was not reflected in participants’ self-reports of psychiatric symptoms, potentially aligning with FTD-typical anosognosia. The present findings converge with those of Gossink et al ,1 underscoring the psychiatric hypervulnerability associated with c9orf72 RE . Our results also add to previously documented empathic deficits2 by revealing increased rates of depressive disorder, post-traumatic stress disorder and substance abuse/dependence, with high comorbidity rates.…”

“…Finally, to converge with the findings of Gossink et al ,1 we assessed empathic abilities by means of the Revised Self-Monitoring Scale (RSMS) and the empathic concern scale of the Interpersonal Reactivity Index (IRI), measuring sensitivity to socioemotional cues and allocentric feelings of sympathy for unfortunate others, respectively. Comparisons to healthy reference samples8 9 revealed significantly reduced scores for both variables (RSMS: t(84)=379.21; p<0.001; IRI: t(670)=45.10, p<0.001; see also table 1), replicating other recent findings 2.…”

“…They used clinical case-record data and performed semistructured biographical interviews with spouses, first-degree relatives and patients with bvFTD with (N=20) and without (N=23) c9orf72 RE . The results revealed limited empathic behaviour early in life and increased rates of compulsive personality traits in c9orf72 RE carriers 1…”

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

“…One of the difficulties in defining the prodromal stage in C9orf72 carriers is due to the frequent presence of a prominent psychopathological, rather than cognitive, symptomatology at disease onset. Patients with C9orf72-associated bvFTD often show a constellation of psychiatric symptoms and syndromes [4,[105][106][107], which can be inaugural of the cognitive disorder. Even more noteworthy, a subset of C9orf72 carriers may present with isolated psychiatric phenotypes preceding dementia onset by several years or decades [46].…”

Frontotemporal Dementia and Late-Onset Bipolar Disorder: The Many Directions of a Busy Road

“…Many studies have also identified a pattern of variability in the heritability of FTD throughout its clinical subtypes; for instance, a more frequent family history in bvFTD in comparison to non-behavioral variants (primary progressive aphasia and motor phenotypes) ( 117 , 118 ). Furthermore, increasing evidence links the C9ORF72 repeat expansion to a manifestation of atypical psychotic symptoms in carriers before bvFTD ( 70 , 119 , 120 ), including “fixed behavioral patterns in daily life" and limited empathy ( 120 ); conversely, most studies reported no direct, clear statistical correlation between C9ORF72 expression and a primary psychiatric disorder ( 121 ), except for Gosink et al ( 120 ), who described more significant pathological personality traits early in life in positive rather than negative C9ORF72 carriers.…”