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Psychopathology in premanifest C9orf72 repeat expansion carriers
  1. Joke De Vocht1,2,3,
  2. Daphne Stam4,
  3. Marie Nicolini5,
  4. Nikita Lamaire2,3,
  5. Maarten Laroy4,
  6. Thomas Vande Casteele4,
  7. Laura Van De Vliet4,
  8. Kristof Vansteelandt4,6,
  9. Ann D'Hondt1,
  10. Louise Emsell4,6,
  11. Ronny Bruffaerts7,
  12. Mathieu Vandenbulcke4,6,
  13. Philip van Damme1,2,3,
  14. Jan Van den Stock4,6
  1. 1Department of Neurology, Neuromuscular Reference Centre, University Hospitals Leuven, Leuven, Belgium
  2. 2Laboratory of Neurobiology, Center for Brain and Disease Research, VIB, Leuven, Belgium
  3. 3Department of Neurosciences, Experimental Neurology, Leuven Brain Institute, KU Leuven, Leuven, Belgium
  4. 4Neuropsychiatry, Leuven Brain Institute, KU Leuven, Leuven, Belgium
  5. 5Interfaculty Center for Biomedical Ethics and Law, KU Leuven, Leuven, Belgium
  6. 6Geriatric Psychiatry, University Psychiatric Centre KU Leuven, Leuven, Belgium
  7. 7Public Health Psychiatry, University Psychiatric Centre KU Leuven, Leuven, Belgium
  1. Correspondence to Professor Jan Van den Stock, Neurosciences, KU Leuven, Leuven, Belgium; jan.vandenstock{at}

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The clinical phenotype of behavioural variant frontotemporal dementia (bvFTD) is characterised by neuropsychiatric symptoms, including loss of empathy, compulsive behaviour, behavioural disinhibition and apathy. An expansion of a hexanucleotide (GGGGCC) repeat in the chromosome 9 open reading frame 72 gene (c9orf72RE) is the most common genetic cause of bvFTD. Neurobiological and behavioural changes have been evidenced in carriers of c9orf72RE, decades before the estimated onset of symptoms. Recently, Gossink and colleagues investigated the hypothesis that the c9orf72RE genotype phenotypically could encompass a neuropsychiatric hypervulnerability, emerging during early childhood. 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) c9orf72RE. The results revealed limited empathic behaviour early in life and increased rates of compulsive personality traits in c9orf72RE carriers.1

Notably, the c9orf72RE does not only cause bvFTD but may also result in amyotrophic lateral sclerosis (ALS), in which it is more frequently associated with neuropsychiatric symptoms, compared with non-c9orf72RE ALS variants. In addition, socioemotional deficits consistent with empathic impairment have been reported in c9orf72RE-carriers with only very mild cognitive and/or functional impairments.2 Also, increased hazard ratios for psychiatric disorders have been reported in kindreds of c9orf72RE carriers.3 These combined findings give rise to the hypothesis that, compared with the general population, the prevalence of psychopathological characteristics is increased in c9orf72RE carriers who do not (yet) fulfil the clinical …

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  • Contributors JDV, PvD, MV and JVdS conceived and designed the study. JDV, DS, MN, ML, TVC, LVDV, NL and AD'H collected the data. JDV, RB and KV analysed the data. JDV and JVdS drafted the manuscript. All authors commented on the manuscript.

  • Funding This work was supported by the Sequoia Fund for Research on Ageing and Mental Health (no grant number) and KU Leuven Research Council (IDN/21/101 and C24/18/095).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.