Links Between the C9orf72 Repeat Expansion and Psychiatric Symptoms
Purpose of Review
To present recent findings on the links between the C9orf72 expansion and psychiatric impairment.
Repeat hexanucleotide expansions in the C9orf72 gene are a cause of familial frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and the mixed phenotype, FTD-ALS. Symptomatic expansion carriers display higher rates of psychotic and other psychiatric symptoms than non-carriers. Neuroanatomical associations of these symptoms have been found in cortical and subcortical areas. Family members of symptomatic carriers have higher rates of primary neuropsychiatric disorders than control populations, and the C9orf72 expansion may contribute to this association. However, the expansion does not appear to directly cause primary psychiatric disorders.
While there is strong evidence associating the C9orf72 expansion with psychotic symptoms in carriers and psychiatric disorders in their kindreds, the link between these two phenomena, if any, remains unclear.
KeywordsC9orf72 Psychiatric Frontotemporal dementia Amyotrophic lateral sclerosis
Compliance with Ethical Standards
Conflict of Interest
Hannah E. Silverman, Jill S. Goldman, and Edward D. Huey each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.• Marogianni C, Rikos D, Provatas A, Dadouli K, Ntellas P, Tsitsi P et al. The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database. Neurobiology of Aging. 2019. This meta-analysis reviews the rates of different phenotypes due to C9orf72 repeat expansions across multiple populations. Google Scholar
- 6.Zhou Q, Qu Q. C9ORF72 and frontotemporal dementia: a systematic review and meta-analysis. Parkinsonism Relat Dis. 2018;46:e51.Google Scholar
- 8.Beck J, Poulter M, Hensman D, Rohrer JD, Mahoney CJ, Adamson G, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Human Genetics. 2013;92(3):345–53.Google Scholar
- 11.Ng AS, Tan E-K. Intermediate C9orf72 alleles in neurological disorders: does size really matter? J Med Genetics. 2017;54(9):591–7.Google Scholar
- 12.Van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, et al. Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol. 2013;12(10):978–88.PubMedGoogle Scholar
- 14.•• Ducharme S, Bajestan S, Dickerson BC, Voon V. Psychiatric presentations of C9orf72 mutation: what are the diagnostic implications for clinicians? J Neuropsychiatry Clin Neurosci. 2017;29(3):195–205 This review summarizes the literature on psychotic symptoms in C9orf72 expansion carriers as well as the studies screening psychiatric patients for the expansion, with a particular focus on the implications of findings for clinicians.PubMedGoogle Scholar
- 18.Hodges J. Hodges’ frontotemporal dementia. Second Edition ed. Cambridge: Cambridge University Press; 2016.Google Scholar
- 25.Waldö ML, Gustafson L, Nilsson K, Traynor BJ, Renton AE, Englund E, et al. Frontotemporal dementia with a C9ORF72 expansion in a Swedish family: clinical and neuropathological characteristics. Am J Neurodegener Dis. 2013;2(4):276.Google Scholar
- 30.Shinagawa S, Naasan G, Karydas AM, Coppola G, Pribadi M, Seeley WW, et al. Clinicopathological study of patients with C9ORF72-associated frontotemporal dementia presenting with delusions. J Geriatr Psychiatr Neurol. 2015;28(2):99–107.Google Scholar
- 33.Zucchi E, Ticozzi N, Mandrioli J. Psychiatric symptoms in amyotrophic lateral sclerosis: beyond a motor neuron disorder. Front Neurosci. 2019;13.Google Scholar
- 34.• Turner MR, Goldacre R, Talbot K, Goldacre MJ. Psychiatric disorders prior to amyotrophic lateral sclerosis. Ann Neurol. 2016;80(6):935–8 This study shows that patients with ALS have increased rates of hospitalization for psychiatric disease in the 5 years preceding their diagnoses.PubMedPubMedCentralGoogle Scholar
- 35.• Longinetti E, Mariosa D, Larsson H, Ye W, Ingre C, Almqvist C, et al. Neurodegenerative and psychiatric diseases among families with amyotrophic lateral sclerosis. Neurology. 2017;89(6):578–85 This large, population-based study investigates, among other things, rates of psychiatric illness in ALS patients and their family members in the years before and after patients received their diagnoses.PubMedPubMedCentralGoogle Scholar
- 36.•• Devenney EM, Landin-Romero R, Irish M, Hornberger M, Mioshi E, Halliday GM, et al. The neural correlates and clinical characteristics of psychosis in the frontotemporal dementia continuum and the C9orf72 expansion. Neuroimage Clin. 2017;13:439–45 This study examines neuroanatomical associations of psychotic symptoms (delusions and hallucinations) in C9orf72 expansion carriers with FTD and FTD-ALS.PubMedGoogle Scholar
- 37.•• Sellami L, Bocchetta M, Masellis M, Cash DM, Dick KM, Van Swieten J, et al. Distinct neuroanatomical correlates of neuropsychiatric symptoms in the three main forms of genetic frontotemporal dementia in the GENFI cohort. J Alzheimers Dis. 2018(Preprint):1–16 This paper examines neuroanatomical associations of individual psychiatric symptoms in C9orf72 expansion carriers with FTD.Google Scholar
- 38.Rohrer JD, Nicholas JM, Cash DM, van Swieten J, Dopper E, Jiskoot L, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol. 2015;14(3):253–62.PubMedPubMedCentralGoogle Scholar
- 39.Huey ED, Nagy PL, Rodriguez-Murillo L, Manoochehri M, Goldman J, Lieberman J, et al. C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. Neurobiol Aging. 2013;34(4):1309. e9–e10.Google Scholar
- 40.Galimberti D, Reif A, Dell’Osso B, Kittel-Schneider S, Leonhard C, Herr A, et al. The C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia. Neurobiol Aging. 2014;35(5):1214. e7–e10.Google Scholar
- 41.Fahey C, Byrne S, McLaughlin R, Kenna K, Shatunov A, Donohoe G, et al. Analysis of the hexanucleotide repeat expansion and founder haplotype at C9ORF72 in an Irish psychosis case-control sample. Neurobiol Aging. 2014;35(6):1510. e1–5.Google Scholar
- 43.• Solje E, Miettunen J, Marttila R, Helisalmi S, Laitinen M, Koivumaa-Honkanen H, et al. The C9ORF72 expansion sizes in patients with psychosis: a population-based study on the Northern Finland Birth Cohort 1966. Psychiatric Genet. 2016;26(2):92–4 In this study, a large cohort of patients with psychosis in Finland was screened for the C9orf72 mutation. No mutation carriers were identified in the sample.Google Scholar
- 44.• Watson A, Pribadi M, Chowdari K, Clifton S, Wood J, Miller BL, et al. C9orf72 repeat expansions that cause frontotemporal dementia are detectable among patients with psychosis. Psychiatry Res. 2016;235:200–2 In this study, a large cohort of patients with psychosis in the USA was screened for the C9orf72 mutation. Four mutation carriers were identified in the sample.PubMedGoogle Scholar
- 46.Floris G, Di Stefano F, Pisanu C, Chillotti C, Murru MR, Congiu D, et al. C9ORF72 repeat expansion and bipolar disorder-is there a link? No mutation detected in a Sardinian cohort of patients with bipolar disorder. Bipolar Dis. 2014;16(6):667.Google Scholar
- 48.• Arthur KC, Rivera AM, Samuels J, Wang Y, Grados M, Goes FS, et al. C9orf72 hexanucleotide repeat expansions are not a common cause of obsessive-compulsive disorder. J Neurol Sci. 2017;375:71–2 In this study, a large cohort of patients with obsessive-compulsive disorder was screened for the C9orf72 mutation. No mutation carriers were identified in the sample.PubMedPubMedCentralGoogle Scholar
- 49.• Solje E, Riipinen P, Helisalmi S, Särkioja T, Laitinen M, Hiltunen M, et al. The role of the FTD-ALS associated C9orf72 expansion in suicide victims. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17(7-8):589–92 In this study, autopsy screenings for the C9orf72 mutation were performed on a large cohort of individuals who died by suicide. No mutation carriers were identified in the sample.PubMedGoogle Scholar
- 50.Byrne S, Heverin M, Elamin M, Bede P, Lynch C, Kenna K, et al. Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: a population-based case–control cohort study of familial and sporadic amyotrophic lateral sclerosis. Ann Neurol. 2013;74(5):699–708.PubMedGoogle Scholar
- 51.•• O’Brien M, Burke T, Heverin M, Vajda A, McLaughlin R, Gibbons J, et al. Clustering of neuropsychiatric disease in first-degree and second-degree relatives of patients with amyotrophic lateral sclerosis. JAMA Neurol. 2017;74(12):1425–30 This study examines incidence of psychiatric illness in family members of patients with ALS (with and without C9orf72 expansions), as compared with the families of healthy controls.PubMedPubMedCentralGoogle Scholar
- 53.•• Devenney EM, Ahmed RM, Halliday G, Piguet O, Kiernan MC, Hodges JR. Psychiatric disorders in C9orf72 kindreds: study of 1,414 family members. Neurology. 2018;91(16):e1498–e507 This study examines incidence of psychiatric illness in family members of patients with ALS, FTD, and FTD-ALS, comparing kindreds of patients with and without the C9orf72 mutation.PubMedGoogle Scholar
- 54.• McLaughlin RL, Schijven D, Van Rheenen W, Van Eijk KR, O’Brien M, Kahn RS, et al. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. Nat Commun. 2017;8:14774 This study reports the shared genetic risk between schizophrenia and ALS, which is partly accounted for by a loci near the C9orf72 gene.PubMedPubMedCentralGoogle Scholar
- 55.Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP. The diagnostic challenge of psychiatric symptoms in neurodegenerative disease; rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry. 2011;72(2):126–33.PubMedPubMedCentralGoogle Scholar
- 59.Schulz R, Sherwood PR. Physical and mental health effects of family caregiving. J Soc Work Educ. 2008;44(sup3):105–13.Google Scholar