Abstract
The hexanucleotide repeat expansion GGGGCC in the C9ORF72 gene larger than 30 repeats has been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent papers investigated the possible pathogenic role and associated clinical phenotypes of intermediate C9ORF72 repeat expansion ranging between 20 and 30 repeats. Some studies suggested its pathogenicity for typical Parkinson’s disease (PD), atypical parkinsonian syndromes, FTD with/without parkinsonism, and ALS with/without parkinsonism or with/without dementia. In our study, we aimed to screen patients affected by atypical parkinsonian syndromes or PD complicated by psychosis or dementia for the presence of C9ORF72 repeat expansions, and in unrelated age- and sex-matched healthy controls. Consecutive unrelated patients with atypical parkinsonian syndromes and patients with PD complicated by psychosis or dementia were included in this study. Atypical parkinsonian syndromes were further divided into two groups: one with patients who met the criteria for the classic forms of atypical parkinsonism [multiple system atrophy (MSA), Lewy body disease (LBD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)] ;and patients who did not meet the above criteria, named non-classical atypical parkinsonism with or without dementia. Ninety-two unrelated patients (48 men, 44 women) were enrolled. None of the patients was found to be carriers of C9ORF72 repeat expansions with more than 30 repeats. Intermediate 20–30 repeat expansions were detected in four female patients (4.3 %). Three of them presented clinical features of atypical parkinsonian syndromes, two with non-classical atypical parkinsonism and dementia FTD-like, and one with non-classical atypical parkinsonism without dementia. The other patient presented clinical features of typical PD complicated by psychosis. Among 121 control subjects, none presented long or short expansion for the C9ORF72 gene. Our findings seem to support the hypothesis that the hexanucleotide expansions of C9ORF72 gene with intermediate repetitions between 20 and 29 repetitions could be associated with typical PD with psychosis or dementia and atypical parkinsonisms with dementia (non-classical atypical parkinsonism with dementia FTD-like) or without dementia (non-classical atypical parkinsonism upper MND-like), although the causal relationship is still unclear. In these latter patients, parkinsonism, more or less levodopa responsive, constituted the symptomatological central core at onset.
Similar content being viewed by others
References
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(245):256
Renton AE, Majounie E, Waite A et al (2011) ITALSGEN Consortium. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268
Majounie E, Renton AE, Mok K et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11(4):323–330. doi:10.1016/S1474-4422(12)70043-1
Cruts M, Gijselinck I, Van Langenhove T, van der Zee J, Van Broeckhoven C (2013) Current insights into the C9ORF72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci 36(450):459
Takada LT, Pimentel ML, DeJesus-Hernandez M et al (2012) Frontotemporal dementia in a Brazilian kindred with the C9ORF72 mutation. Arch Neurol 69(1149):1153
Savica R, Adeli A, Vemuri P et al (2012) Characterization of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72. Arch Neurol 69(1164):1169
Luigetti M, Quaranta D, Conte A et al (2013) Frontotemporal dementia, parkinsonism and lower motor neuron involvement in a patient with C9ORF72 expansion. Amyotroph Lateral Scler Frontotemporal Degener 14(66):69
Hsiung GY, DeJesus-Hernandez M, Feldman HH et al (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135(709):722
Van Langenhove T, van der Zee J, Gijselinck I et al (2013) Distinct clinical characteristics of C9ORF72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol 70(1):9
Lindquist S, Duno M, Batbayli M, Puschmann A, Braendgaard H, Mardosiene S, Svenstrup K, Pinborg L, Vestergaard K, Hjermind L, Stokholm J, Andersen B, Johannsen P, Nielsen J (2012) Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin Genet 83:279–283
Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T, Adamson G, Mudanohwo E, McColgan P, Haworth A, Wild EJ, Sweeney MG, Houlden H, Mead S, Tabrizi SJ (2014) C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology 82(4):292–299
Schottlaender LV, Polke JM, Ling H et al (2015) The analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism. Neurobiol Aging 36(2):1221.e1–1221.e6
Theuns J, Verstraeten A, Sleegers K, Wauters E, Gijselinck I, Smolders S et al (2014) Global investigation and meta-analysis of the C9ORF72 (G4C2)n repeat in Parkinson disease. Neurology 83(21):1906–1913
Majounie E, Abramzon Y, Renton AE, Keller MF, Traynor BJ, Singleton AB (2012) Large C9ORF72 repeat expansions are not a common cause of Parkinson’s disease. Neurobiol Aging 33(10):2527.e1–2527.e2
Ticozzi N, Tiloca C, Calini D, Gagliardi S, Altieri A, Colombrita C, Cereda C, Ratti A, Pezzoli G, Borroni B, Goldwurm S, Padovani A, Silani V (2014) C9ORF72 repeat expansions are restricted to the ALS-FTD spectrum. Neurobiol Aging 35(4):936.e13–936.e17
Harms MB, Neumann D, Benitez BA et al (2013) Parkinson disease is not associated with C9ORF72 repeat expansions. Neurobiol Aging 34:1519.e1–1519.e2
DeJesus-Hernandez M, Rayaprolu S, Soto-Ortolaza AI et al (2013) Analysis of the C9ORF72 repeat in Parkinson’s disease, essential tremor and restless legs syndrome. Parkinsonism Relat Disord 19(198):201
Xi Z, Zinman L, Grinberg Y et al (2012) Investigation of C9ORF72 in 4 neurodegenerative disorders. Arch Neurol 69(1583):1590
Jiao B, Guo JF, Wang YQ et al (2013) C9ORF72 mutation is rare in Alzheimer s disease, Parkinson’s disease, and essential tremor in China. Front Cell Neurosci 7:164
Akimoto C, Forsgren L, Linder J et al (2013) No GGGGCC hexanucleotide repeat expansion in C9ORF72 in parkinsonism patients in Sweden. Amyotroph Lateral Scler Frontotemporal Degener 14(26):29
Lesage S, Le Ber I, Condroyer C et al (2013) C9ORF72 repeat expansions are a rare genetic cause of parkinsonism. Brain 136(385):391
Yeh TH, Lai SC, Weng YH et al (2013) Screening for C9ORF72 repeat expansions in parkinsonian syndromes. Neurobiol Aging 34(1311):1314
Daoud H, Noreau A, Rochefort D et al (2013) Investigation of C9ORF72 repeat expansions in Parkinson’s disease. Neurobiol Aging 34(1710):1719
Nuytemans K, Bademci G, Kohli MM et al (2013) C9ORF72 intermediate repeat copies are a significant risk factor for Parkinson disease. Ann Hum Genet 77(351):363
Nuytemans K, Inchausti V, Beecham GW, Wang L, Dickson DW, Trojanowski JQ, Lee VM, Mash DC, Frosch MP, Foroud TM, Honig LS, Montine TJ, Dawson TM, Martin ER, Scott WK, Vance JM (2014) Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson’s disease. Mov Disord 29(6):827–830. doi:10.1002/mds.25838
Scholz SW, Majounie E, Revesz T, Holton JL, Okun MS, Houlden H, Singleton AB (2015) Multiple system atrophy is not caused by C9orf72 hexanucleotide repeat expansions. Neurobiol Aging 36(2):1223
Goldman JS, Kuo SH (2014) Multiple system atrophy and repeat expansions in C9orf72—reply. JAMA Neurol 71(9):1191–1192
Gelb DJ, Oliver E, Gilman S (1999) Diagnostic criteria for Parkinson disease. Arch Neurol 56:33–39
Gilman S, Wenning GK, Low PA et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(670):676
Litvan I, Agid Y, Calne D et al (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47(1):9
Riley DE, Lange AE, Lewis A et al (1990) Cortico-basal ganglionic degeneration. Neurology 40(1203):1212
McKeith IG, Dickson DW, Lowe J et al (2005) Consortium on DLB. Diagnosis and management of dementiawith Lewy bodies: third report of the DLB Consortium. Neurology 2005(65):1863–1872
Stamelou M, Quinn NP, Bhatia KP (2013) “Atypical” atypical parkinsonism: new genetic conditions presenting with features of progressive supranuclear palsy, corticobasal degeneration, or multiple system atrophy-a diagnostic guide. Mov Disord 28(9):1184–1199
Untergrasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, Rozen SG (2012) Primer3 new capabilities and interfaces. Nucleic Acids Res 40(15):e115
Koressaar T, Remm M (2007) Enhancements and modifications of primer design program Primer3. Bioinformatics 23(10):1289–1291
Floris G, Borghero G, Cannas A, Di Stefano F, Costantino E et al (2012) Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype? J Neurol 259(8):1749–1751
Shinagawa S, Nakajima S, Plitman E, Graff-Guerrero A, Mimura M et al (2014) Psychosis in frontotemporal dementia. J Alzheimers Dis 42(2):485–499
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Ethical standards statement
This study has been approved by the appropriate institutional authority and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Additional information
A. Cannas, P. Solla, and A. Chio contributed equally to the study.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Cannas, A., Solla, P., Borghero, G. et al. C9ORF72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or Parkinson’s disease complicated by psychosis or dementia in a Sardinian population. J Neurol 262, 2498–2503 (2015). https://doi.org/10.1007/s00415-015-7873-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-015-7873-6