C9orf72 expansion as a possible genetic cause of Huntington disease phenocopy syndrome
Abstract
Huntington disease (HD), the most common inherited cause of chorea, is an autosomal dominant disorder, caused by an expanded trinucleotide CAG repeat (>39) in the HTT gene on chromosome 4p16.3. Among patients diagnosed as HD solely on clinical grounds, a certain number was negative on genetic testing for HD. Therefore, HD-like disorders comprised a number of genetic causes of chorea, that may be indistinguishable from HD (e.g. HD phenocopy syndrome). Recent data suggested that the C9orf72 expansion may be the most common genetic cause of HD phenocopy presentations. In continuation with this observation, we analyzed a small cohort of 39 patients with HD phenocopy syndrome and detected the C9orf72 expansion in one female patient (2.6%) with two-year lasting mild generalized chorea and severe oro-bucco-lingual dyskinesia, who complained on forgetfullness (neuropsychological testing revealed dysexecutive syndrome with preserved episodic memory and recognition), unexplainable fears and increased appetite. Our results confirmed a possible role of the C9orf72 expansion in the genetic background of HD phenocopy syndrome.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
C9orf72 expansion mutations are associated with ALS/FTLD and also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome.
“For instance, C9orf72 expansion mutations are associated not only with ALS/FTLD, but also with symptoms reminiscent of Parkinson disease, Alzheimer disease, Huntington disease, and corticobasal syndrome, reinforcing the imperfect connection between clinical and molecular phenotypes and emphasizing the need for molecular diagnostics [155–164].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [159]
Cites
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975) · Journal of Psychiatric Research · doi:10.1016/0022-3956(75)90026-6 · Cited by 88,282 · see citing works
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.011 · Cited by 4,936 · see citing works
A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.010 · Cited by 4,409 · see citing works
Beck, J., Poulter, M., Hensman, D., Rohrer, J. D., Mahoney, C. J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.01.011 · Cited by 345 · see citing works
<i>C9orf72</i> expansions are the most common genetic cause of Huntington disease phenocopies
Hensman Moss, D. J., Poulter, M., Beck, J., Hehir, J., Polke, J. M., Campbell, T., Adamson, G., Mudanohwo, E., McColgan, P., Haworth, A., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000061 · Cited by 203 · see citing works
Huntington Disease Phenocopy Is a Familial Prion Disease
Moore, R. C., Xiang, F., Monaghan, J., Han, D. G., Zhang, Z., Edström, L., Anvret, M., & Prusiner, S. B. (2001) · The American Journal of Human Genetics · doi:10.1086/324414 · Cited by 153 · see citing works
Akimoto, C., Volk, A. E., van Blitterswijk, M., den Broeck, M. V., Leblond, C. S., Lumbroso, S., Camu, W., Neitzel, B., Onodera, O., van Rheenen, W., et al. (2014) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2014-102360 · Cited by 131 · see citing works
Huntington's disease phenocopies are clinically and genetically heterogeneous
Wild, E. J., Mudanohwo, E. E., Sweeney, M. G., Schneider, S. A., Beck, J. A., Bhatia, K. P., Rossor, M. N., Davis, M. B., & Tabrizi, S. J. (2008) · Movement Disorders · doi:10.1002/mds.21915 · Cited by 115 · see citing works
Huntington's disease phenocopy syndromes
Wild, E. J., & Tabrizi, S. J. (2007) · Current Opinion in Neurology · doi:10.1097/wco.0b013e3282f12074 · Cited by 96 · see citing works
Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease
Aziz, N. A., Jurgens, C. K., Landwehrmeyer, G. B., on behalf of the EHDN Registry Study Group, van Roon‐Mom, W., van Ommen, G. B., Stijnen, T., & Roos, R. A. C. (2009) · Neurology · doi:10.1212/wnl.0b013e3181bd1121 · Cited by 90 · see citing works
Expanding the genetics of huntingtonism
Feigin, A., & Talbot, K. (2013) · Neurology · doi:10.1212/wnl.0000000000000067 · Cited by 5 · see citing works
Flagged first, then by citations
1 of the 13 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
Recent advances in amyotrophic lateral sclerosis
Riva, N., Agosta, F., Lunetta, C., Filippi, M., & Quattrini, A. (2016) · Journal of Neurology · doi:10.1007/s00415-016-8091-6 · Cited by 88 · see citing works
Suh, E. R., Lee, E. B., Neal, D., Wood, E. M., Toledo, J. B., Rennert, L., Irwin, D. J., McMillan, C. T., Krock, B. L., Elman, L. B., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1445-9 · Cited by 72 · see citing works
“The C9orf72 expansion is also associated with considerable heterogeneity in clinical phenotype including Huntington disease-like disorders [22] and idiopathic Parkinson’s disease [11, 23, 24].”
BackgroundClinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion
Mossevelde, S. V., van der Zee, J., Gijselinck, I., Sleegers, K., Bleecker, J. D., Sieben, A., Vandenberghe, R. R., Langenhove, T. V., Baets, J., Deryck, O., et al. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2016.4847 · Cited by 62 · see citing works
Huntington's Disease, Huntington's Disease Look‐Alikes, and Benign Hereditary Chorea: What's New?
Schneider, S. A., & Bird, T. D. (2016) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12312 · Cited by 54 · see citing works
Bourinaris, T., & Houlden, H. (2018) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12677 · Cited by 54 · see citing works
“The possibility that the C9orf72 hexanucleotide expansion could interact with other repeat expansion disorders, including the CAG expansions disorders of several SCA genes and HD, possibly altering the phenotypic expression of either condition, has been suggested in some papers.(74,80,81,86) This finding could mean th…”
BackgroundClinical and neuroimaging phenotypes of genetic parkinsonism from infancy to adolescence
Morales‐Briceño, H., Mohammad, S. S., Post, B., Fois, A. F., Dale, R. C., Tchan, M. C., & Fung, V. S. C. (2019) · Brain · doi:10.1093/brain/awz345 · Cited by 43 · see citing works
Wilke, C., Pomper, J. K., Biskup, S., Puskás, C., Berg, D., & Synofzik, M. (2016) · Journal of Neurology · doi:10.1007/s00415-016-8021-7 · Cited by 43 · see citing works
“C9orf72 repeat expansions can also present with hyperkinetic movement disorders, representing a common genetic cause of Huntington’s disease phenocopies [10, 39, 51] and sometimes also presentingwith dystonia [11, 26, 52].”
BackgroundRecent advances in genetics of chorea
Mencacci, N. E., & Carecchio, M. (2016) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000352 · Cited by 32 · see citing works
Herrmann, D., & Parlato, R. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2806-1 · Cited by 29 · see citing works
“Notably, the C9orf72 HRE is not exclusive to ALS-FTD, but it is also associated with HD-like phenotypes (Kostic et al. 2014) and significantly increased risk of developing AD (Cacace et al. 2013; Shu et al. 2016).”
BackgroundNovel Imaging Biomarkers for Huntington’s Disease and Other Hereditary Choreas
Fazio, P., Paucar, M., Svenningsson, P., & Varrone, A. (2018) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-018-0890-y · Cited by 25 · see citing works
Ishiura, H., & Tsuji, S. (2015) · Journal of Neurogenetics · doi:10.3109/01677063.2015.1085980 · Cited by 18 · see citing works
“The repeat expansions were also found in patients with a Huntington ’ s disease-like phenotype (Beck et al, 2013; Hensman Moss et al, 2014; Kostic et al, 2014; Koutsis et al, 2015).”
BackgroundPre-symptomatic diagnosis in ALS
Corcia, P., Lumbroso, S., Cazeneuve, C., Mouzat, K., Camu, W., & Vourc’h, P. (2020) · Revue Neurologique · doi:10.1016/j.neurol.2019.07.027 · Cited by 14 · see citing works
Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog
Langseth, A. J., Kim, J., Ugolino, J., Shah, Y., Hwang, H., Wang, J., Bergles, D. E., & Brown, S. P. (2017) · Scientific Reports · doi:10.1038/s41598-017-05864-2 · Cited by 12 · see citing works
The non–Huntington disease choreas
Walker, R. H. (2016) · Neurology Clinical Practice · doi:10.1212/cpj.0000000000000236 · Cited by 12 · see citing works
Zhao, M., Cheah, F. S. H., Chen, M., Lee, C. G. L., Law, H., & Chong, S. S. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180984 · Cited by 12 · see citing works
Distinct neurological disorders with C9orf72 mutations: genetics, pathogenesis, and therapy
Chi, S., Jiang, T., Tan, L., & Yu, J. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.033 · Cited by 11 · see citing works
“…Beck et al., 2013), and the clinical features just resemble those of classical HD patients, with movement disorders, psychiatric disturbance, and cognitive impairment being the typical clinical manifestations (Hensman et al., 2014; Kostić et al., 2014; Koutsis et al., 2015; Beck et al., 2013).”
InfluentialC9orf72 Hexanucleotide Repeat in Huntington-Like Patients: Systematic Review and Meta-Analysis
Alva‐Díaz, C., Alarcon-Ruiz, C. A., Pacheco‐Barrios, K., Mori, N., Pacheco‐Mendoza, J., Traynor, B. J., Rivera‐Valdivia, A., Lertwilaiwittaya, P., Bird, T. D., & Cornejo‐Olivas, M. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.551780 · Cited by 10 · see citing works
“Most of these studies were conducted in European countries (Hensman Moss et al., 2014a; Kostic et al., 2014; Koutsis et al., 2015; Fedotova et al., 2016; Mariani et al., 2016; Martins et al., 2018a; Rikos et al., 2020).”
BackgroundResultInfluentialClinical spectrum of C9orf72 expansion in a cohort of Huntington’s disease phenocopies
Martins, J., Damásio, J., Mendes, A., Vila‐Chã, N., Alves, J. E., Ramos, C. G., Cavaco, S., Silva, J., Alonso, I. D. C. M. P., & Magalhães, M. (2018) · Neurological Sciences · doi:10.1007/s10072-018-3268-7 · Cited by 9 · see citing works
Frontotemporal lobar dementia and amyotrophic lateral sclerosis associated with c9orf72 expansion
Ber, I. L. (2015) · Revue Neurologique · doi:10.1016/j.neurol.2015.04.004 · Cited by 8 · see citing works
A review on approach to a twitchy tongue in neurology
Salari, M., Rezaei, K., Mirdehghan, A., Behzadi, A., & Etemadifar, M. (2023) · Neurological Sciences · doi:10.1007/s10072-023-06771-3 · Cited by 8 · see citing works
Nguyen, Q., Ortigoza‐Escobar, J. D., Burgunder, J., Mariotti, C., Carsten Saft, C., Hjermind, L. E., Youssov, K., Landwehrmeyer, G. B., & Bachoud‐Lévi, A. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.817753 · Cited by 7 · see citing works
“All were review articles but six that were series of case description [cases (17, 19), familial (14, 15), or cohort (18, 22) descriptions].”
BackgroundClinical Update on C9orf72: Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, and Beyond
Saracino, D., & Ber, I. L. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-51140-1_5 · Cited by 7 · see citing works
Expanding the spectrum of C9ORF72-related neurodegenerative disorders in the Greek population
Kartanou, C., Kontogeorgiou, Z., Rentzos, M., Potagas, C. M., Aristeidou, S., Kapaki, E. N., Paraskevas, G. P., Constantinides, V. C., Stefanis, L., Papageorgiou, S. G., et al. (2022) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2022.120450 · Cited by 6 · see citing works
Screening for C9orf72 Expansion Mutation in Serbian Patients with Early-Onset Dementia
Mandić‐Stojmenović, G., Stefanova, E. D., Dobričić, V., Novaković, I. V., Stojković, T., Ješić, A., & Kostić, V. (2015) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000438748 · Cited by 4 · see citing works
Self-citationPaucar, M., Laffita‐Mesa, J. M., Niemelä, V., Malmgren, H., Nennesmo, I., Lagerstedt‐Robinson, K., Nordenskjöld, M., & Svenningsson, P. (2023) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2023.120707 · Cited by 4 · see citing works
“In this context, two smaller studies found few cases with C9orf72 HRE [22,23] whereas three previous screenings yielded negative results [26–28].”
ResultInfluentialGENES ATXN2 AND C9ORF72 AS UNIVERSAL FACTORS OF DIFFERENT NEUROLOGICAL DISORDERS DEVELOPMENT
(2016) · The Neurological Journal · doi:10.18821/1560-9545-2016-21-6-323-329 · Cited by 3 · see citing works
Rikos, D., Marogianni, C., Provatas, A., Bourinaris, T., Arnaoutoglou, M., Stathis, P. G., Patrinos, G. P., Dardiotis, E., Hadjigeorgiou, G. M., & Xiromerisiou, G. (2020) · Tremor and Other Hyperkinetic Movements · doi:10.5334/tohm.61 · Cited by 3 · see citing works
C9orf72 genetic screening in amyotrophic lateral sclerosis patients from Serbia
Marjanović, A., Palibrk, A., Dobričić, V., Milicevic, O. S., Branković, M., Virić, V., Drinic, A., Mandić‐Stojmenović, G., Janković, M. Z., Basta, I. Z., et al. (2023) · Genetika · doi:10.2298/gensr2301001m · Cited by 2 · see citing works
Self-citationEthnic and Epidemiological Peculiarities of Movement Disorders across the World
Moura, J., Balint, B., Cullinane, P. W., Alhashash, H., Magrinelli, F., Latorre, A., & Bhatia, K. P. (2025) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.70475 · Cited by 1 · see citing works
Behavioral Abnormalities in Other Genetic and Nongenetic Causes of Chorea
Maciel, R., Maia, D. P., & Cardoso, F. (2022) · doi:10.1093/med/9780197574317.003.0016 · Cited by 1 · see citing works
Dissecting the Genetic Basis of Parkinson Disease, Dystonia and Chorea
Mencacci, N. (2016) · UCL Discovery (University College London)
Toward Eradicating All Diseases
Ma, Q. (2021) · Advances in human and social aspects of technology book series · doi:10.4018/978-1-7998-6772-2.ch014
C9ORF72 repeat expansion is not associated with atypical parkinsonism in the Serbian population
Marjanović, A., Dobričić, V., Ječmenica‐Lukić, M., Stanković, I., Milicevic, O. S., Mišković, N., Branković, M., Janković, M. Z., Novaković, I. V., Svetel, M. V., et al. (2022) · Genetika · doi:10.2298/gensr2203313m
Self-citationde Calbiac, H. (2019) · theses.fr (ABES) · doi:10.70675/bafe951fz8332z4b0azb55bzac8a4af1955b
- Authors
- Kostić, V. S., Dobričić, V., Stanković, I., Ralić, V., & Stefanova, E.
- Affiliations
- University of Belgrade (RS)
- Corresponding author
- Kostić, Vladimir S.
- Venue
- Journal of Neurology
- Published
- 2014-07-18
- Volume
- 261
- Issue
- 10
- Pages
- 1917-1921
- ISSN
- 0012-1037 (ISSN-L)
- 0340-5354
- 1432-1459
- OpenAlex
- W2130529099
- Cited by
- 37
- References
- 13
- Citations by year
- 2025: 1 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 8 · 2015: 4
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Science and Engineering Research Board
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- Huntington's disease, C9orf72 expansion, chorea, trinucleotide repeat expansion, dysexecutive syndrome, dyskinesia, genetic testing, autosomal dominant disorder
- MeSH terms
- C9orf72 Protein, Adult, Aged, Female, Genetic Testing, Humans, Huntington Disease, Male, Middle Aged, Phenotype, Proteins, Trinucleotide Repeat Expansion, Fluorodeoxyglucose F18, Genetic Predisposition to Disease, Positron-Emission Tomography, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
