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C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies
Open accessAbstract
OBJECTIVE: In many cases where Huntington disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. A repeat expansion in the C9orf72 gene has recently been identified as a major cause of familial and sporadic frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Our objective was to determine whether this mutation causes HD phenocopies. METHODS: A cohort of 514 HD phenocopy patients were analyzed for the C9orf72 expansion using repeat primed PCR. In cases where the expansion was found, Southern hybridization was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases. RESULTS: Ten subjects (1.95%) had the expansion, making it the most common identified genetic cause of HD phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterized by the presence of movement disorders, including dystonia, chorea, myoclonus, tremor, and rigidity. Furthermore, the age at onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion and included one case with pediatric onset. DISCUSSION: This study extends the known phenotype of the C9orf72 expansion in both age at onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD phenocopy patients based on these data.
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“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 [164]
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“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].”
BackgroundC9orf72 expansion as a possible genetic cause of Huntington disease phenocopy syndrome
Kostić, V. S., Dobričić, V., Stanković, I., Ralić, V., & Stefanova, E. (2014) · Journal of Neurology · doi:10.1007/s00415-014-7430-8 · Cited by 37
Giannoccaro, M. P., Bartoletti‐Stella, A., Piras, S., Pession, A., Massis, P. D., Oppi, F., Maserati, M. S., Pasini, E., Baiardi, S., Avoni, P., et al. (2017) · Journal of Neurology · doi:10.1007/s00415-017-8540-x · Cited by 37
Termsarasab, P. (2019) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000000763 · Cited by 39
Expanding the Spectrum of Movement Disorders Associated With C9orf72 Hexanucleotide Expansions
Estevez‐Fraga, C., Magrinelli, F., Moss, D. J. H., Mulroy, E., Lazzaro, G. D., Latorre, A., Mackenzie, M., Houlden, H., Tabrizi, S. J., & Bhatia, K. P. (2021) · Neurology Genetics · doi:10.1212/nxg.0000000000000575 · Cited by 36
Self-citationAydin, G., Dekomien, G., Hoffjan, S., Gerding, W. M., Epplen, J. T., & Arning, L. (2018) · BMC Neurology · doi:10.1186/s12883-017-1009-9 · Cited by 34
Koutsis, G., Karadima, G., Kartanou, C., Kladi, A., & Πάνας, Μ. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.08.020 · Cited by 33
Genetics of Movement Disorders and the Practicing Clinician; Who and What to Test for?
Fonzo, A. D., Monfrini, E., & Erro, R. (2018) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-018-0847-1 · Cited by 34
Recent advances in genetics of chorea
Mencacci, N. E., & Carecchio, M. (2016) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000352 · Cited by 32
Cannas, A., Solla, P., Borghero, G., Floris, G., Chiò, A., Mascia, M. M., Modugno, N., Muroni, A., Orofino, G., Stefano, F. D., et al. (2015) · Journal of Neurology · doi:10.1007/s00415-015-7873-6 · Cited by 32
“A recent work reported that C9orf72 expansions were the most common genetic cause of Huntington disease phenocopies [11].”
BackgroundHuntington's disease-like disorders in Latin America and the Caribbean
Walker, R. H., Gatto, E. M., Bustamante, M. L., Bernal-Pacheco, Ó., Cardoso, F., Castilhos, R. M., Chaná‐Cuevas, P., Cornejo‐Olivas, M., Estrada-Bellmann, I. E., Jardim, L. B., et al. (2018) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2018.05.021 · Cited by 30
Emerging role of RNA•DNA hybrids inC9orf72-linked neurodegeneration
Wang, J., Haeusler, A. R., & Simko, E. A. J. (2015) · Cell Cycle · doi:10.1080/15384101.2014.995490 · Cited by 31
C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases
de Souza, P. V. S., Pinto, W. B. V. D. R., & Oliveira, A. S. B. (2015) · Arquivos de Neuro-Psiquiatria · doi:10.1590/0004-282x20140229 · Cited by 26
“3) CAG (40-83) Spinocerebellar ataxia type 2 (ATXN2; 12q24.”
BackgroundInfluentialA systematic review of neuroimaging studies
de Godoy, L., Prado, R., Bicalho, I. C. S., Magalhães, D., Caramelli, P., Teixeira, A. L., & de Souza, L. C. (2015) · Cited by 25
Novel 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 24
Crook, A., Jacobs, C., Newton-John, T. R. O., O’Shea, R., & McEwen, A. (2021) · Journal of Neurology · doi:10.1007/s00415-021-10461-5 · Cited by 22
C9orf72/ALFA-1 controls TFEB/HLH-30-dependent metabolism through dynamic regulation of Rag GTPases
Ji, Y. J., Ugolino, J., Zhang, T., Lu, J., Kim, D., & Wang, J. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008738 · Cited by 22
“In addition to being the most common cause of ALS and FTD, two related neurodegenerative conditions [3], there is genetic evidence to suggest that the C9orf72 repeat expansion also contributes to Alzheimer’s disease [4–7], Huntington’s disease [8], and other neurological conditions, including multiple system atrophy […”
BackgroundGoodier, J. L., Soares, A. O., Pereira, G., Devine, L. R., Sánchez, L., Cole, R. N., & Garcia-Perez, J. L. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00982-x · Cited by 21
Furr-Stimming, E. E., & Bega, D. (2022) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/con.0000000000001169 · Cited by 20
Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts
Dratch, L., Azage, M., Baldwin, A., Johnson, K., Paul, R., Bardakjian, T., Michon, S.-C., Amado, D. A., Baer, M., Deik, A., et al. (2023) · Journal of Neurology · doi:10.1007/s00415-023-12058-6 · Cited by 23
“If this is non-diagnostic, testing should be broadened to an ataxia RE panel as well as C9orf72 RE, which is not included on many ataxia panels [21].”
C9ORF72 hexanucleotide repeat expansion: From ALS and FTD to a broader pathogenic role?
Sellier, C., Corcia, P., Vourc’h, P., & Dupuis, L. (2024) · Revue Neurologique · doi:10.1016/j.neurol.2024.03.008 · Cited by 24
Pure cerebellar ataxia linked to large C9orf72 repeat expansion
Corcia, P., Vourc’h, P., Guennoc, A., Amador, M. D. M., Blasco, H., Andres, C. R., Couratier, P., Gordon, P. H., & Meininger, V. (2015) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.3109/21678421.2015.1113298 · Cited by 21
Frontotemporal Dementia and Chorea Associated with a Compound Heterozygous TREM2 Mutation
Redaelli, V., Salsano, E., Colleoni, L., Corbetta, P., Tringali, G., Sole, A. D., Giaccone, G., & Rossi, G. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180018 · Cited by 20
Marzban, H., Kong, J., Mehr, S. E., Vriend, J. P., Li, J., Guan, T., Chung, S., Mirzaei, N., Marzban, A., Shojaei, S., et al. (2016) · Current Molecular Pharmacology · doi:10.2174/1874467209666160112125446 · Cited by 20
“Although clinical symptoms of movement disorders such as rigidity, tremor, chorea and dystonia are similar in HD patients who have HD phenocopies, no CAG repeats are found in the ge-netic test results, but rather C9orf72 repeats are the most common genetic indicator [104].”
BackgroundIshiura, H., & Tsuji, S. (2015) · Journal of Neurogenetics · doi:10.3109/01677063.2015.1085980 · Cited by 19
“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).”
BackgroundHuntington disease-like 2: insight into neurodegeneration from an African disease
Krause, A., Anderson, D. G., Ferreira‐Correia, A., Dawson, J., Baine, F., Li, P. P., & Margolis, R. L. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00906-y · Cited by 17
“2 seems to be the most common HD phenocopy in European populations, accounting for 1.95% of patients with an HD phe-nocopy in a UK cohort 19 .”
InfluentialC9ORF72 and the FTD-ALS spectrum: a systematic review of neuroimaging studies
Prado, L. D. G. R., Bicalho, I. C. S., Magalhães, D., Caramelli, P., Teixeira, A. L., & de Souza, L. C. (2015) · Dementia & Neuropsychologia · doi:10.1590/1980-57642015dn94000413 · Cited by 17
Xeroderma pigmentosum is a definite cause of Huntington's disease‐like syndrome
García‐Moreno, H., Fassihi, H., Sarkany, R., Phukan, J., Warner, T. T., Lehmann, A. R., & Giunti, P. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.511 · Cited by 17
Cognitive Profile of C9orf72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Patel, A. N., & Sampson, J. B. (2015) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-015-0582-9 · Cited by 17
C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Cruts, M., Engelborghs, S., van der Zee, J., & Broeckhoven, C. V. (2015) · VUBIR (Vrije Universiteit Brussel) · Cited by 16
Is There Convincing Evidence that Intermediate Repeats in the HTT Gene Cause Huntington’s Disease?
Oosterloo, M., van Belzen, M. J., Bijlsma, E. K., & Roos, R. A. C. (2015) · Journal of Huntington s Disease · doi:10.3233/jhd-140120 · Cited by 16
Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies
Kun‐Rodrigues, C., Ross, O. A., Orme, T., Shepherd, C. E., Parkkinen, L., Darwent, L., Hernandez, D. G., Ansorge, O., Clark, L. N., Honig, L. S., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.08.023 · Cited by 15
Kresojević, N. D., Mandić‐Stojmenović, G., Dobričić, V., Petrović, I. N., Brajković, L., Stefanova, E. D., Svetel, M. V., & Kostić, V. (2019) · Movement Disorders Clinical Practice · doi:10.1002/mdc3.12892 · Cited by 14
Aberrant Rna Homeostasis in Amyotrophic Lateral Sclerosis: Potential for New Therapeutic targets?
Donnelly, C. J., Grima, J. C., & Sattler, R. (2014) · Neurodegenerative Disease Management · doi:10.2217/nmt.14.36 · Cited by 15
Metadata
- Authors
- Hensman Moss, D. J., Poulter, M., Beck, J., Hehir, J., Polke, J. M., Campbell, T., Adamson, G., Mudanohwo, E., McColgan, P., Haworth, A., Wild, E. J., Sweeney, M. G., Houlden, H., Mead, S., & Tabrizi, S. J.
- Affiliations
- From the Departments of Neurodegenerative Disease (D.J.H.M., P.M., E.J.W., S.M., S.J.T.) and Molecular Neuroscience (H.H.), UCL Institute of Neurology, London; MRC Prion Unit (M.P., J.B., T.C., G.A.), London; and Neurogenetics Unit (J.H., J.M.P., E.M., A.H., M.G.S., H.H.), National Hospital for Neurology and Neurosurgery, University College London Hospitals, UK.
- MRC Prion Unit (GB)
- ORCID
- Venue
- Neurology
- Published
- 2014-01-28
- Volume
- 82
- Issue
- 4
- Pages
- 292-299
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3929197
- OpenAlex
- W2159280728
- Cited by
- 203
- References
- 37
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 12 · 2023: 9 · 2022: 13 · 2021: 13 · 2020: 19 · 2019: 10 · 2018: 27 · 2017: 16 · 2016: 29 · 2015: 23 · 2014: 17
- FWCI
- 11.45
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-05-13)
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- CHDI Foundation
- National Institute for Health and Care Research (ACF-2009-18-016, CL-2009-18-005)
- Academy of Medical Sciences (AMS-SGCL6-Wild)
- University College London
- University College London Hospitals NHS Foundation Trust
- Medical Research Council (MR/J004758/1, MR/L02053X/1, EU FP7)
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- C9orf72, repeat expansion, genetic testing, movement disorders, dystonia, chorea, myoclonus, tremor, rigidity, age of onset, pediatric onset, frontotemporal lobar degeneration, amyotrophic lateral sclerosis
- MeSH terms
- C9orf72 Protein, Adolescent, Adult, Child, Cognition Disorders, DNA Mutational Analysis, Female, Humans, Huntington Disease, Magnetic Resonance Imaging, Male, Mental Status Schedule, Middle Aged, Phenotype, Proteins, Severity of Illness Index, Cohort Studies, Age of Onset, DNA Repeat Expansion, Young Adult
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