Motor, cognitive and behavioural profiles of C9orf72 expansion-related amyotrophic lateral sclerosis.
ALS
Frontotemporal dementia
Genetics
Motor neuron disease
Journal
Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161
Informations de publication
Date de publication:
Feb 2023
Feb 2023
Historique:
received:
09
08
2022
accepted:
17
10
2022
revised:
16
10
2022
pubmed:
30
10
2022
medline:
2
2
2023
entrez:
29
10
2022
Statut:
ppublish
Résumé
Amyotrophic lateral sclerosis (ALS) individuals carrying the hexanucleotide repeat expansion (HRE) in the C9orf72 gene (C9Pos) have been described as presenting distinct features compared to the general ALS population (C9Neg). We aim to identify the phenotypic traits more closely associated with the HRE and analyse the role of the repeat length as a modifier factor. We studied a cohort of 960 ALS patients (101 familial and 859 sporadic cases). Motor phenotype was determined using the MRC scale, the lower motor neuron score (LMNS) and the Penn upper motor neuron score (PUMNS). Neuropsychological profile was studied using the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), the Frontal Behavioral Inventory (FBI), the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI). A two-step PCR protocol and Southern blotting were performed to determine the presence and the size of C9orf72 HRE, respectively. C9orf72 HRE was detected in 55/960 ALS patients. C9Pos patients showed a younger onset, higher odds of bulbar onset, increased burden of UMN signs, reduced survival and higher frequency of concurrent dementia. We found an inverse correlation between the HRE length and the performance at ECAS ALS-specific tasks (P = 0.031). Patients also showed higher burden of behavioural disinhibition (P = 1.6 × 10 Our study provides an extensive characterization of motor, cognitive and behavioural features of C9orf72-related ALS, indicating that the C9orf72 HRE size may represent a modifier of the cognitive phenotype.
Identifiants
pubmed: 36308529
doi: 10.1007/s00415-022-11433-z
pii: 10.1007/s00415-022-11433-z
pmc: PMC9886586
doi:
Substances chimiques
C9orf72 Protein
0
Proteins
0
C9orf72 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
898-908Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
Références
Mejzini R, Fletcher LL, Pitout IL, Fletcher S, Wilton SD, Akkari PA (2019) ALS genetics, mechanisms, and therapeutics: where are we now? Front Neurosci 13:1310. https://doi.org/10.3389/fnins.2019.01310
doi: 10.3389/fnins.2019.01310
pubmed: 31866818
pmcid: 6909825
Umoh ME, Fournier C, Li Y, Polak M, Shaw L, Landers JE, Hu W, Gearing M, Glass JD (2016) Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population. Neurology 87:1024–1030. https://doi.org/10.1212/WNL.0000000000003067
doi: 10.1212/WNL.0000000000003067
pubmed: 27488601
pmcid: 5027809
Smeyers J, Banchi EG, Latouche M (2021) C9ORF72: what it is, what it does, and why it matters. Front Cell Neurosci 15:661447. https://doi.org/10.3389/fncel.2021.661447
doi: 10.3389/fncel.2021.661447
pubmed: 34025358
pmcid: 8131521
Ratti A, Corrado L, Castellotti B, Del Bo R, Fogh I, Cereda C, Tiloca C, D’Ascenzo C, Bagarotti A, Pesnati V, Ranieri M, Gagliardi S, Calini D, Mazzini L, Taroni F, Corti S, Ceroni M, Oggioni GD, Lin K, Powell JF, Sorarù G, Ticozzi N, Comi GP, D’Alfonso S, Gellera C, Silani V, SLAGEN Consortium (2012) C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect. Neurobiol Aging 33:2528.e7-e14. https://doi.org/10.1016/j.neurobiolaging.2012.06.008
doi: 10.1016/j.neurobiolaging.2012.06.008
pubmed: 22766072
Chio A, Borghero G, Restagno G, Mora G, Drepper C, Trajnor BJ, Sendtner M, Brunetti M, Ossola I, Calvo A, Pugliatti M, Sotgiu MA, Murru MR, Marrosu MG, Marrosu F, Marinou K, Mandrioli J, Sola P, Caponnetto C, Mancardi G, Mandich P, La Bella V, Spataro R, Conte A, Monsurrò MR, Tedeschi G, Pisano F, Bartolomei I, Salvi F, Lauria Pinter G, Simone I, Logroscino G, Gambardella A, Quattrone A, Lunetta C, Volanti P, Zollino M, Penco S, Battistini S, ITALSGEN consortium, Renton AE, Majounie A, Abramzon Y, Conforti FL, Giannini F, Corbo M, Sabatelli M (2012) Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain 135:784–793. https://doi.org/10.1093/brain/awr366
doi: 10.1093/brain/awr366
pubmed: 22366794
pmcid: 3286333
Stewart H, Rutherford NJ, Briemberg H, Briemberg H, Krieger C, Cashman N, Fabros M, Baker M, Fok A, DeJesus-Hernandez M, Eisen A, Rademakers R, Mackenzie IRA (2012) Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol 123:409–417. https://doi.org/10.1007/s00401-011-0937-5
doi: 10.1007/s00401-011-0937-5
pubmed: 22228244
pmcid: 3322555
Irwin DJ, McMillan CT, Brettschneider J, Libon DJ, Powers J, Rascovsky K, Toledo JB, Boller A, Bekisz J, Chandrasekaran K, McCarty Wood E, Shaw LM, Woo JH, Cook PA, Wolk DA, Arnold SE, Van Deerlin VM, McCluskey LF, Elman L, Lee VM-Y, Trojanowski JQ, Grossman M (2013) Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 84:163–169. https://doi.org/10.1136/jnnp-2012-303507
doi: 10.1136/jnnp-2012-303507
pubmed: 23117491
Trojsi F, Siciliano M, Femiano C, Santangelo G, Lunetta C, Calvo A, Moglia C, Marinou K, Ticozzi N, Ferro C, Scialò C, Sorarù G, Conte A, Falzone YM, Tortelli R, Russo M, Sansone VA, Chiò A, Mora G, Silani V, Volanti P, Caponnetto C, Querin G, Sabatelli M, Riva N, Logroscino G, Messina S, Fasano A, Monsurrò MR, Tedeschi G, Mandrioli J (2019) Comparative analysis of C9orf72 and sporadic disease in a large multicenter ALS population: the effect of male sex on survival of C9orf72 positive patients. Front Neurosci 13:485. https://doi.org/10.3389/fnins.2019.00485
doi: 10.3389/fnins.2019.00485
pubmed: 31156370
pmcid: 6534038
Snowden JS, Harris J, Richardson A, Rollinson S, Thompson JC, Neary D, Mann DMA, Pickering-Brown S (2013) Frontotemporal dementia with amyotrophic lateral sclerosis: a clinical comparison of patients with and without repeat expansions in C9orf72. Amyotroph Lateral Scler Frontotemporal Degener 14:172–176. https://doi.org/10.3109/21678421.2013.765485
doi: 10.3109/21678421.2013.765485
pubmed: 23421625
Ratti A, Peverelli S, D’Adda E, Colombrita C, Gennuso M, Prelle A, Silani V (2022) Genetic and epigenetic disease modifiers in an Italian C9orf72 family expressing ALS, FTD or PD clinical phenotypes. Amyotroph Lateral Scler Frontotemporal Degener 23:292–298. https://doi.org/10.1080/21678421.2021.1962355
doi: 10.1080/21678421.2021.1962355
pubmed: 34382491
Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Engelborghs S, De Bleecker J, Ivanoiu A, Deryck O, Edbauer D, Zhang M, Heeman B, Bäumer V, Van den Broeck M, Mattheijssens M, Peeters K, Rogaeva E, De Jonghe P, Cras P, Martin J-J, de Deyn PP, Cruts M, Van Broeckhoven C (2016) The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. Mol Psychiatry 21:1112–1124. https://doi.org/10.1038/mp.2015.159
doi: 10.1038/mp.2015.159
pubmed: 26481318
Roggenbuck J (2021) C9orf72 and the Care of the Patient With ALS or FTD. Progress and Recommendations After 10 Years. Neurol Genet 7:e542. https://doi.org/10.1212/NXG.0000000000000542
doi: 10.1212/NXG.0000000000000542
pubmed: 33575483
Amado DA, Davidson BL (2021) Gene therapy for ALS: a review. Mol Ther 29:3345–3358. https://doi.org/10.1016/j.ymthe.2021.04.008
doi: 10.1016/j.ymthe.2021.04.008
pubmed: 33839324
pmcid: 8636154
Westeneng H-J, Debray TPA, Visser AE, van Eijk RPA, Rooney JPK, Calvo A, Martin S, McDermott CJ, Thompson AG, Pinto S, Kobeleva X, Rosenbohm A, Stubendorff B, Sommer H, Middelkoop BM, Dekker AM, van Vugt JJFA, van Rheenen W, Vajda A, Heverin M, Kazoka M, Hollinger H, Gromicho M, Körner S, Ringer TM, Rödiger A, Gunkel A, Shaw CE, Bredenoord AL, van Es MA, Corcia P, Couratier P, Weber M, Grosskreutz J, Ludolph AC, Petri S, de Carvalho M, Van Damme P, Talbot K, Turner MR, Shaw PJ, Al-Chalabi A, Chiò A, Hardiman O, Moons KGM, Velfink JH, van den Berg LH (2018) Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model. Lancet Neurol 17:423–433. https://doi.org/10.1016/S1474-4422(18)30089-9
doi: 10.1016/S1474-4422(18)30089-9
pubmed: 29598923
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Scler Other Motor Neuron Disord 1:293–299. https://doi.org/10.1080/146608200300079536
doi: 10.1080/146608200300079536
Corcia P, Beltran S, Lautrette G, Bakkouche S, Couratier P (2019) Staging amyotrophic lateral sclerosis: a new focus on progression. Rev Neurol 175:277–282. https://doi.org/10.1016/j.neurol.2018.09.017
doi: 10.1016/j.neurol.2018.09.017
pubmed: 30606512
Devine MS, Ballard E, O’Rourke P, Kiernan MC, Mccombe PA, Henderson RD (2016) Targeted assessment of lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis. Amyotrophic Lateral Scler and Frontotemporal Degener 17:184–190. https://doi.org/10.3109/21678421.2015.1125502
doi: 10.3109/21678421.2015.1125502
Quinn C, Edmundson C, Dahodwala N, Elman L (2020) Reliable and efficient scale to assess upper motor neuron disease burden in amyotrophic lateral sclerosis. Muscle Nerve 61:508–511. https://doi.org/10.1002/mus.26764
doi: 10.1002/mus.26764
pubmed: 31743477
Poletti B, Solca F, Carelli L, Madotto F, Lafronza A, Faini A, Monti A, Zago S, Calini D, Tiloca C, Doretti A, Verde F, Ratti A, Ticozzi N, Abrahams S, Silani V (2016) The validation of the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Amyotroph Lateral Scler Frontotemporal Degener 17:489–498. https://doi.org/10.1080/21678421.2016.1183679
doi: 10.1080/21678421.2016.1183679
pubmed: 27219526
Gosselt IK, Nijboer TCW, Van Es MA (2020) An overview of screening instruments for cognition and behavior in patients with ALS: selecting the appropriate tool for clinical practice. Amyotroph Lateral Scler Frontotemporal Degener 21:324–336. https://doi.org/10.1080/21678421.2020.1732424
doi: 10.1080/21678421.2020.1732424
pubmed: 32157912
Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554. https://doi.org/10.1212/wnl.51.6.1546
doi: 10.1212/wnl.51.6.1546
pubmed: 9855500
Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, van Swieten JC, Seelaar H, Dopper EGP, Onyike CU, Hillis AE, Josephs KA, Boeve BF, Kertesz A, Seeley WW, Rankin KP, Johnson JK, Gorno-Tempini M-L, Rosen H, Prioleau-Latham CE, Lee A, Kipps CM, Lillo P, Piguet O, Rohrer JD, Rossor MN, Warren JD, Fox NC, Galasko D, Salmon DP, Black SE, Mesulam M, Weintraub S, Dickerson BC, Diehl-Schmid J, Pasquier F, Deramecourt V, Lebert F, Pijnenburg Y, Chow TW, Manes F, Grafman J, Cappa SF, Freedman M, Grossman M, Miller BL (2011) Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134:2456–2477. https://doi.org/10.1093/brain/awr179
doi: 10.1093/brain/awr179
pubmed: 21810890
pmcid: 3170532
Strong MJ, Abrahams S, Goldstein LH, Woolley S, McLaughlin P, Snowden J, Mioshi E, Roberts-South A, Benatar M, Hortobágyi T, Rosenfeld J, Silani V, Ince PG, Turner MR (2017) Amyotrophic lateral sclerosis—frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 18:153–174. https://doi.org/10.1080/21678421.2016.1267768
doi: 10.1080/21678421.2016.1267768
pubmed: 28054827
pmcid: 7409990
Wang YP, Gorenstein C (2013) Psychometric properties of the Beck Depression Inventory-II: a comprehensive review. Braz J Psychiatry 35:416–431. https://doi.org/10.1590/1516-4446-2012-1048
doi: 10.1590/1516-4446-2012-1048
pubmed: 24402217
Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA (1983) Manual for the State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto
Beck J, Poulter M, Hensman D, Rohrer JD, Mahoney CJ, Adamson G, Campbell T, Uphill J, Borg A, Fratta P, Orrell RW, Malaspina A, Rowe J, Brown J, Hodges J, Sidle K, Polke JM, Houlden H, Schott JM, Fox NC, Rossor MN, Tabrizi SJ, Isaacs AM, Hardy J, Warren JD, Collinge J, Mead S (2013) Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 92:345–353. https://doi.org/10.1016/j.ajhg.2013.01.011
doi: 10.1016/j.ajhg.2013.01.011
pubmed: 23434116
pmcid: 3591848
Theuns J, Verstraeten A, Sleegers K, Wauters E, Gijselinck I, Smolders S, Crostiers D, Corsmit E, Elinck E, Sharma M, Krüger R, Lesage S, Brice A, Chung SJ, Kim M-J, Kim YJ, Ross OA, Wszolek ZK, Rogaeva E, Xi Z, Lang AE, Klein C, Weissbach A, Mellick GD, Silburn PA, Hadjigeorgiou GM, Dardiotis E, Hattori N, Ogaki K, Tan E-K, Zhao Y, Aasly J, Valente EM, Petrucci S, Annesi G, Quattrone A, Ferrarese C, Brighina L, Deutschländer A, Puschmann A, Nilsson C, Garraux G, LeDoux MS, Pfeiffer RF, Boczarska-Jedynak M, Opala G, Maranganore DM, Engelborghs S, De Deyn PP, Cras P, Cruts M, Broeckhoven V, GEO-PD Consortium (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906–1913. https://doi.org/10.1212/WNL.0000000000001012
doi: 10.1212/WNL.0000000000001012
pubmed: 25326098
pmcid: 4248456
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 35:936.e13-e17. https://doi.org/10.1016/j.neurobiolaging.2013.09.037
doi: 10.1016/j.neurobiolaging.2013.09.037
pubmed: 24169076
Iazzolino B, Peotta L, Zucchetti JP, Canosa A, Manera U, Vasta R, Grassano M, Palumbo F, Brunetti M, Barberis M, Sbaiz L, Moglia C, Calvo A, Chiò A (2021) Differential neuropsychological profile of patients with amyotrophic lateral sclerosis with and without C9orf72 mutation. Neurology 96:e141–e152. https://doi.org/10.1212/WNL.0000000000011093
doi: 10.1212/WNL.0000000000011093
pubmed: 33106391
Van Mossevelde S, Van der Zee J, Cruts M, Van Broeckhoven C (2017) Relationship between C9orf72 repeat size and clinical phenotype. Curr Opin Genet Dev 44:117–124. https://doi.org/10.1016/j.gde.2017.02.008
doi: 10.1016/j.gde.2017.02.008
pubmed: 28319737
Dols-Icardo O, García-Redondo A, Rojas-García R, Sánchez-Valle R, Noguera A, Gómez-Tortosa E, Pastor P, Hernández I, Esteban-Pérez J, Suárez-Calvet M, Antón-Aguirre S, Amer G, Ortega-Cubero S, Blesa R, Fortea J, Alcolea D, Capdevilla A, Antonell A, Lladó M-B, Mora JS, Galán-Dávila RD, Rivera FJ, Lleó A, Clarimón J (2014) Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum Mol Genet 23:749–754. https://doi.org/10.1093/hmg/ddt460
doi: 10.1093/hmg/ddt460
pubmed: 24057670
Suh E, Lee EB, Neal D, Wood EM, Toledo JB, Rennert L, Irwin DJ, McMillan CT, Krock B, Elman LB, McCluskey LF, Grossman M, Xie SX, Trojanowski JQ, Van Deerlin VM (2015) Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration. Acta Neuropathol 130:363–372. https://doi.org/10.1007/s00401-015-1445-9
doi: 10.1007/s00401-015-1445-9
pubmed: 26022924
pmcid: 4545720
Nordin A, Akimoto C, Wuolikainen A, Alstermark H, Jonsson P, Birve A, Marklund SL, Graffmo KS, Forsberg K, Brännström APM (2015) Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Hum Mol Genet 24:3133–3142. https://doi.org/10.1093/hmg/ddv064
doi: 10.1093/hmg/ddv064
pubmed: 25712133
van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, Brown PH, Baker MC, Finch NA, Bauer PO, Serrano G, Beach TG, Josephs KA, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, Boylan KB, Petrucelli L, Dickson DW, Rademakers R (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 12:978–988. https://doi.org/10.1016/S1474-4422(13)70210-2
doi: 10.1016/S1474-4422(13)70210-2
pubmed: 24011653
Hübers A, Marroquin N, Schmoll B, Vielhaber S, Just M, Mayer B, Högel J, Dorst J, Mertens T, Just W, Aulitzky A, Wais LAC, Kubisch C, Weishaupt JH, Volk AE (2014) Polymerase chain reaction and Southern blot-based analysis of the C9orf72 hexanucleotide repeat in different motor neuron diseases. Neurobiol Aging 35:1214.e1-e6. https://doi.org/10.1016/j.neurobiolaging.2013.11.034
doi: 10.1016/j.neurobiolaging.2013.11.034
pubmed: 24378086
Jackson JL, Finch NA, Baker MC, Kachergus JM, DeJesus-Hernandez M, Pereira K, Cristopher E, Prudencio M, Heckman MG, Thompson EA, Dickson DW, Shah J, Oskarsson B, Petrucelli L, Rademakers R, van Blitterswijk M (2020) Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers. Mol Neurodegener 15:7. https://doi.org/10.1186/s13024-020-0359-8
doi: 10.1186/s13024-020-0359-8
pubmed: 32000838
pmcid: 6993399
Maranzano A, Poletti B, Solca F, Torre S, Colombo E, Faré M, Ferrucci R, Carelli L, Verde F, Morelli C, Silani V, Ticozzi N (2022) Upper motor neuron dysfunction is associated with the presence of behavioural impairment in patients with amyotrophic lateral sclerosis. Eur J Neurol 29:1402–1409. https://doi.org/10.1111/ene.15243
doi: 10.1111/ene.15243
pubmed: 34989063
Poletti B, Carelli L, Lunetta C, Ticozzi N, Silani V (2020) Advance care planning and mental capacity in ALS: a current challenge for an unsolved matter. Neurol Sci 41:2997–2998. https://doi.org/10.1007/s10072-020-04462-x
doi: 10.1007/s10072-020-04462-x
pubmed: 32435995