{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T05:06:07Z","timestamp":1773896767048,"version":"3.50.1"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012940","name":"Universit\u00e4tsklinikum T\u00fcbingen","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012940","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurol"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Introduction<\/jats:title>\n            <jats:p>While\u2009\u2265\u200940 CAG repeat expansions in <jats:italic>HTT<\/jats:italic> present a well-established cause of Huntington\u2019s disease (HD), an enrichment of <jats:italic>HTT<\/jats:italic> repeat expansions was recently reported also in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including FTD\/ALS patients with additional HD neuropathology. This raises the question whether the phenotypic spectrum of <jats:italic>HTT<\/jats:italic> expansions can be extended to ALS and FTD, and whether <jats:italic>HTT<\/jats:italic> should be considered as a new causative gene of FTD\/ALS. If <jats:italic>HTT<\/jats:italic> repeat expansions were indeed systematically related to FTD\/ALS, one would expect an increased frequency\u00a0of <jats:italic>HTT<\/jats:italic> carriers in FTD\/ALS, who can clinically\/neuropathologically not be explained better than by the presence of the <jats:italic>HTT<\/jats:italic> repeat expansions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Screening of <jats:italic>HTT<\/jats:italic> repeat expansions in 249 consecutive patients with ALS or FTD by short-read genome sequencing took place. The post-mortem neuropathological examination was performed in the identified <jats:italic>HTT<\/jats:italic> repeat expansion carrier.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>One <jats:italic>HTT<\/jats:italic> repeat expansion [40\/22 repeats (\u00b1\u20091)] was identified in an ALS patient, giving a frequency of 0.4% (1\/249) (frequency in the general population: 0.03\u20130.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed\u2014in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions\u2014HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our study does not support the notion of an increased frequency of <jats:italic>HTT<\/jats:italic> repeat expansions in FTD\/ALS. Moreover, the phenotype of the <jats:italic>HTT<\/jats:italic> carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which\u2014given the low repeat number\u2014is likely to become manifest only later in life. These findings corroborate the concept that <jats:italic>HTT<\/jats:italic> repeat expansions are likely co-existent\/coincidental, but not causative in FTD\/ALS.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00415-024-12822-2","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T12:31:26Z","timestamp":1734006686000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Frequency and neuropathology of HTT repeat expansions in FTD\/ALS: co-existence rather than causation"],"prefix":"10.1007","volume":"272","author":[{"given":"Milan","family":"Zimmermann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Mengel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Raupach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Haack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2280-7273","authenticated-orcid":false,"given":"Matthis","family":"Synofzik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"issue":"448\u2013460","key":"12822_CR1","first-page":"e444","volume":"109","author":"R Dewan","year":"2021","unstructured":"Dewan R, Chia R, Ding J, Hickman RA, Stein TD, Abramzon Y, Ahmed S, Sabir MS, Portley MK, Tucci A, Ibanez K, Shankaracharya FNU, Keagle P, Rossi G, Caroppo P, Tagliavini F, Waldo ML, Johansson PM, Nilsson CF, American Genome C, Rowe JB, Benussi L, Binetti G, Ghidoni R, Jabbari E, Viollet C, Glass JD, Singleton AB, Silani V, Ross OA, Ryten M, Torkamani A, Tanaka T, Ferrucci L, Resnick SM, Pickering-Brown S, Brady CB, Kowal N, Hardy JA, Van Deerlin V, Vonsattel JP, Harms MB, Morris HR, Ferrari R, Landers JE, Chio A, Gibbs JR, Dalgard CL, Scholz SW, Traynor BJ, American Genome C, Consortium FS, Genomics England Research C, International ALSFTDGC, International FTDGC, International LBDGC, Consortium NA, Consortium P (2021) Pathogenic Huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 109(448\u2013460):e444","journal-title":"Neuron"},{"key":"12822_CR2","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1001\/jamaneurol.2019.0423","volume":"76","author":"SL Gardiner","year":"2019","unstructured":"Gardiner SL, Boogaard MW, Trompet S, de Mutsert R, Rosendaal FR, Gussekloo J, Jukema JW, Roos RAC, Aziz NA (2019) Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts. JAMA Neurol 76:650\u2013656","journal-title":"JAMA Neurol"},{"key":"12822_CR3","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1016\/j.neuron.2021.04.010","volume":"109","author":"Q Thomas","year":"2021","unstructured":"Thomas Q, Coarelli G, Heinzmann A, Le Ber I, Amador MDM, Durr A (2021) Questioning the causality of HTT CAG-repeat expansions in FTD\/ALS. Neuron 109:1945\u20131946","journal-title":"Neuron"},{"key":"12822_CR4","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1002\/acn3.51673","volume":"9","author":"A Manini","year":"2022","unstructured":"Manini A, Gagliardi D, Meneri M, Antognozzi S, Del Bo R, Scaglione C, Comi GP, Corti S, Ronchi D (2022) Analysis of HTT CAG repeat expansion in Italian patients with amyotrophic lateral sclerosis. Ann Clin Transl Neurol 9:1820\u20131825","journal-title":"Ann Clin Transl Neurol"},{"key":"12822_CR5","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1016\/j.neuron.2021.04.020","volume":"109","author":"R Dewan","year":"2021","unstructured":"Dewan R, Scholz SW, Chio A, Traynor BJ (2021) Highlighting the clinical potential of HTT repeat expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 109:1947\u20131948","journal-title":"Neuron"},{"key":"12822_CR6","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1080\/146608200300079536","volume":"1","author":"BR Brooks","year":"2000","unstructured":"Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron D (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293\u2013299","journal-title":"Amyotroph Lateral Scler Other Motor Neuron Disord"},{"key":"12822_CR7","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.clinph.2007.09.143","volume":"119","author":"M de Carvalho","year":"2008","unstructured":"de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H, Nodera H, Shefner J, Swash M (2008) Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 119:497\u2013503","journal-title":"Clin Neurophysiol"},{"key":"12822_CR8","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1002\/ana.26045","volume":"89","author":"A Hannaford","year":"2021","unstructured":"Hannaford A, Pavey N, van den Bos M, Geevasinga N, Menon P, Shefner JM, Kiernan MC, Vucic S (2021) Diagnostic utility of gold coast criteria in amyotrophic lateral sclerosis. Ann Neurol 89:979\u2013986","journal-title":"Ann Neurol"},{"key":"12822_CR9","doi-asserted-by":"publisher","first-page":"S14","DOI":"10.1097\/WAD.0b013e31815c3445","volume":"21","author":"K Rascovsky","year":"2007","unstructured":"Rascovsky K, Hodges JR, Kipps CM, Johnson JK, Seeley WW, Mendez MF, Knopman D, Kertesz A, Mesulam M, Salmon DP, Galasko D, Chow TW, Decarli C, Hillis A, Josephs K, Kramer JH, Weintraub S, Grossman M, Gorno-Tempini ML, Miller BM (2007) Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): current limitations and future directions. Alzheimer Dis Assoc Disord 21:S14-18","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"12822_CR10","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1212\/WNL.0b013e31821103e6","volume":"76","author":"ML Gorno-Tempini","year":"2011","unstructured":"Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M (2011) Classification of primary progressive aphasia and its variants. Neurology 76:1006\u20131014","journal-title":"Neurology"},{"key":"12822_CR11","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1080\/21678421.2016.1267768","volume":"18","author":"MJ Strong","year":"2017","unstructured":"Strong MJ, Abrahams S, Goldstein LH, Woolley S, McLaughlin P, Snowden J, Mioshi E, Roberts-South A, Benatar M, HortobaGyi T, Rosenfeld J, Silani V, Ince PG, Turner MR (2017) Amyotrophic lateral sclerosis\u2014frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 18:153\u2013174","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"12822_CR12","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s00401-008-0477-9","volume":"117","author":"M Neumann","year":"2009","unstructured":"Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, Forman MS, Troost D, Kretzschmar HA, Trojanowski JQ, Lee VM (2009) Phosphorylation of S409\/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137\u2013149","journal-title":"Acta Neuropathol"},{"key":"12822_CR13","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1097\/NEN.0b013e318198d320","volume":"68","author":"ES Herndon","year":"2009","unstructured":"Herndon ES, Hladik CL, Shang P, Burns DK, Raisanen J, White CL 3rd (2009) Neuroanatomic profile of polyglutamine immunoreactivity in Huntington disease brains. J Neuropathol Exp Neurol 68:250\u2013261","journal-title":"J Neuropathol Exp Neurol"},{"key":"12822_CR14","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1093\/jnen\/nlae022","volume":"83","author":"JC Hedreen","year":"2024","unstructured":"Hedreen JC, Berretta S, White Iii CL (2024) Postmortem neuropathology in early Huntington disease. J Neuropathol Exp Neurol 83:294\u2013306","journal-title":"J Neuropathol Exp Neurol"},{"key":"12822_CR15","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1038\/ejhg.2016.13","volume":"24","author":"MS Thion","year":"2016","unstructured":"Thion MS, Tezenas du Montcel S, Golmard JL, Vacher S, Barjhoux L, Sornin V, Cazeneuve C, Bieche I, Sinilnikova O, Stoppa-Lyonnet D, Durr A, Humbert S (2016) CAG repeat size in Huntingtin alleles is associated with cancer prognosis. Eur J Hum Genet 24:1310\u20131315","journal-title":"Eur J Hum Genet"},{"key":"12822_CR16","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1002\/mds.870110204","volume":"11","author":"Huntington Study Group","year":"1996","unstructured":"Huntington Study Group (1996) Unified Huntington\u2019s disease rating scale: reliability and consistency. Mov Disord. 11:136\u2013142","journal-title":"Mov Disord."},{"key":"12822_CR17","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/S1474-4422(22)00120-X","volume":"21","author":"SJ Tabrizi","year":"2022","unstructured":"Tabrizi SJ, Schobel S, Gantman EC, Mansbach A, Borowsky B, Konstantinova P, Mestre TA, Panagoulias J, Ross CA, Zauderer M, Mullin AP, Romero K, Sivakumaran S, Turner EC, Long JD, Sampaio C, Huntington\u2019s Disease Regulatory Science C (2022) A biological classification of Huntington\u2019s disease: the integrated staging system. Lancet Neurol 21:632\u2013644","journal-title":"Lancet Neurol"},{"key":"12822_CR18","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","volume":"44","author":"JP Vonsattel","year":"1985","unstructured":"Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington\u2019s disease. J Neuropathol Exp Neurol 44:559\u2013577","journal-title":"J Neuropathol Exp Neurol"},{"key":"12822_CR19","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1002\/1531-8249(200101)49:1<29::AID-ANA7>3.0.CO;2-B","volume":"49","author":"E Gomez-Tortosa","year":"2001","unstructured":"Gomez-Tortosa E, MacDonald ME, Friend JC, Taylor SA, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel JP, Myers RH (2001) Quantitative neuropathological changes in presymptomatic Huntington\u2019s disease. Ann Neurol 49:29\u201334","journal-title":"Ann Neurol"},{"key":"12822_CR20","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.ajhg.2021.12.002","volume":"109","author":"Langbehn DR, Registry Investigators of the European Huntington Disease N","year":"2022","unstructured":"Langbehn DR, Registry Investigators of the European Huntington Disease N (2022) Longer CAG repeat length is associated with shorter survival after disease onset in Huntington disease. Am J Hum Genet 109:172\u2013179","journal-title":"Am J Hum Genet"},{"key":"12822_CR21","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s00401-021-02385-1","volume":"143","author":"RA Hickman","year":"2022","unstructured":"Hickman RA, Dewan R, Cortes E, Traynor BJ, Marder K, Vonsattel JP (2022) Amyotrophic lateral sclerosis is over-represented in two Huntington\u2019s disease brain bank cohorts: further evidence to support genetic pleiotropy of pathogenic HTT gene expansion. Acta Neuropathol 143:105\u2013108","journal-title":"Acta Neuropathol"},{"key":"12822_CR22","doi-asserted-by":"publisher","first-page":"eade2044","DOI":"10.1126\/sciadv.ade2044","volume":"9","author":"L Henden","year":"2023","unstructured":"Henden L, Fearnley LG, Grima N, McCann EP, Dobson-Stone C, Fitzpatrick L, Friend K, Hobson L, Chan Moi Fat S, Rowe DB, D\u2019Silva S, Kwok JB, Halliday GM, Kiernan MC, Mazumder S, Timmins HC, Zoing M, Pamphlett R, Adams L, Bahlo M, Blair IP, Williams KL (2023) Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Sci Adv 9:eade2044","journal-title":"Sci Adv"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-024-12822-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00415-024-12822-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-024-12822-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T17:54:57Z","timestamp":1738173297000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00415-024-12822-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,12]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["12822"],"URL":"https:\/\/doi.org\/10.1007\/s00415-024-12822-2","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,12]]},"assertion":[{"value":"1 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 September 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 September 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 December 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Dr. Milan Zimmermann reports no disclosures. Dr. David Mengel reports no disclosures. Dr. Katrin Klein reports no disclosures. Dr. Tobias Haack reports no disclosures. Dr. Manuela Neumann reports no disclosures. Dr. Matthis Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Solaxa, Biogen, Reata, GenOrph, AviadoBio, Biohaven, Zevra,and Lilly, all unrelated to the present manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"58"}}