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000273945 037__ $$aDZNE-2024-01419
000273945 041__ $$aEnglish
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000273945 1001_ $$0P:(DE-2719)9000951$$aZimmermann, Milan$$b0$$eFirst author
000273945 245__ $$aFrequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation.
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000273945 520__ $$aWhile ≥ 40 CAG repeat expansions in HTT present a well-established cause of Huntington's disease (HD), an enrichment of HTT 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 HTT expansions can be extended to ALS and FTD, and whether HTT should be considered as a new causative gene of FTD/ALS. If HTT repeat expansions were indeed systematically related to FTD/ALS, one would expect an increased frequency of HTT carriers in FTD/ALS, who can clinically/neuropathologically not be explained better than by the presence of the HTT repeat expansions.Screening of HTT 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 HTT repeat expansion carrier.One HTT repeat expansion [40/22 repeats (± 1)] was identified in an ALS patient, giving a frequency of 0.4% (1/249) (frequency in the general population: 0.03-0.18%). This patient showed a classic ALS phenotype, but no clinical or imaging signs of HD. Post-mortem brain examination revealed-in addition to ALS-typical degeneration of upper and lower motor neurons with TDP-43 inclusions-HD-typical polyQ-aggregates in gyrus cinguli, striatum and frontal lobe, yet without evidence of striatal degeneration.Our study does not support the notion of an increased frequency of HTT repeat expansions in FTD/ALS. Moreover, the phenotype of the HTT carrier identified can be better explained by two co-existent, but independent diseases: (i) ALS and (ii) presymptomatic HD, which-given the low repeat number-is likely to become manifest only later in life. These findings corroborate the concept that HTT repeat expansions are likely co-existent/coincidental, but not causative in FTD/ALS.
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000273945 650_7 $$2Other$$aALS
000273945 650_7 $$2Other$$aAmyotrophic lateral sclerosis
000273945 650_7 $$2Other$$aFrontotemporal dementia
000273945 650_7 $$2Other$$aHTT
000273945 650_7 $$2Other$$aHuntington
000273945 650_7 $$2Other$$aMAPT
000273945 650_7 $$2NLM Chemicals$$aHuntingtin Protein
000273945 650_7 $$2NLM Chemicals$$aHTT protein, human
000273945 650_2 $$2MeSH$$aHumans
000273945 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000273945 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000273945 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000273945 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: pathology
000273945 650_2 $$2MeSH$$aMale
000273945 650_2 $$2MeSH$$aFemale
000273945 650_2 $$2MeSH$$aHuntingtin Protein: genetics
000273945 650_2 $$2MeSH$$aMiddle Aged
000273945 650_2 $$2MeSH$$aAged
000273945 650_2 $$2MeSH$$aTrinucleotide Repeat Expansion: genetics
000273945 650_2 $$2MeSH$$aBrain: pathology
000273945 650_2 $$2MeSH$$aBrain: diagnostic imaging
000273945 7001_ $$0P:(DE-2719)9000375$$aMengel, David$$b1$$udzne
000273945 7001_ $$aRaupach, Katrin$$b2
000273945 7001_ $$aHaack, Tobias$$b3
000273945 7001_ $$0P:(DE-2719)2810592$$aNeumann, Manuela$$b4$$udzne
000273945 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b5$$eLast author
000273945 773__ $$0PERI:(DE-600)1421299-7$$a10.1007/s00415-024-12822-2$$gVol. 272, no. 1, p. 58$$n1$$p58$$tJournal of neurology$$v272$$x0367-004X$$y2025
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