Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation.

introductionWhile ≥ 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.

methodsScreening 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.

resultsOne 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.

conclusionsOur 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.