Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
Dewan R., Chia R., Ding J., Hickman RA., Stein TD., Abramzon Y., Ahmed S., Sabir MS., Portley MK., Tucci A., Ibáñez K., Shankaracharya FNU., Keagle P., Rossi G., Caroppo P., Tagliavini F., Waldo ML., Johansson PM., Nilsson CF., American Genome Center (TAGC) ., FALS Sequencing Consortium ., Genomics England Research Consortium ., International ALS/FTD Genomics Consortium (iAFGC) ., International FTD Genetics Consortium (IFGC) ., International LBD Genomics Consortium (iLBDGC) ., NYGC ALS Consortium ., PROSPECT Consortium ., 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., Chiò A., Gibbs JR., Dalgard CL., Scholz SW., Traynor BJ.
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.