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Frequency and neuropathology of HTT repeat expansions in FTD/ALS: co-existence rather than causation
Milan Zimmermann1,2, David Mengel1,2,3, Katrin Raupach4
1Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, Tuebingen University Hospital, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.
Insights
This study found no increased frequency of HTT repeat expansions in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. The identified case suggests co-occurring ALS and presymptomatic Huntington's disease (HD), not a causative link.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Huntington's disease (HD) is caused by HTT gene CAG repeat expansions (≥40 repeats).
- Recent reports suggest HTT expansions in some amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients.
- This raises questions about HTT expansions as a potential cause for FTD/ALS.
Purpose of the Study:
- To investigate the frequency of HTT repeat expansions in patients with ALS or FTD.
- To determine if HTT expansions are a causative factor in FTD/ALS.
Main Methods:
- Genome sequencing was used to screen 249 patients with ALS or FTD for HTT repeat expansions.
- Neuropathological examination was performed on an identified HTT repeat expansion carrier.
Main Results:
- One HTT repeat expansion (40/22 repeats) was found in an ALS patient, a frequency of 0.4% (general population: 0.03-0.18%).
- The patient presented with ALS but no clinical signs of HD; post-mortem analysis revealed ALS pathology and HD-typical polyQ-aggregates.
- No striatal degeneration, characteristic of HD, was observed.
Conclusions:
- The study does not support an increased frequency of HTT repeat expansions in FTD/ALS.
- The findings suggest the patient had two independent conditions: ALS and presymptomatic HD.
- HTT repeat expansions are likely coincidental, not causative, in FTD/ALS.
Introduction:
While ≥ 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.
Methods:
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.
Results:
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.
Conclusions:
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.
