Methods We genotyped the HTT gene CAG repeat number and APOE-Ɛ isoforms in a case-control series including patients with either clinical or neuropathological diagnosis of α-synucleinopathy.
Results We identified three Parkinson's disease (PD) patients (0.30%) and two healthy controls (0.19%) carrying low-penetrance HTT repeat expansions whereas none of the dementia with Lewy bodies (DLB) or multisystem atrophy (MSA) patients carried pathogenic HTT expansions. In addition, a clear increase in the number of HTT CAG repeats was found among DLB and PD groups influenced by the male gender and also by the APOE4 allele among DLB patients. HTT intermediate alleles' (IAs) distribution frequency increased in the MSA group compared with controls (8.8% vs. 3.9%, respectively). These differences were indeed statistically significant in the MSA group with neuropathological confirmation. Two MSA HTT CAG IAs carriers with 32 HTT CAG repeats showed isolated polyQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA.
Conclusions Our results point to a link between HTT CAG number, HTT IAs, and expanded HTT CAG repeats with other non-HD brain pathology and support the hypothesis that they can share common neurodegenerative pathways.
Reference: Pérez-Oliveira, S., Álvarez, I., Rosas, I., Menendez-González, M., Blázquez-Estrada, M., Aguilar, M., Corte, D., Buongiorno, M., Molina-Porcel, L., Aldecoa, I., Martí, M.J., Sánchez-Juan, P., Infante, J., González-Aramburu, I., García-González, P., Rosende-Roca, M., Boada, M., Ruiz, A., Periñán, M.T., Macías-García, D., Muñoz-Delgado, L., Gómez-Garre, P., Mir, P., Clarimón, J., Lleo, A., Alcolea, D., De la Casa-Fages, B., Duarte, I., Álvarez, V. and Pastor, P. (2022), Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies. Mov Disord. https://doi.org/10.1002/mds.29153