Abstract
BackgroundAlthough Huntington's disease (HD) is caused by a single dominant gene, it is clear that there are genetic modifiers that may influence the age of onset and disease progression.ObjectivesWe sought to investigate whether new inflammation‐related genetic variants may contribute to the onset and progression of HD.MethodsWe first used postmortem brain material from patients at different stages of HD to look at the protein expression of toll‐like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2). We then genotyped the TREM2 R47H gene variant and 3 TLR4 single nucleotide polymorphisms in a large cohort of HD patients from the European Huntington's Disease Network REGISTRY.ResultsWe found an increase in the number of cells expressing TREM2 and TLR4 in postmortem brain samples from patients dying with HD. We also found that the TREM2 R47H gene variant was associated with changes in cognitive decline in the large cohort of HD patients, whereas 2 of 3 TLR4 single nucleotide polymorphisms assessed were associated with changes in motor progression in this same group.ConclusionsThese findings identify TREM2 and TLR4 as potential genetic modifiers for HD and suggest that inflammation influences disease progression in this condition. © 2019 International Parkinson and Movement Disorder Society
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the HTT gene 1 which presents with a combination of motor, cognitive and psychiatric deficits
Quantification of the number of cells expressing triggering receptor expressed on myeloid cells 2 (TREM2) and Toll-like receptor 4 (TLR4) revealed a significant increase in both markers in HD patients as compared to controls (Fig. 1c,d; p < 0.001)
While we found no association between ages of onset (AoO) and motor and cognitive decline, nor between CAG repeats length and motor and cognitive decline, the already established negative correlation between AoO and CAG repeat length was reproduced in the total population (Kendall’s taub -0.255, P 0.0001)
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the HTT gene 1 which presents with a combination of motor, cognitive and psychiatric deficits. Despite its clear genetic basis, HD patients show variable ages of onset (AoO) and progression rate, and while CAG repeat length has been shown to correlate with the AoO of motor signs [2,3,4,5,6,7,8,9,10], this has been of limited clinical use in predicting AoO for an individual 11. Patients with similar initial clinical presentations can follow very different clinical courses 12, with variable rates of disease progression that are poorly correlated to CAG repeat length. Genetic polymorphisms adjacent to the CAG repeats have been shown to influence disease onset [3, 4, 10, 17, 18] as have genes related to DNA repair [19,20,21]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
