TY  - JOUR
AU  - Aziz, Ahmad
AU  - van der Burg, Jorien M M
AU  - Tabrizi, Sarah J
AU  - Landwehrmeyer, G Bernhard
TI  - Overlap between age-at-onset and disease-progression determinants in Huntington disease.
JO  - Neurology
VL  - 90
IS  - 24
SN  - 0028-3878
CY  - [S.l.]
PB  - Ovid
M1  - DZNE-2020-06420
SP  - e2099-e2106
PY  - 2018
AB  - A fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD.Using observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD.A total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat-dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation.Our findings imply that targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers.
KW  - Age of Onset
KW  - Disease Progression
KW  - Humans
KW  - Huntington Disease: epidemiology
KW  - Huntington Disease: genetics
KW  - Huntington Disease: pathology
LB  - PUB:(DE-HGF)16
C6  - pmid:29743208
C2  - pmc:PMC5996832
DO  - DOI:10.1212/WNL.0000000000005690
UR  - https://pub.dzne.de/record/140098
ER  -