Association of CAG Repeats With Long-term Progression in Huntington Disease - Sorbonne Université Access content directly
Journal Articles JAMA neurology Year : 2019

Association of CAG Repeats With Long-term Progression in Huntington Disease

Gail Owen
  • Function : Author
Beth Borowsky
  • Function : Author
Tanka Acharya
  • Function : Author
Sophie Andrews
  • Function : Author
Natalie Arran
  • Function : Author
Eric Axelson
  • Function : Author
Natalie Bechtel
  • Function : Author
Claire Berna
  • Function : Author
Stefan Bohlen
  • Function : Author
Jenny Callaghan
  • Function : Author
Amy Cassidy
  • Function : Author
Allison Coleman
  • Function : Author
Helen Crawford
  • Function : Author
Rachelle Dar Santos
  • Function : Author
Joji Decolongon
  • Function : Author
Eve Dumas
  • Function : Author
Mannie Fan
  • Function : Author
Chris Frost
  • Function : Author
Rhia Ghosh
  • Function : Author
Claire Gibbard
  • Function : Author
Davina Hensman-Moss
  • Function : Author
Nicola Hobbs
  • Function : Author
Eileanoir Johnson
  • Function : Author
Rebecca Jones
  • Function : Author
Caroline Jurgens
  • Function : Author
Ruth Keogh
  • Function : Author
Tamara Koren
  • Function : Author
Izelle Labuschagne
  • Function : Author
Nayana Lahiri
  • Function : Author
Ian Malone
  • Function : Author
Peter Mccolgan
  • Function : Author
Alison O’regan
  • Function : Author
Marina Papoutsi
  • Function : Author
Tracey Pepple
  • Function : Author
Terri Petkau
  • Function : Author
Sarah Queller
  • Function : Author
Joy Read
  • Function : Author
Miranda Say
  • Function : Author
Anne Schoonderbeek
  • Function : Author
Cheryl Stopford
  • Function : Author
Aaron Sturrock
  • Function : Author
Ellen ’t Hart
  • Function : Author
Simon van Den Bogaard
  • Function : Author
Jeroen van Der Grond
  • Function : Author
Chiachi Wang
  • Function : Author
Nathalia Weber
  • Function : Author
Daisy Whitehead
  • Function : Author
Marie-Noelle Witjes-Ane
  • Function : Author

Abstract

Importance: In Huntington disease (HD), mutation severity is defined by the length of the CAG trinucleotide sequence, a well-known predictor of clinical onset age. The association with disease trajectory is less well characterized. Quantifiable summary measures of trajectory applicable over decades of early disease progression are lacking. An accurate model of the age-CAG association with early progression is critical to clinical trial design, informing both sample size and intervention timing. Objective: To succinctly capture the decades-long early progression of HD and its dependence on CAG repeat length. Design, setting, and participants: Prospective study at 4 academic HD treatment and research centers. Participants were the combined sample from the TRACK-HD and Track-On HD studies consisting of 290 gene carriers (presymptomatic to stage II), recruited from research registries at participating centers, and 153 nonbiologically related controls, generally spouses or friends. Recruitment was targeted to match a balanced, prespecified spectrum of age, CAG repeat length, and diagnostic status. In the TRACK-HD and Track-On HD studies, 13 and 5 potential participants, respectively, failed study screening. Follow-up ranged from 0 to 6 years. The study dates were January 2008 to November 2014. These analyses were performed between December 2015 and January 2019. Main outcomes and measures: The outcome measures were principal component summary scores of motor-cognitive function and of brain volumes. The main outcome was the association of these scores with age and CAG repeat length. Results: We analyzed 2065 visits from 443 participants (247 female [55.8%]; mean [SD] age, 44.4 [10.3] years). Motor-cognitive measures were highly correlated and had similar CAG repeat length-dependent associations with age. A composite summary score accounted for 67.6% of their combined variance. This score was well approximated by a score combining 3 items (total motor score, Symbol Digit Modalities Test, and Stroop word reading) from the Unified Huntington's Disease Rating Scale. For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease. In contrast, 3 distinct patterns emerged among brain measures (basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes). The basal ganglia pattern showed considerable change in even the youngest participants but demonstrated minimal acceleration of loss with aging. Each clinical and brain summary score was strongly associated with the onset and rate of decline in total functional capacity. Conclusions and relevance: Results of this study suggest that succinct summary measures of function and brain loss characterize HD progression across a wide disease span. CAG repeat length strongly predicts their decline rate. This work aids our understanding of the age and CAG repeat length-dependent association between changes in the brain and clinical manifestations of HD.

Dates and versions

hal-04578993 , version 1 (17-05-2024)

Identifiers

Cite

Douglas Langbehn, Julie Stout, Sarah Gregory, James Mills, Alexandra Durr, et al.. Association of CAG Repeats With Long-term Progression in Huntington Disease. JAMA neurology, 2019, 76 (11), pp.1375. ⟨10.1001/jamaneurol.2019.2368⟩. ⟨hal-04578993⟩
0 View
0 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More