HTT CAG Repeat Size, Age at Onset Associated With Huntington Disease Progression

DNA sequence
DNA sequence
Investigators sought to assess factors contributing to progression of functional, cognitive, and motor impairment in Huntington disease.

Findings from a study in Neurology indicate that there is an overlap between determinants of age at onset and disease progression in Huntington disease (HD), suggesting that therapies that delay age at onset and target CAG repeat-dependent mechanisms may slow HD progression among patients with clinically manifest disease.

Observational data of patients in the Enroll-HD study ( Identifier: NCT01574053)with a known age at clinical HD onset/diagnosis, a mutant CAG repeat size of at least 36, and at least 2 follow-up assessments following HD diagnosis were included in the study (n=3411). Investigators evaluated the association of HTT CAG repeat size and age at onset, which was considered significant and accounted for 69.3% of the total variance (β = −0.066, P <.001).

For the purposes of the study, the researchers sought to measure the variability in the rate of HD progression. They specifically focused on the CAG repeat size, considering that a larger expansion of the CAG repeat is often associated with greater symptom severity and earlier symptom onset.

CAG repeat-dependent mechanisms demonstrated the most significant factor driving the rate of HD progression as it related to its functional, motor, and cognitive components. In patients with a higher mutant HTT CAG repeat size and a later age at disease onset, the investigators observed faster and slower rates of functional decline, respectively.

Additionally, a larger HTT CAG repeat size correlated with higher rates of motor progression. There was a significant decline of the cognitive summary score per year by 0.26 points (range -4.79 to 6.65, 95% CI, -0.27 to -0.25, P <.001). The rate of cognitive decline was slower among patients with a later age at HD onset compared with patients with an earlier onset or earlier-than-expected onset based on the HTT CAG repeat size.

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The lack of biochemical and imaging quantification markers for measuring disease progression represents a possible limitation of the analysis.

Based on the findings, the researchers believe that “targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, has the potential to affect the rate of functional, motor, and cognitive impairment in manifest HD.”


Aziz NA, van der Burg JMM, Tabrizi SJ, Landwehrmeyer GB. Overlap between age-at-onset and disease-progression determinants in Huntington disease [published online May 9, 2018]. Neurology. doi: 10.1212/WNL.0000000000005690