Age-Related Cognitive Changes as a Function of CAG Repeat in Child and Adolescent Carriers of Mutant Huntingtin

Abstract

Limited data exists regarding the disease course of Huntington's Disease (HD) in children and young adults. Here, we evaluate the trajectory of various cognitive skill development as a function of cytosine-adenine-guanine (CAG) repeat length in children and adolescents that carry the mutation that causes HD. We discovered that the development of verbal skills seems to plateau earlier as CAG repeat length increases. These findings increase our understanding of the relationship between neurodegeneration and neurodevelopment and may have far-reaching implications for future gene-therapy treatment strategies. ANN NEUROL 2021;89:1036-1040.

Figure 1

Predicted developmental trajectories of A) language development, B) memory, C) executive function, and D) visual perception (y-axes) across age (x-axes) separated by CAG repeat length (solid, colored lines). The solid-colored lines were created using the models described in the Methods section. The dashed, turquoise lines represent the developmental trajectories of 104 non-expanded controls who were at-risk for inheriting the mutation that causes HD based on family history but who had a CAG <36. The models used to construct these lines were similar to those described in the Methods section, but were independent of CAG repeat length. These models were constructed for visualization purposes only and the participants with a CAG repeat length of 36 or above were not compared to the healthy controls.

Figure 2

This figure is based on the results from the verbal fluency trajectories by CAG repeat while also considering known relationships between the onset of neurodegeneration and the interaction between CAG repeat length and age. Specifically, the person with a CAG of 37 (peach color) has the opportunity for full brain development and maturation, which peaks at approximately 30 years of age. There is then a steady state phase prior to the onset of neurodegeneration that leads into a state of neurodegeneration that begins approximately 15–20 years prior to the predicted motor onset. In contrast, the person with a CAG of 46 has stunted neurodevelopment because neurodegenerative processes begin prior to the age of 30.