Abnormal brain development in child and adolescent carriers of mutant huntingtin

Abstract

Objective: The huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development.

Methods: Children and adolescents (age 6-18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated.

Results: Age-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions.

Conclusion: Our results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.

Figure 1. Illustration of accelerated longitudinal design

Age is shown on the x-axis and cerebrum volume (gray and white matter combined) is shown on the y-axis. Single diamonds represent a single observation in an individual, while connected diamonds show repeated observations within the same individual. The thick, black line illustrates the growth curve across age based on a combination of cross-sectional and longitudinal components. To preserve gene status confidentiality, the figure illustrates the combined gene-expanded and gene-nonexpanded groups.

Figure 2. Sample characteristics

(A) Individuals (diamonds) and repeated observations within the same individual (connected diamonds). The sample included 172 unique individuals (stacked at x = 0), a subset of whom were assessed more than once (connected diamonds). (B) Distribution of CAG repeats among individuals in the gene-expanded (GE) range (top panel) and in the gene-nonexpanded (GNE) range (bottom panel). (C) The range of estimated years to Huntington disease (HD) onset from time of testing (x-axis) for each CAG repeat observed in the sample (y-axis). For instance, for CAG = 50, the range was 14–30 years to estimated disease onset from the time of testing. Hotter colors represent higher CAG repeats and the vertical, dashed lines mark 10 and 20 years from disease onset, respectively.

Figure 3. Developmental trajectories of the striatum, striatal volume difference between gene-expanded (GE) and gene-nonexpanded (GNE), impact of CAG repeat expansion, and developmental trajectories of the globus pallidus

(A) Mean estimated age-dependent change of striatal volume in the GE (red) and GNE (green) groups. Note that the GE curve is based on individuals with CAG ≤50, and that results were averaged across sex. (B) Striatal volume difference (y-axis) between GE group (red) and GNE group (horizontal, black line) across age (x-axis), along with 95% confidence limits of the difference scores. (C) The impact of CAG repeat length on striatal volume (y-axis) across age (x-axis). CAG repeats ≤50 did not affect striatal growth curves (horizontal line labeled ≤50). For repeats >50, additional repeats were associated with accelerated striatal decline in adolescence, and possibly with greater hypertrophy before age 10. (D) Mean estimated age-dependent change of the globus pallidus.

Figure 4. Age-dependent changes of intracranial volume (ICV), cerebellum, and cerebrum for CAG ≤50

(A) Age-dependent change of ICV was comparable between groups but differed between male and female participants, F_4,113 = 11.06, p = 1.82 × 10⁻⁷. The volume difference between male and female participants was significantly larger in the gene-expanded (GE) group than the gene-nonexpanded (GNE) group (GE vs GNE sex difference = 78.9 mL, SE = 31.5 mL, t [121] = 2.51, p = 0.0135). (B) The groups did not differ significantly in age-related change of the cerebellum. The difference in cerebellum volume between male and female participants was significantly larger in the GE group than the GNE group (GE vs GNE sex difference = 7.72 mL, SE = 3.08 mL, t [137] = 2.51, p = 0.0134). (C) The sex-dependent volume difference was also significantly greater in GE than in GNE for the cerebrum (difference = 61.37 mL, SE = 24.90, t [127] = 2.46, p = 0.0115. In addition, age-dependent decline of the cerebrum was significantly faster in the GE group than the GNE group (−3.33 mL/y, SE = 0.94, t [119] = −3.54, p = 0.0006).