Abnormal brain development in child and adolescent carriers of mutant huntingtin

Plas, Ellen van der; Langbehn, Douglas R.; Conrad, Amy L.; Koscik, Timothy R.; Терещенко, А.В.; Epping, Eric A.; Magnotta, Vincent A.; Nopoulos, Peg

doi:10.1212/wnl.0000000000008066

Cited by 80 publications

(114 citation statements)

References 45 publications

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“…Our current findings provide the first evidence for existing altered brain developmental processes at the system level in the heterozygous zQ175 KI HD model. In line with our observation in the human HD study ( van der Plas et al. 2019 ), these data indicate new aspects of the HD pathogenesis which is important to guide future therapeutic development.…”

Section: Introductionsupporting

confidence: 87%

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Abnormal Brain Development in Huntington’ Disease Is Recapitulated in the zQ175 Knock-In Mouse Model

Zhang

Liu

et al. 2020

Cerebral Cortex Communications

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Emerging cellular and molecular studies are providing compelling evidence that altered brain development contributes to the pathogenesis of Huntington’s disease (HD). There has been lacking longitudinal system-level data obtained from in vivo HD models supporting this hypothesis. Our human MRI study in children and adolescents with HD indicates that striatal development differs between the HD and control groups, with initial hypertrophy and more rapid volume decline in HD group. In this study, we aimed to determine whether brain develop recapitulates the human HD during the postnatal period. Longitudinal structural MRI scans were conducted in the heterozygous zQ175 HD mice and their littermate controls. We found that male zQ175 HD mice recapitulated the region-specific abnormal volume development in the striatum and globus pallidus, with early hypertrophy and then rapidly decline in the regional volume. In contrast, female zQ175 HD mice did not show significant difference in brain volume development with their littermate controls. This is the first longitudinal study of brain volume development at the system level in HD mice. Our results suggest that altered brain development may contribute to the HD pathogenesis. The potential effect of gene therapies targeting on neurodevelopmental event is worth to consider for HD therapeutic intervention.

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Section: Introductionsupporting

confidence: 87%

“…In line with these findings, we have recently reported significant brain region-selective developmental abnormalities in seventy-five child and adolescent carriers of mutant HTT ( van der Plas et al. 2019 ).…”

Section: Introductionsupporting

confidence: 79%

Abnormal Brain Development in Huntington’ Disease Is Recapitulated in the zQ175 Knock-In Mouse Model

Zhang

Liu

et al. 2020

Cerebral Cortex Communications

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“…31 or Huntington's Disease. 32,33 These different trajectories are confirmed when observing the specific regions of decreased GM in the VBM analyses, and even allow for clearly showing that pediatric and adult/late onset patients display distinctive patterns of damage in a given time-spot and different trajectories from a longitudinal perspective. Specifically, pediatric DM1 patients showed reduced GM volume, mainly located at subcortical level at baseline, which additionally extended to cortical regions at followup, particularly the frontal lobe.…”

Section: Discussionmentioning

confidence: 65%

Neurodegeneration trajectory in pediatric and adult/late DM1: A follow‐up MRI study across a decade

Labayru

Jiménez-Marín

Fernández

et al. 2020

Ann Clin Transl Neurol

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Objective: To characterize the progression of brain structural abnormalities in adults with pediatric and adult/late onset DM1, as well as to examine the potential predictive markers of such progression. Methods: 21 DM1 patients (pediatric onset: N = 9; adult/late onset: N = 12) and 18 healthy controls (HC) were assessed longitudinally over 9.17 years through brain MRI. Additionally, patients underwent neuropsychological, genetic, and muscular impairment assessment. Inter-group comparisons of total and voxel-level regional brain volume were conducted through Voxel Based Morphometry (VBM); cross-sectionally and longitudinally, analyzing the associations between brain changes and demographic, clinical, and cognitive outcomes. Results: The percentage of GM loss did not significantly differ in any of the groups compared with HC and when assessed independently, adult/late DM1 patients and their HC group suffered a significant loss in WM volume. Regional VBM analyses revealed subcortical GM damage in both DM1 groups, evolving to frontal regions in the pediatric onset patients. Muscular impairment and the outcomes of certain neuropsychological tests were significantly associated with follow-up GM damage, while visuoconstruction, attention, and executive function tests showed sensitivity to WM degeneration over time. Interpretation: Distinct patterns of brain atrophy and its progression over time in pediatric and adult/late onset DM1 patients are suggested. Results indicate a possible neurodevelopmental origin of the brain abnormalities in DM1, along with the possible existence of an additional neurodegenerative process. Fronto-subcortical networks appear to be involved in the disease progression at young adulthood in pediatric onset DM1 patients. The involvement of a multimodal integration network in DM1 is discussed.

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“…Overall, these findings suggest that HD, at least in its early-onset juvenile forms, may not be a purely neurodegenerative disorder and that abnormal neurodevelopment may be a component of its pathophysiology. This notion is further supported by several studies in children and adolescent HD gene carriers who are estimated to be decades from onset, showing altered intracranial volume [4] and brain region morphology [5,6].…”

Section: Increased Asymmetric Divisionmentioning

confidence: 64%

“…Moreover, the morphology of brain regions is substantially different in adult pre-manifest HD mutation carriers, with increased volume of the cerebral cortex and decreased volume of the basal ganglia and cerebral white matter [5]. A recent longitudinal study in children and adolescent HD gene carriers who were estimated to be on average 35 years from clinical onset revealed that an initial hypertrophy of striatal volume precedes the volume decline that develops with age [6]. Furthermore, two recent whole-exome sequencing studies have identified compound heterozygous variants in the HTT gene in patients with Rett-like syndrome, a neurodevelopmental disorder [7,8].…”

Section: Introductionmentioning

confidence: 99%

Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

Zhang

Ooi

Utami

et al. 2019

Preprint

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Huntington disease (HD) manifests in both adult and juvenile forms. Mutant HTT gene carriers are thought to undergo normal brain development followed by a degenerative phase, resulting in progressive clinical manifestations. However, recent studies in children and prodromal individuals at risk for HD have raised the possibility of abnormal neurodevelopment.Although key findings in rodent models support this notion, direct evidence in the context of human physiology remains lacking. Using a panel of isogenic HD human embryonic pluripotent stem cells and cerebral organoids, we investigated the impact of mutant HTT on early neurodevelopment. We find that ventricular zone-like neuroepithelial progenitor layer expansion is blunted in an HTT CAG repeat length-dependent manner due to premature neurogenesis in HD cerebral organoids, driven by cell intrinsic processes. Transcriptional profiling and imaging analysis revealed impaired cell cycle regulatory processes, increased G1 length, and increased asymmetric division of apical progenitors, collectively contributing to premature neuronal differentiation. We demonstrate increased activity of the ATM-p53 pathway, an up-stream regulator of cell cycle processes, and show that treatment with ATM antagonists partially rescues the blunted neuroepithelial progenitor expansion in HD organoids. Our findings suggest that CAG repeat length regulates the balance between neural progenitor expansion and differentiation during early neurodevelopment. Our results 1/26further support the view that HD, at least in its early-onset forms, may not be a purely neurodegenerative disorder, and that abnormal neurodevelopment may be a component of HD pathophysiology.

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Abnormal brain development in child and adolescent carriers of mutant huntingtin

Cited by 80 publications

References 45 publications

Abnormal Brain Development in Huntington’ Disease Is Recapitulated in the zQ175 Knock-In Mouse Model

Abnormal Brain Development in Huntington’ Disease Is Recapitulated in the zQ175 Knock-In Mouse Model

Neurodegeneration trajectory in pediatric and adult/late DM1: A follow‐up MRI study across a decade

Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

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