Behavioral features in child and adolescent huntingtin gene‐mutation carriers

Reasoner, Erin E.; Plas, Ellen van der; Al‐Kaylani, Hend M.; Langbehn, Douglas R.; Conrad, Amy L.; Schultz, Jordan L.; Epping, Eric A.; Magnotta, Vincent; Nopoulos, Peg

doi:10.1002/brb3.2630

Cited by 4 publications

(1 citation statement)

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“…28,29 This hypothesis is further supported by study of young carriers of the Huntington gene expansions who show enhanced cognitive performance 30 and reduced anxiety and depression compared to familial non-carriers. 31 Neurodevelopmental effects of the Huntington's gene CAG repeat expansion recently have been confirmed during human embryonic brain development as early as 13 weeks gestation. 32 These included mislocalized junctional complexes and of the mutant protein huntingtin, abnormal neuroprogenitor cell polarity and differentiation, and altered mitosis and cell cycle progression.…”

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confidence: 99%

Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

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Malik

Bocchetta

et al. 2022

Brain

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While frontotemporal dementia (frontotemporal dementia) has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with aging. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we have examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between the ages of 19 and 30y. Structural brain differences and improved performance on some cognitive tests was found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26y. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia causing genetic mutations. These results have implications for design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes in the neurodevelopmental period.

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Section: Introductionmentioning

confidence: 99%

Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

Finger

Malik

Bocchetta

et al. 2022

Brain

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Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy

Neema,

Schultz,

Langbehn

et al. 2024

Annals of Neurology

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ObjectiveHuntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging‐related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years‐to‐onset paradigm in a unique sample of children and young adults at risk for HD.MethodsCognitive, behavioral, motor, and brain structural measures from premanifest gene‐expanded (n = 79) and gene nonexpanded (n = 112) participants (6–21 years) in the Kids‐HD study were examined. All measures in the gene‐expanded group were modeled using a mixed‐effects regression approach to assess years‐to‐onset‐based changes while controlling for normal growth. Simultaneously, structure–function associations were also examined.ResultsDecades from motor onset, gene‐expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences.InterpretationMutant HTT may drive the development of a larger than normal brain that subserves superior early‐life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024

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Behavioral features in child and adolescent huntingtin gene‐mutation carriers

et al. 2022

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Introduction:We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development.Methods: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms.Results: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. Conclusions:The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth.These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.

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Behavioral features in child and adolescent huntingtin gene‐mutation carriers

Cited by 4 publications

References 68 publications

Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy

Behavioral features in child and adolescent huntingtin gene‐mutation carriers

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