Fronto-striatal circuitry in children at risk for Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation involving an expansion of the CAG trinucleotide repeats in the gene encoding for huntingtin (HTT) protein. The discovery of the disease-causing faulty gene (mutant huntingtin; mHTT) has enabled valid presymptomatic gene assessment for HD with results being categorized as 'gene-expanded (GE; CAG repeats ? 36)' or 'gene non-expanded (GNE)'. Individuals tested to be gene-expanded are destined to develop HD symptoms and will receive clinical diagnosis at an average age of 40 years when abnormal motor symptoms manifest. Those who are GNE will not develop HD. The availability of genetic testing has also provided a valuable research opportunity to study the pathoetiology of HD in PreHD subjects (those tested to be 'gene-expanded' but are in the prediagnostic stage of HD). The genetic mutation results in widespread neuronal degeneration preferentially within the striatum. The clinical manifestations of HD include a triad of motor, cognitive and psychiatric symptoms.;The current study reports the baseline profile of the fronto-striatal structure and function in children at risk for HD. We have found that children who are on average 30 years ahead of HD diagnosis to have developmental alterations in the brain structure and function directly linked to the effect of mHTT. Brain morphology analysis revealed specific subcortical gray and white matter changes. The changes include disproportionately smaller caudate and putamen volumes and increased radial diffusivity localized to the external capsule which were more evident in males with HTT gene expansion. Fronto-striatal circuit functional assessment revealed a drop in motor functionality (both at rest and active performance) and externalizing behavior problems indicative of compromised inhibition than aggression. Children from HD families but do not have the genetic mutation also showed development aberrations in both brain structure and function when compared to healthy controls. Importantly, the altered structural morphology and functional profile seen in the GNE group differed from that of the GE children, emphasizing the impact of mHTT. The findings from those who share similar household environment but differ in genetic expansion status are important in highlighting the potential interaction of gene-environment effect on the manifestation of mHTT related changes seen in the children with the genetic expansion for HD.;Investigation of subtle but persistent effects of mHTT on normal neural developmental processes may further our understanding of the pathogenesis of HD. Continuous longitudinal comprehensive assessments of the mHTT associated neurophenotype would aid in prognostic scenario estimation and thereby lead to effective clinical decision making to maximize the benefit of early intervention. (Abstract shortened by ProQuest.).