Longitudinal Clinical and Biological Characteristics in Juvenile-Onset Huntington's Disease.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare form of Huntington's disease (HD) characterized by symptom onset before the age of 21 years. Observational data in this cohort is lacking. OBJECTIVES: Quantify measures of disease progression for use in clinical trials of patients with JOHD. METHODS: Participants who received a motor diagnosis of HD before the age of 21 were included in the Kids-JOHD study. The comparator group consisted of children and young adults who were at-risk for inheriting the genetic mutation that causes HD, but who were found to have a CAG repeat in the non-expanded range (gene non-expanded [GNE]). RESULTS: Data were obtained between March 17, 2006, and February 13, 2020. There were 26 JOHD participants and 78 GNE participants who were comparable on age (16.03 vs. 14.43, respectively) and sex (53.8% female vs. 57.7% female, respectively). The mean annualized decrease in striatal volume in the JOHD group was -3.99% compared to -0.06% in the GNE (mean difference [MD], -3.93%; 95% confidence intervals [CI], [-4.98 to -2.80], FDR < 0.0001). The mean increase in the Unified Huntington's Disease Rating Scale Total Motor Score per year in the JOHD group was 7.29 points compared to a mean decrease of -0.21 point in the GNE (MD, 7.5; 95% CI, [5.71-9.28], FDR < 0·0001). CONCLUSIONS: These findings demonstrate that structural brain imaging and clinical measures in JOHD may be potential biomarkers of disease progression for use in clinical trials. Collaborative efforts are required to validate these results in a larger cohort of patients with JOHD. © 2022 International Parkinson and Movement Disorder Society.

Sex-specific effects of the Huntington gene on normal neurodevelopment.

Huntington disease is a neurodegenerative disorder caused by a gene (HTT) with a unique feature of trinucleotide repeats ranging from 10 to 35 in healthy people; when expanded beyond 39 repeats, Huntington disease develops. Animal models demonstrate that HTT is vital to brain development; however, this has not been studied in humans. Moreover, evidence suggests that triplet repeat genes may have been vital in evolution of the human brain. Here we evaluate brain structure using magnetic resonance imaging and brain function using cognitive tests in a sample of school-aged children ages 6 to 18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. We find that the number of repeats in HTT, below disease threshold, confers advantageous changes in brain structure and general intelligence (IQ): the higher the number of repeats, the greater the change in brain structure, and the higher the IQ. The pattern of structural brain changes associated with HTT is strikingly different between males and females. HTT may confer an advantage or a disadvantage depending on the repeat length, playing a key role in either the evolution of a superior human brain or development of a uniquely human brain disease. © 2016 Wiley Periodicals, Inc.

A genome-wide CNV analysis of schizophrenia reveals a potential role for a multiple-hit model.

Schizophrenia is a chronic and severe psychiatric disorder that is highly heritable. While both common and rare genetic variants contribute to disease risk, many questions still remain about disease etiology. We performed a genome-wide analysis of copy number variants (CNVs) in 166 schizophrenia subjects and 52 psychiatrically healthy controls. First, overall CNV characteristics were compared between cases and controls. The only statistically significant finding was that deletions comprised a greater proportion of CNVs in cases. High interest CNVs were then identified as conservative using the following filtering criteria: (i) known deleterious CNVs; (ii) CNVs > 1 Mb that were novel (not found in a database of control individuals); and (iii) CNVs < 1 Mb that were novel and that overlapped the coding region of a gene of interest. Cases did not harbor a higher proportion of conservative CNVs in comparison to controls. However, similar to previous reports, cases had a slightly higher proportion of individuals with clinically significant CNVs (known deleterious or conservative CNVs > 1 Mb) or with multiple conservative CNVs. Two case individuals with the highest burden of conservative CNVs also share a recurrent 15q11.2 BP1-2 deletion, indicating a role for a potential multiple-hit CNV model for schizophrenia. In total, we report three 15q11.2 BP1-2 deletion individuals with schizophrenia, adding to a growing body of evidence that this CNV is involved in disease etiology.

Patterns of serotonergic antidepressant usage in prodromal Huntington disease.

Antidepressant usage in prodromal Huntington Disease (HD) remains uncharacterized, despite its relevance in designing experiments, studying outcomes of HD, and evaluating the efficacy of therapeutic interventions. We searched baseline medication logs of 787 prodromal HD and 215 healthy comparison (HC) participants for antidepressant use. Descriptive and mixed-effects logistic regression modeling characterized usage across participants. At baseline, approximately one in five prodromal HD participants took antidepressants. Of those, the vast majority took serotonergic antidepressants (selective serotonin reuptake inhibitor (SSRI) or serotonin/norepinephrine reuptake inhibitor (SNRI)). Significantly more prodromal HD participants used serotonergic antidepressants than their HC counterparts. Because of the prevalence of these medications, further analyses focused on this group alone. Mixed-effects logistic regression modeling revealed significant relationships of both closer proximity to diagnosis and female sex with greater likelihood to be prescribed a serotonergic antidepressant. More prodromal HD participants took antidepressants in general and specifically the subclass of serotonergic antidepressants than their at-risk counterparts, particularly when they were closer to predicted time of conversion to manifest HD. These propensities must be considered in studies of prodromal HD participants.

Behavioral features in child and adolescent huntingtin gene-mutation carriers.

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.

Cortical Features in Child and Adolescent Carriers of Mutant Huntingtin (mHTT).

BACKGROUND: Molecular studies provide evidence that mutant huntingtin (mHTT) affects early cortical development; however, cortical development has not been evaluated in child and adolescent carriers of mHTT. OBJECTIVE: To evaluate the impact of mHTT on the developmental trajectories of cortical thickness and surface area. METHODS: Children and adolescents (6-18 years) participated in the KidsHD study. mHTT carrier status was determined for research purposes only to classify participants as gene expanded (GE) and gene non-expanded (GNE). Cortical features were extracted from 3T neuroimaging using FreeSurfer. Nonlinear mixed effects models were conducted to determine if age, group, and CAG repeat were associated with cortical morphometry. RESULTS: Age-related changes in cortical morphometry were similar across groups. Expanded CAG repeat was not significantly associated with cortical features. CONCLUSION: While striatal development is markedly different in GE and GNE, developmental change of the cortex appears grossly normal among child and adolescent carrier of mHTT.

Correlation of CAG repeat length between the maternal and paternal allele of the Huntingtin gene: evidence for assortative mating.

Triplet repeats contribute to normal variation in behavioral traits and when expanded, cause brain disorders. While Huntington's Disease is known to be caused by a CAG triplet repeat in the gene Huntingtin, the effect of CAG repeats on brain function below disease threshold has not been studied. The current study shows a significant correlation between the CAG repeat length of the maternal and paternal allele in the Huntingtin gene among healthy subjects, suggesting assortative mating.

G72 influences longitudinal change in frontal lobe volume in schizophrenia.

Schizophrenia is a neurodevelopmental psychiatric disorder characterized by a variety of structural brain abnormalities that appear to progress across the course of illness. Schizophrenia also is highly heritable, and one gene that has emerged as a possible susceptibility factor is G72. G72 influences brain development and activity by an as-yet unclear mechanism, and multiple studies have reported associations between G72 and schizophrenia. We were interested in linking these domains of investigation by determining whether G72 also influences the rate of longitudinal structural brain changes in individuals with schizophrenia. As part of the Iowa Longitudinal Study of Recent Onset Psychoses, we genotyped four G72 polymorphisms previously associated with schizophrenia in 110 subjects with schizophrenia or schizoaffective disorder from whom we had obtained two brain MRI scans an average of 3 years apart. The four polymorphisms captured three haplotypes, one of which was strongly associated with an increased rate of frontal lobe volume decrement. This same haplotype was also associated with more severe psychotic symptoms at the time of the second scan. These data thus suggest that variation in G72 modulates the progressive brain changes that characterize schizophrenia.

Subcortical T1-Rho MRI Abnormalities in Juvenile-Onset Huntington's Disease.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 years, which are classified as juvenile-onset Huntington's disease (JOHD). Our study aims to measure subcortical metabolic abnormalities in JOHD participants. T1-Rho (T1ρ) MRI was used to compare brain regions of 13 JOHD participants and 39 controls. Region-of-interest analyses were used to assess differences in quantitative T1ρ relaxation times. We found that the mean relaxation times in the caudate (p < 0.001), putamen (p < 0.001), globus pallidus (p < 0.001), and thalamus (p < 0.001) were increased in JOHD participants compared to controls. Furthermore, increased T1ρ relaxation times in these areas were significantly associated with lower volumes amongst participants in the JOHD group. These findings suggest metabolic abnormalities in brain regions previously shown to degenerate in JOHD. We also analyzed the relationships between mean regional T1ρ relaxation times and Universal Huntington's Disease Rating Scale (UHDRS) scores. UHDRS was used to evaluate participants' motor function, cognitive function, behavior, and functional capacity. Mean T1ρ relaxation times in the caudate (p = 0.003), putamen (p = 0.005), globus pallidus (p = 0.009), and thalamus (p = 0.015) were directly proportional to the UHDRS score. This suggests that the T1ρ relaxation time may also predict HD-related motor deficits. Our findings suggest that subcortical metabolic abnormalities drive the unique hypokinetic symptoms in JOHD.

Abnormal development of cerebellar-striatal circuitry in Huntington disease.

OBJECTIVE: To test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between presymptomatic patients with the Huntington disease (HD) gene expansion (GE) and patients with a family history of HD but without the GE (GNE), we evaluated functional MRI data from the Kids-HD study. METHODS: We utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 and 18 years old. Participants were divided into GE (CAG 36-59) and GNE (CAG <36) groups. Seed-to-seed correlations were calculated among 4 regions that provide input signals to the anterior cerebellum: (1) dorsocaudal putamen, (2) globus pallidus externa, (3) subthalamic nucleus, and (4) pontine nuclei; and 2 regions that represented output from the cerebellum: the dentate nucleus to the (1) ventrolateral thalamus and (2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups. RESULTS: Four of the six striatal-cerebellum correlations showed significantly different trajectories between groups. All showed a pattern where in the early age ranges (6-12 years) there was hyperconnectivity in the GE compared to the GNE, with those trajectories showing linear decline in the latter half of the age range. CONCLUSION: These results parallel previous findings showing striatal hypertrophy in children with GE as early as age 6. These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with HD GE, possibly setting the stage for cerebellar compensatory mechanisms.

Developmental Trajectory of Height, Weight, and BMI in Children and Adolescents at Risk for Huntington's Disease: Effect of mHTT on Growth.

BACKGROUND: The gene (Huntingtin or HTT) causing Huntington's disease (HD) is vital for development and is expressed throughout the brain and body lifelong. The mutant form (mHTT) may influence growth and development. OBJECTIVE: To determine the impact of mHTT on human measures of growth, including height, weight, and body mass index (BMI), between child and adolescent carriers of mHTT and control peers. METHODS: Children ages 6-18 years of age (n = 186) at risk for HD were enrolled in the KidsHD study. For research purposes only, genetic testing was performed to classify participants as Gene-Expanded (GE = 78) or as Gene Non-Expanded (GNE = 108). Outcome measures included height, weight, and body mass index (BMI). Mixed models were used to determine if non-linear age trends differed between groups for BMI, height, and weight. RESULTS: Differences were seen in the trajectory of BMI in which the GE group reached a plateau in late adolescence with no further increase, compared with a nearly linear increase in the GNE group. There was a significant sex interaction pattern where GE males were taller than GNE males in adolescence, in the presence of similar weight. In contrast, GE females weighed significantly less than their GNE counterparts in adolescence, in the presence of similar height. CONCLUSION: Measures of growth are abnormal in child and adolescent carriers of mHTT, decades before HD onset. Although further studies are needed for replication, the current findings suggest that developmental aberrations may be systemic and a vital part of disease pathology.

Behavioral Deficits in Juvenile Onset Huntington's Disease.

Reports of behavioral disturbance in Juvenile-Onset Huntington's Disease (JOHD) have been based primarily on qualitative caregiver reports or retrospective medical record reviews. This study aims to quantify differences in behavior in patients with JOHD using informant- and self-report questionnaires. Informants of 21 children/young adults (12 female) with JOHD and 115 children/young adults (64 female) with a family history of Huntington's Disease, but who did not inherit the disease themselves (Gene-Non-Expanded; GNE) completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Pediatric Behavior Scale (PBS). Mixed linear regression models (age/sex adjusted) were conducted to assess group differences on these measures. The JOHD group had significantly higher scores, indicating more problems, than the GNE group on all BRIEF subscales, and measures of Aggression/Opposition and Hyperactivity/Inattention of the PBS (all p < 0.05). There were no group differences in Depression/Anxiety. Inhibit, Plan/Organize, Initiate, and Aggression/Opposition had significant negative correlations with Cytosine-Adenine-Guanine (CAG) repeat length (all p < 0.05) meaning that individuals with higher CAG repeats scored lower on these measures. There was greater discrepancy between higher informant-vs. lower self-reported scores in the JOHD group, supporting the notion of lack of insight for the JOHD-affected group. These results provide quantitative evidence of behavioral characteristics of JOHD.

Brain structure in juvenile-onset Huntington disease.

OBJECTIVE: To assess brain morphometry in a sample of patients with juvenile-onset Huntington disease (JOHD) and several mouse models of Huntington disease (HD) that likely represent the human JOHD phenotype. METHODS: Despite sharing the mutation in the Huntingtin gene, adult-onset HD characteristically presents as a hyperkinetic motor disorder, while JOHD typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolls individuals 5 to 25 years of age who have already received the clinical diagnosis. A total of 19 children with juvenile HD (JHD) (mean CAG = 72) were studied. Patients with JHD were compared to healthy controls (n = 234) using a cross-sectional study design. Volumetric data from structural MRI was compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, HdhQ250 HD mice models. RESULTS: Participants with JHD had substantially reduced intracranial volumes. After controlling for the small intracranial volume size, the volumes of subcortical regions (caudate, putamen, globus pallidus, and thalamus) and of cortical white matter were significantly decreased in patients with JHD. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and a higher volume of cerebellum, mirroring the human MRI results. CONCLUSIONS: The primary pathology of JOHD extends beyond changes in the striatal volume. Brain morphology in both mice and human patients with JHD shows proportional cerebellar enlargement. This pattern of brain changes may explain the unique picture of hypokinetic motor symptoms in JHD, which is not seen in the hyperkinetic chorea-like phenotype of adult-onset HD.

Abnormal brain development in child and adolescent carriers of mutant huntingtin.

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.

Basic helix-loop-helix transcription factor NEUROG1 and schizophrenia: effects on illness susceptibility, MRI brain morphometry and cognitive abilities.

Transcription factors, including the basic helix-loop-helix (bHLH) family, regulate numerous genes and play vital roles in controlling gene expression. Consequently, transcription factor mutations can lead to phenotypic pleiotropy, and may be a candidate mechanism underlying the complex genetics and heterogeneous phenotype of schizophrenia. Neurogenin1 (NEUROG1; a.k.a. Ngn1 or Neurod3), a bHLH transcription factor encoded on a known schizophrenia linkage region in 5q31.1, induces glutamatergic and suppresses GABAergic neuronal differentiation during embryonic neurodevelopment. The goal of this study is to investigate NEUROG1 effects on schizophrenia risk and on phenotypic features of schizophrenia. We tested 392 patients with schizophrenia or schizoaffective disorder and 226 healthy normal volunteers for association with NEUROG1. Major alleles on two NEUROG1-associated SNPs (rs2344484-C-allele and rs8192558-G-allele) were significantly more prevalent among patients (p

Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism.

CONTEXT: Autism is a heritable neurodevelopmental disorder characterized biologically by enlargement of the head and brain and abnormalities of serotonin neurotransmission. OBJECTIVE: To evaluate whether 5-HTTLPR, a functional promoter polymorphism of the serotonin transporter gene SLC6A4, influences cerebral cortical structure volumes in young male children with autism. DESIGN: Association study of a genetic variant with quantitative traits. SETTING: Autism research centers at the University of North Carolina (UNC), Chapel Hill, and the University of Washington (UW), Seattle. PARTICIPANTS: Forty-four male children, 2 to 4 years old, with autism participating in longitudinal brain magnetic resonance imaging studies. MAIN OUTCOME MEASURES: Cerebral cortical and cerebellar gray and white matter volumes. RESULTS: We found that 5-HTTLPR genotype influenced gray matter volumes of the cerebral cortex (F(2,23) = 7.29, P = .004) and of 3 lobe-based subregions in the UNC sample of 29 children (frontal lobe gray matter: F(2,23) = 6.36, P = .01). The 5-HTTLPR short allele appeared to be additively associated with increasing gray matter volumes, an observation affirmed by tests of linear genotype effects (cortical gray matter: F(1,24) = 14.11, P = .001; frontal lobe gray matter: F(1,24) = 13.20, P = .001). Genotype did not influence cerebellar volumes. Confirmation was pursued by means of the UW sample of 15 children. While effects were not significant in the UW sample alone, the patterns of adjusted means resembled those found in the UNC sample. Positive Cochran-Mantel-Haenszel test results supported the concordance of relationships across the 2 sites, and analyses of covariance of the combined sample that included a site covariate showed significant linear genotype effects on structure volumes (cortical gray matter: F(1,38) = 5.73, P = .02; frontal lobe gray matter: F(1,38) = 11.73, P = .002). Effect sizes of 5-HTTLPR genotype on total cortical and frontal lobe gray matter volumes were 10% and 16%, respectively. CONCLUSION: The SLC6A4 promoter polymorphism 5-HTTLPR influences cerebral cortical gray matter volumes in young male children with autism.

Toward defining schizophrenia as a more useful clinical concept.

Delineating schizophrenia remains elusive despite considerable interest and study for more than a century. During this time, a variety of terms and defining features have been ascribed to the construct. The predominant contemporary construct, for which substantial limitations persist, has changed little in the past 30 years. With the approaching arrival of the DSM-V, interest in the nosology of schizophrenia has rebounded. Recent publications have focused principally on the following: integrating dimensional approaches to diagnosis, subtypes of schizophrenia, endophenotypes, and identifying those at early risk as part of a staging process. Some have even suggested replacing the term. Although an etiopathic diagnosis remains out of reach, contemporary research is marching down several distinct paths toward defining schizophrenia as a construct of greater clinical utility.

Effect of Trinucleotide Repeats in the Huntington's Gene on Intelligence.

BACKGROUND: Huntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58. METHODS: We evaluated brain function in children ages 6-18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. Linear regression was used to determine if number of CAG repeats predicted measures of brain function. FINDINGS: The number of repeats in HTT, had a non-linear effect on a measure of general intelligence with an inverted U shape pattern. Increasing repeat length was associated with higher GAI scores up until roughly 40-41 repeats. After this peak, increasing repeat length was associated with declining GAI scores. INTERPRETATION: HTT may confer an advantage or a disadvantage depending upon the repeat length, playing a key role in the determination of intelligence, or causing a uniquely human brain disease.

A survey-based study identifies common but unrecognized symptoms in a large series of juvenile Huntington's disease.

AIM: The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics. MATERIALS & METHODS: A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. RESULTS: A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%). CONCLUSION: Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.