Self-concept and academic achievement in children with chronic kidney disease.

BACKGROUND: Within the pediatric population, a positive self-concept is associated with better academic achievement. Children with chronic kidney disease (CKD) are at risk for lower quality of life and academic underachievement. Little is known about self-concept among children with CKD and how self-concept influences academic achievement. The objectives of the present study were to (1) describe patient-reported self-concept among children with CKD and (2) evaluate the relationship between self-concept and academic performance. METHODS: This cross-sectional study included 23 children, aged 6-16 years, with mild to moderate CKD (cause of disease due to congenital anomalies of the kidney and urinary tract) and 26 age-matched comparators. Participants completed the Self-Description Questionnaire (SDQ) and the Wide Range Achievement Test (WRAT-4). Linear regression models were used to evaluate self-concept as a predictor of academic achievement in the CKD cohort. RESULTS: Self-concept ratings were comparable between children with CKD and non-CKD comparators; however, academic achievement trended lower for the CKD patients on measures of arithmetic (estimate = - 0.278, 95% confidence interval (CI) [- 0.530: - 0.026], t(45) = - 1.99, p = 0.053). All of the SDQ domains predicted WRAT-4 arithmetic performance, such that higher scores on the SDQ were associated with higher scores in mathematics. Kidney function did not have an effect on the relationship between self-concept and academic achievement. CONCLUSIONS: Despite the presence of a chronic disease, children with CKD endorse a positive self-concept. Positive self-concept may predict academic success in this population.

Screening for Academic Risk Among Students With Cleft Lip and/or Palate: Patterns of Risk and Qualities of Effective Tools.

This study evaluated the effectiveness of academic screening measures in relation to parent-reported diagnoses.Multicenter, retrospective cohort study including structured interviews, questionnaires, and chart reviews.Six North American cleft centers.Children (n = 391) with cleft lip and/or palate, ages 8 to 10 years of age (192 male) and their guardians were recruited during regular clinic visits.Parent and child ratings on the Pediatric Quality of Life Inventory (PedsQL) School Scale, child report on CleftQ School Scale, parent report on the Adaptive Behavior Assessment System-Third Edition Functional Academics (ABAS-FA) Scale and Child Behavior Checklist (CBCL) School Competency Scale, parent interview, and medical chart review.Risk for concerns ranged from 12% to 41%, with higher risk reflected on the CBCL-SC compared to other measures. Males with cleft palate were consistently at the highest risk. Only 9% of the sample had a parent-reported diagnosis of a learning or language disability. Ratings from the ABAS-FA and CBCL-SC had the highest utility in identifying those with language and/or learning concerns.As cleft teams work to develop standardized batteries for screening and monitoring of patients, it is important to evaluate the effectiveness of measures in identifying those at highest risk. When screening for language and learning disorders, questions related to potential academic struggles, such as increased school effort or increased school distress, are most useful. Referrals for follow-up evaluation are recommended for those identified at high risk.

Psychosocial Outcomes in Children with Cleft Lip and/or Palate: Associations of Demographic, Cleft Morphologic, and Treatment-Related Variables.

OBJECTIVE: To determine associations of demographic, morphologic, and treatment protocol parameters with quality of life (QoL), appearance/speech satisfaction, and psychological adjustment. DESIGN: Observational study utilizing retrospective report of protocol variables and current outcome variables. SETTING: Six North American cleft treatment clinics. PARTICIPANTS: Children, ages 8.0-10.99 years, with Cleft Lip ± Alveolus, Cleft Palate, Cleft Lip and Palate, and parents (N = 284). OUTCOME MEASURES: Pediatric QoL Inventory (PedsQL): Parent, Child, Family Impact Module (FIM); Patient Reported Outcome Measurement Information System (PROMIS); Child Behavior Checklist (CBCL); CLEFT-Q. RESULTS: Outcome scores were average with few differences by cleft type. Multiple regression analyses yielded significant associations (Ps < .05) between socioeconomic status, race, and age at assessment and parent- and self-reported measures. Females had higher PROMIS Depression (ß=.20) but lower CBCL Affective (ß = -.16) and PROMIS Stigma scores (ß= -.24). Incomplete cleft lip was associated with lower PROMIS Depression, and more positive ratings of CLEFT-Q: Nose, Nostril, Lip Scar; CBCL Competence scores, (ßs = -.17 to .17). Younger Age at Lip Closure was associated with higher CBCL School Competence (ß= -.18). Younger Age at Palate Closure was associated with higher Child PedsQL Total, Physical, Psychosocial QoL, and better CLEFT-Q Speech Function (ßs = -.18 to -.15). Furlow Palatoplasty was associated with more CBCL Externalizing Problems (ß = .17) higher CBCL Activities (ß = .16). For all diagnoses, fewer Total Cleft-Related Surgeries was associated with lower PROMIS Stigma and higher CBCL Total Competence and Activities (ßs = -.16 to .15). CONCLUSIONS: Demographic characteristics, lip morphology, and treatment variables are related to later psychological functioning.

Using fNIRS to evaluate ADHD medication effects on neuronal activity: A systematic literature review.

Background: Functional near infrared spectroscopy (fNIRS) is a relatively non-invasive and inexpensive functional neuroimaging technique that has shown promise as a method for understanding the differences in neuronal activity associated with various neurodevelopmental conditions, including ADHD. Additionally, fNIRS has been suggested as a possible tool to understand the impact of psychotropic medications on brain activity in individuals with ADHD, but this approach is still in its infancy. Objective: The purpose of this systematic literature review was to synthesize the extant research literature on the use of fNIRS to assess the effects of ADHD medications on brain activity in children and adolescents with ADHD. Methods: A literature search following Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses (PRISMA) guidelines was conducted for peer-reviewed articles related to ADHD, medication, and fNIRS in PsychInfo, Scopus, and PubMed electronic databases. Results: The search yielded 23 published studies meeting inclusion criteria. There was a high degree of heterogeneity in terms of the research methodology and procedures, which is explained in part by the distinct goals and approaches of the studies reviewed. However, there was also relative consistency in outcomes among a select group of studies that demonstrated a similar research focus. Conclusion: Although fNIRS has great potential to further our understanding of the effects of ADHD medications on the neuronal activity of children and adolescents with ADHD, the current research base is still relatively small and there are limitations and methodological inconsistencies that should be addressed in future studies.

Neurocognitive deficits may not resolve following pediatric kidney transplantation.

BACKGROUND: Pediatric chronic kidney disease (CKD) patients are at risk for cognitive deficits with worsening disease progression. Limited, existing cross-sectional studies suggest that cognitive deficits may improve following kidney transplantation. We sought to assess cognitive performance in relationship to kidney transplantation and kidney-specific medical variables in a sample of pediatric kidney transplant patients who provided cross-sectional and longitudinal observations. METHODS: A retrospective chart review was conducted in patients who completed pre- and/or post-transplant neurocognitive testing at the University of Iowa from 2015-2021. Cognitive outcomes were investigated with developmentally appropriate, standardized measures. Mixed linear models estimated the impact of transplant status on cognitive function (z-scores). Subsequent post-hoc t-tests on change scores were limited to patients who had provided pre- and post-transplant assessments. RESULTS: Thirty eight patients underwent cognitive assessments: 10 had both pre- and post-transplant cognitive assessments, 11 had pre-transplant assessments only, and 17 had post-transplant data only. Post-transplant status was associated with significantly lower full-scale IQ and slower processing speed compared to pre-transplant status (estimate = -0.32, 95% confidence interval [CI] = -0.52: -0.12; estimate = -0.86, CI = -1.17: -0.55, respectively). Post-hoc analyses confirmed results from the mixed models (FSIQ change score = -0.34, 95% CI = -0.56: -0.12; processing speed change score = -0.98, CI = -1.28: -0.68). Finally, being ≥80 months old at transplant was associated with substantially lower FSIQ compared to being <80 months (estimate = -1.25, 95% CI = -1.94: -0.56). CONCLUSIONS: Our results highlight the importance of monitoring cognitive function following pediatric kidney transplant and identify older transplant age as a risk factor for cognitive deficits.

A Multisite Study Investigating Child and Parent Proxy Reported Quality of Life in Children With Cleft Lip and/or Palate.

This observational, multisite cohort study explored health-related quality of life (HRQoL) in children with cleft lip and/or palate (CL/P), including interrater agreement and ratings for this group relative to clinical cutoff scores and published means for healthy and chronically ill children.Participants (338 children ages 8-10 years, 45.9% male and their parents, 82.0% female) across 6 sites completed the Pediatric Quality of Life Inventory Generic Core Scales (PedsQL).Intraclass correlation revealed poor interrater agreement for most HRQoL domains. Although ratings were generally higher than those expected for children with a chronic illness, child ratings were below healthy means for school functioning, and parent proxy ratings were below healthy means for all domains except physical functioning. Lower ratings consistent with chronic illness means were found for self-reported emotional and psychosocial functioning in children with cleft lip and palate (CLP), as well as parent proxy-reported emotional, school, and psychosocial functioning for children with cleft palate (CP). Scores were most likely to be in the clinical range for children with CP for social, school, and total functioning.Although parent proxy report provides important information about observed functioning, poor interrater agreement indicates that both child and parent proxy reported HRQoL should be included in outcomes assessment for CL/P. HRQoL ratings may be higher for children with CL/P compared to youth with other chronic illnesses, but psychosocial functioning may be negatively impacted when compared with healthy youth, particularly for emotional, social, and school functioning in children with CLP or CP.

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.

A preliminary examination of expressive writing in boys with isolated orofacial clefts.

BACKGROUND: Children with isolated cleft of the lip and/or palate (iCL/P) are at a higher risk for language and reading issues. The current pilot study evaluated concurrent writing skills of children with iCL/P compared to unaffected participants with average (uAR) and impaired (uIR) reading. It was hypothesized that children with iCL/P would perform lower than age-expectations. METHODS: Twenty-three males, aged 8-11 years old, were recruited through clinics, local advertisements, and state dyslexia groups (iCL/P = 7, uAR = 8, uIR = 8). Group differences on measures of cognitive processes and writing were evaluated using ANCOVA. Relationships between these measures were compared for each group through Pearson correlations. RESULTS: Participants with iCL/P performed within the average range across all measures; group differences were only found for the uIR group. For those with iCL/P, writing was correlated to global cognitive skills rather than more specific skills. CONCLUSIONS: While this small sample of children with iCL/P demonstrated average writing skills, patterns suggest performance is related to global cognitive reasoning rather than specific cognitive processes as found in unaffected children with impaired reading. Further research is needed to better understand writing in iCL/P and the relationship to reading and cognitive processes. IMPACT: Research in children with isolated cleft of the lip and/or palate (iCL/P) has demonstrated higher rates of language and reading disorders. No work has assessed written expression in children with iCL/P in over 40 years. This study is the first to evaluate elements of written expression and associated cognitive processes among children with iCL/P in comparison to unaffected children with either average or impaired reading skills. Measures of writing were within the average range for children with iCL/P and demonstrated correlation to global cognitive reasoning rather than to specific cognitive processes as found in unaffected children with impaired reading.

Characterizing academic performance in pediatric acute lymphoblastic leukemia with population-based achievement tests.

BACKGROUND: Recent shifts from radiation to chemotherapy-based treatment for acute lymphoblastic leukemia (ALL) have contributed to reduced long-term morbidity. Despite this, ALL survivors remain at increased risk for long-term cognitive impairments. AIM: To identify demographic and treatment factors associated with school performance in pediatric survivors of ALL. METHODS: We collected standardized test scores for reading, math, and science obtained in a school setting from grades 3-11 in 63 ALL survivors (46.0% boys). Most participants were assessed across multiple grades (median number of grades n = 5, range 1-7), and 269 observations were considered in the analyses. Treatment exposures were extracted from medical records. Socio-economic status was estimated using participation in free/reduced lunch programs at school. Mixed effects linear regression models were conducted to determine factors associated with school performance. RESULTS: ALL survivors' scores were comparable to state norms on reading, math, and science performances. On multivariable analysis, participation in free/reduced lunch programs was significantly associated with lower reading scores (ß = -12.52; 95% CI -22.26:-2.77, p = .01). Exposure to radiation during treatment was also associated with lower reading test scores (ß = -30.81, 95% CI -52.00:-9.62, p = .01). No significant associations between demographics and treatment parameters were observed for math and science test scores. CONCLUSIONS: We utilized population-based achievement tests conducted from grades 3-11 to characterize school performance in ALL survivors. Our results imply that survivors with low socio-economic status and those exposed to radiation during treatment could benefit from early monitoring and intervention to maximize academic success.

Sex Differences in the Association of Pretransfusion Hemoglobin Levels with Brain Structure and Function in the Preterm Infant.

OBJECTIVE: To assess sex-specific differences in early brain structure and function of preterm infants after red blood cell (RBC) transfusions. STUDY DESIGN: A single-center subset of infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled from the National Institute of Child Health and Human Development's Neonatal Research Network Transfusion of Prematures Trial. Hemoglobin (Hb) concentration obtained directly before each transfusion (pretransfusion Hb [ptHb]) was obtained longitudinally throughout each infant's neonatal intensive care unit stay and used as a marker of degree of anemia (n = 97). Measures of regional brain volumes using magnetic resonance imaging were obtained at ∼40 weeks postmenstrual age or at hospital discharge, if earlier (n = 29). Measures of brain function were obtained at 12 months corrected age using the Bayley Scales of Infant & Toddler Development, 3rd Edition (n = 34). RESULTS: PtHb was positively correlated with neonatal cerebral white matter volume in males (B = +0.283; P = .006), but not females (B = -0.099; P = .713), resulting in a significant sex interaction (P = .010). Bayley-III gross motor scores and a pooled mean score were significantly lower in association with higher ptHb in females (gross motor score: B = -3.758; P = .013; pooled mean score: B = -1.225; P = .030), but not males (gross motor score: B = +1.758; P = .167; pooled mean score: B = +0.621; P = .359). Higher ptHb was associated with descriptively lower performance on multiple Bayley-III subscales in females, but not in males. CONCLUSIONS: This study demonstrates sex-specific associations between an early marker of anemia and RBC transfusion status (ie, ptHb) with both neonatal white matter volume and early cognitive function at age 12 months in preterm infants.

Brain Developmental Trajectories in Children and Young Adults with Isolated Cleft Lip and/or Cleft Palate.

The present study evaluated brain development in persons with isolated cleft lip and/or cleft palate (iCL/P) compared to unaffected controls using an accelerated longitudinal design. A sample of 134 males and females, ages 7-27 years, with iCL/P (184 observations, total) was compared to 144 unaffected controls (208 evaluations, total) on Wechsler Index scores and volumetric data from structural MRI scans. Boys with isolated cleft palate had verbal IQ 15.5 points lower than perceptual IQ; a clinically significant difference. Participants with iCL/P had differential growth trajectories of regional cerebrum matter and consistently lower volumes of cerebellar gray matter and subcortical matter.

Age-Related Cognitive Changes as a Function of CAG Repeat in Child and Adolescent Carriers of Mutant Huntingtin.

Limited data exists regarding the disease course of Huntington's Disease (HD) in children and young adults. Here, we evaluate the trajectory of various cognitive skill development as a function of cytosine-adenine-guanine (CAG) repeat length in children and adolescents that carry the mutation that causes HD. We discovered that the development of verbal skills seems to plateau earlier as CAG repeat length increases. These findings increase our understanding of the relationship between neurodegeneration and neurodevelopment and may have far-reaching implications for future gene-therapy treatment strategies. ANN NEUROL 2021;89:1036-1040.

Long-term outcome of brain structure in female preterm infants: possible associations of liberal versus restrictive red blood cell transfusions.

BACKGROUND: Preterm infants who receive differential red blood cell (RBC) transfusions at birth may show brain structure differences across development, including abnormalities in white matter (WM) structure and organization. This study investigated long-term outcomes of brain structure in female infants born preterm, at an average age of 13 years old, who received red blood cell (RBC) transfusions in the neonatal period according to a liberal or restrictive approach. Results from this study will increase understanding of the effects of transfusion on the developing brain. STUDY DESIGN AND METHODS: This follow-up study included female preterm infants who participated in a clinical trial and had been randomized at birth to either a liberal or restrictive hematocrit threshold. Brain structures were measured in childhood using structural magnetic resonance imaging (MRI) scans. Due to the low number of females in the restrictive transfusion group at follow-up, additional females were recruited for inclusion. Main outcome measures included cerebral and subcortical brain region volumes. RESULTS: Total intracranial volume was significantly decreased in females who were randomized to higher average hematocrit levels at birth. Infants in the liberal transfusion group had proportionately smaller volumes in all measures of regional cerebral WM and subcortical brain volumes, reaching significance for temporal lobe WM and caudate volumes. CONCLUSION: Female premature infants who received a liberal transfusion threshold at birth had decreased WM volumes, which suggests the potential long-term neurodevelopmental risks associated with liberal transfusion practices.

Early pediatric chronic kidney disease is associated with brain volumetric gray matter abnormalities.

BACKGROUND: The impact of pediatric chronic kidney disease (pCKD) on the brain remains poorly defined. The objective of this study was to compare brain morphometry between children with early-stage pCKD and typically developing peers using structural magnetic resonance imaging (MRI). METHODS: The sample age range was 6-16 years. A total of 18 children with a diagnosis of pCKD (CKD stages 1-3) due to congenital anomalies of the kidney and urinary tract and 24 typically developing peers were included. Volumetric data from MRI and neurocognitive testing were compared using linear models including pCKD status, age, maternal education level, and socioeconomic status. RESULTS: Cerebellar gray matter volume was significantly smaller in pCKD, t(38) = -2.71, p = 0.01. In contrast, cerebral gray matter volume was increased in pCKD, t(38) = 2.08, p = 0.04. Reduced cerebellum gray matter volume was associated with disease severity, operationalized as estimated glomerular filtration rate (eGFR), t(14) = 2.21, p = 0.04 and predicted lower verbal fluency scores in the pCKD sample. Enlarged cerebral gray matter in the pCKD sample predicted lower scores on mathematics assessment. CONCLUSIONS: This study provides preliminary evidence for a morphometric underpinning to the cognitive deficits observed in pCKD. IMPACT: The impact of pediatric chronic kidney disease (CKD) on the brain remains poorly defined, with no data linking brain morphometry and observed cognitive deficits noted in this population. We explored the relationship between brain morphometry (using structural magnetic resonance imaging), cognition, and markers of CKD. Cerebellar and cerebral gray matter volumes are different in early CKD. Volumetric decreases in cerebellar gray matter are predicted by lower eGFR, suggesting a link between disease and brain morphometry. Reduced cerebellar gray matter predicted lower verbal fluency for those with pCKD. Enlarged cerebral gray matter in the pCKD sample predicted lower mathematics performance.

Preliminary evaluation of pre-speech and neurodevelopmental measures in 7-11-week-old infants with isolated oral clefts.

BACKGROUND: The purpose of this research study was to evaluate the earliest markers of vocal functioning and neurological development in infants with isolated oral cleft of the lip and/or palate (iCL/P). METHODS: Participants were recruited through advertisements and clinic visits at a local mid-western university. A total of eight participants (four unaffected and four with iCL/P), ranging in age from 7.29 to 11.57 weeks, were enrolled and completed demographic and pre-speech measures. A subset of six males (four unaffected and two with iCL/P) successfully completed a structural magnetic resonance imaging scan. RESULTS: Patterns of disrupted vocal control and reduced myelinated white matter were found in participants with iCL/P. CONCLUSIONS: The findings of this study provide a foundation from which to build further research on the neuronal development of infants with oral clefts: the need to evaluate measures of cortical development, inclusion of information on anesthesia exposure and airway obstruction, and suggestions for avoiding identified pitfalls/blocks to obtaining data are discussed. IMPACT: Research in children with isolated oral clefts has demonstrated higher rates of learning disorders connected to subtle differences in brain structure. There is no work evaluating the potential impact of exposure to anesthesia on development. This is the first known attempt to evaluate brain structure and function in infants with isolated oral clefts before exposure to anesthesia. Potential trends of early vocal issues and structural brain differences (less myelinated white matter) were identified in infants with isolated oral clefts compared to unaffected controls. Differences in brain structure and function in infants with isolated oral clefts may be present before surgery.

Retrospective Evaluation of Number of Surgeries and Parent Ratings of Academic and Behavioral Functioning Among Children With Isolated Oral Clefts.

OBJECTIVE: The purpose of this study was to evaluate possible relationships between number of surgeries and parent ratings of academic functioning among children with isolated oral clefts. DESIGN: Multicenter, retrospective cohort study including structured interviews, questionnaires, and chart reviews. SETTING: Completion of questionnaires occurred during clinical visits at 6 different cleft centers across North America. PARTICIPANTS: Parents of 285 children with isolated clefts of the lip and/or palate, aged 8 to 10 years old, participated in structured interviews and completed questionnaires regarding the academic and behavioral functioning of their children. MAIN OUTCOME MEASURES: Parent interview and medical chart review of number of surgeries to date and parent ratings on the Adaptive Behavior Assessment System, Third Edition-Functional Academics Scale (ABAS-FA) and Child Behavior Checklist (CBCL) Total Competency Scale. RESULTS: Parent ratings of ABAS-FA were at or above normative expectations, while ratings across CBCL Competency Scales were lower than normative expectations. Socioeconomic status (SES), age, and race were consistent predictors of parent ratings (higher SES, older age, and Caucasian race were associated with better functioning). Number of surgeries did not add significantly to academic ratings but did significantly contribute to ratings of social and activity participation. Patients with more surgeries were rated with lower functioning in these domains. CONCLUSIONS: Findings do not support a connection between number of surgeries and later ratings of academic functioning but do support a connection to social and activity involvement. Recommendations for conducting direct studies of the connection between surgeries and academic functioning as well as clinical considerations for surgeries and impact on social and activity involvement are discussed.

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.

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.