Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.

We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.

Risk Factors Associated With Long-term Feeding Problems in Preterm Infants: A Scoping Review.

BACKGROUND: Infants who are born preterm are at a high risk of encountering feeding problems. PURPOSE: The aim of this scoping review is to identify risk factors associated with feeding problems that persist beyond infancy in children (aged 1-6 years) who were born preterm (<37 weeks' gestation). METHODS: To perform this scoping review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework was applied. To be included in this study, articles had to be published in peer-reviewed journals, had an empirical study design, examined feeding problems relating to the child's feeding ability or refusal to eat certain texture of foods, and assessed risk factors (age, weight, and medical conditions) associated with long-term feeding problems in children who were born preterm. RESULTS: After abstract and full-text screening, a total of 9 articles meeting the inclusion criteria were included in this study. Findings from this study identified that gestational age and birth weight are significant risk factors and that sex, duration of mechanical ventilation, and length of tube feedings are potential risk factors. IMPLICATIONS FOR PRACTICE: This study confirms that younger and smaller infants are at a high risk of encountering oral feeding difficulties and early interventions services should be focused on these preterm infants. IMPLICATIONS FOR RESEARCH: Evaluation of timing and intensity (dose) of early interventions strategies should be investigated to provide more targeted and effective interventions for younger and smaller preterm infants.

Differentiating Motor Coordination in Children with Cerebral Palsy and Typically Developing Populations Through Exploratory Factor Analysis of Robotic Assessments.

General motor and executive functions are integral for tasks of daily living and are typically assessed when quantifying impairment of an individual. Robotic tasks offer highly repeatable and objective measures of motor and cognitive function. Additionally, robotic tasks and measures have been used successfully to quantify impairment of children with cerebral palsy (CP). Many robotic tasks include multiple performance parameters, so interpretation of results and identification of impairment can be difficult, especially when multiple tasks are completed. This study used exploratory factor analysis to investigate a potential set of quantitative models of motor and cognitive function in children, and compare performance of participants with CP to these models. The three calculated factors achieved strong differentiation between participants with mild CP and the typically developing population. This demonstrates the feasibility of these factors to quantify impairment and track improvements related to therapies.Clinical Relevance- This establishes a method to differentiate atypical motor performance related to CP using a robotic reversed visually guided reaching task.

Differentiating Motor Coordination and Position Sense in Children with Cerebral Palsy and Typically Developing Populations Through Robotic Assessments.

Motor function and coordination improve as children age. Robotic assessments of motor function and coordination have been shown to be repeatable, objective, and accurate. Additionally, robotic assessments have been used to measure and quantify deficits in motor function and coordination in children with cerebral palsy (CP). Normative models of motor function and coordination based on age have not been used widely to differentiate impaired performance from typical performance. This study presents preliminary results of identifying deficits in motor function and coordination assessed with a robotic reaching task and using a normative model of typical performance that accounts for age, sex, and handedness. The models were compared with data from three participants with CP to evaluate whether the models could be used to identify deficits in motor function. The models indicated motor deficits in one participant when performing a visually guided reaching task with respect to initial speed and distance ratios. There was no evidence of motor control deficits in the other two participants. Future work will refine the models to be able to better identify and quantify motor control impairments with the potential to target therapy around quantifiable goals.

Navigating health care systems for military-connected children with autism spectrum disorder: A qualitative study of military families experiencing mandatory relocation.

BACKGROUND: Most military families experience mandatory relocation, or posting, several times during the military career. For Canadian military families who must access provincial or territorial health care systems, maintaining reasonable continuity of care is a persistent issue. Such challenges may be amplified when a child in a military family has special needs within the health and educational systems. OBJECTIVE: The purpose of this qualitative study was to gain a better understanding of Canadian Armed Forces families' experiences in navigating health care systems on behalf of a child with autism spectrum disorder (ASD) in the context of mandatory relocation. METHODS: Parents of children with ASD, where at least one parent serves in the Canadian Armed Forces and had faced military-related relocation, were recruited. Semi-structured interviews were recorded, transcribed verbatim, and analyzed thematically. RESULTS: Twelve participants represented 12 families and 15 children with ASD. Participants discussed two primary themes. (1) High mobility inherent in the military lifestyle can create disruptions and discontinuities to service, including delays in diagnosis or intervention, losses and gains in available services determined by the direction of posting, and the need to start health care access processes over again when relocating. (2) Navigating health systems for children with ASD creates personal stress and frustration related to relocating, and has career implications for both parents. CONCLUSIONS: Military-related relocation can create significant disruption in access to health and educational services for Canadian military families who have a child with ASD, and take a personal toll on these families.

De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy.

PurposeHemiplegia is a subtype of cerebral palsy (CP) in which one side of the body is affected. Our earlier study of unselected children with CP demonstrated de novo and clinically relevant rare inherited genomic copy-number variations (CNVs) in 9.6% of participants. Here, we examined the prevalence and types of CNVs specifically in hemiplegic CP.MethodsWe genotyped 97 unrelated probands with hemiplegic CP and their parents. We compared their CNVs to those of 10,851 population controls, in order to identify rare CNVs (<0.1% frequency) that might be relevant to CP. We also sequenced exomes of "CNV-positive" trios.ResultsWe detected de novo CNVs and/or sex chromosome abnormalities in 7/97 (7.2%) of probands, impacting important developmental genes such as GRIK2, LAMA1, DMD, PTPRM, and DIP2C. In 18/97 individuals (18.6%), rare inherited CNVs were found, affecting loci associated with known genomic disorders (17p12, 22q11.21) or involving genes linked to neurodevelopmental disorders.ConclusionWe found an increased rate of de novo CNVs in the hemiplegic CP subtype (7.2%) compared to controls (1%). This result is similar to that for an unselected CP group. Combined with rare inherited CNVs, the genomic data impacts the understanding of the potential etiology of hemiplegic CP in 23/97 (23.7%) of participants.

Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression.

PURPOSE: The purpose of the current study was to assess the penetrance of NRXN1 deletions. METHODS: We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. RESULTS: We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3' end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5' NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035). CONCLUSIONS: The results support the importance of exons near the 5' end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61.

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure.

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level.

Working memory and visuospatial deficits correlate with oculomotor control in children with fetal alcohol spectrum disorder.

Previous studies have demonstrated that children with Fetal Alcohol Spectrum Disorder (FASD) exhibit deficits in measures of eye movement control that probe aspects of visuospatial processing and working memory. The goal of the present study was to examine, in a large cohort of children with FASD, prenatal alcohol exposure (PAE) but not FASD, and typically developing control children, the relationship between performance in eye movement tasks and standardized psychometric tests that assess visuospatial processing and working memory. Participants for this dataset were drawn from a large, multi-site investigation, and included children and adolescents aged 5-17 years diagnosed with an FASD (n=71), those with PAE but no clinical FASD diagnosis (n=20), and typically developing controls (n=111). Participants completed a neurobehavioral test battery and a series of saccadic eye movement tasks. The FASD group performed worse than controls on the psychometric and eye movement measures of working memory and visuospatial skills. Within the FASD group, digit recall, block recall, and animal sorting were negatively correlated with sequence errors on the memory-guided task, and arrows was negatively correlated with prosaccade endpoint error. There were no significant correlations in the control group. These data suggest that psychometric tests and eye movement control tasks may assess similar domains of cognitive function, and these assessment tools may be measuring overlapping brain regions damaged due to prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests and are able to assess multiple domains of cognition simultaneously, thereby allowing for an efficient and accurate assessment.

Deficits in response inhibition correlate with oculomotor control in children with fetal alcohol spectrum disorder and prenatal alcohol exposure.

Children with fetal alcohol spectrum disorder (FASD) or prenatal alcohol exposure (PAE) frequently exhibit impairment on tasks measuring inhibition. The objective of this study was to determine if a performance-based relationship exists between psychometric tests and eye movement tasks in children with FASD. Participants for this dataset were aged 5-17 years and included those diagnosed with an FASD (n=72), those with PAE but no clinical FASD diagnosis (n=21), and typically developing controls (n=139). Participants completed a neurobehavioral test battery, which included the NEPSY-II subtests of auditory attention, response set, and inhibition. Each participant completed a series of saccadic eye movement tasks, which included the antisaccade and memory-guided tasks. Both the FASD and the PAE groups performed worse than controls on the subtest measures of attention and inhibition. Compared with controls, the FASD group made more errors on the antisaccade and memory-guided tasks. Among the combined FASD/PAE group, inhibition and switching errors were negatively correlated with direction errors on the antisaccade task but not on the memory-guided task. There were no significant correlations in the control group. These data suggests that response inhibition deficits in children with FASD/PAE are associated with difficulty controlling saccadic eye movements which may point to overlapping brain regions damaged by prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests that are used during FASD diagnosis, and may therefore help with early identification of children who would benefit from a multidisciplinary diagnostic assessment.

The use of complementary and alternative medicine in children with chronic medical conditions.

OBJECTIVES: The objectives of this study were to examine whether progressive medical conditions lead to greater use of complementary and alternative medicine (CAM) as compared with more stable conditions, to see whether disease severity influences CAM use, and to identify the main motivations behind CAM use. METHODS: Subjects were selected from outpatient clinics at Hotel Dieu Hospital. Surveys were conducted by mail and telephone. Medical diagnosis and severity were obtained from medical files. Statistical tests included chi, Kruskal-Wallis, and correlations. RESULTS: One hundred ninety-four children were surveyed. The "progressive" group included 15 patients with Duchenne muscular dystrophy and 22 patients with cystic fibrosis. The "nonprogressive" group included 85 patients with cerebral palsy (CP), 49 with diabetes mellitus, and 23 with spina bifida. Twenty-three percent were using CAM. CP had the highest use; diabetes mellitus had the lowest. Popular therapies included massage and dietary/herbal remedies. Progressiveness had no impact on CAM use. Within the CP group, greater disease severity was associated with higher use (P < 0.001). The main reason for CAM use was to complement conventional medicine. CONCLUSIONS: Disease progressiveness had no impact on CAM use, but severity within the CP group did. Complementing conventional medicine was the main motive. Understanding the reasons and patterns of use of CAM is beneficial in efforts to improve the care of children with chronic medical conditions.