Callosal agenesis and congenital mirror movements: outcomes associated with DCC mutations.

Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability. WHAT THIS PAPER ADDS: Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum. A DCC pathogenic variant in isolation is associated with the best prognosis.

Language Skills in Children Born Preterm (<30 Wks' Gestation) Throughout Childhood: Associations With Biological and Socioenvironmental Factors.

OBJECTIVE: To examine the individual and collective contribution of biological and socioenvironmental factors associated with language function at 2, 5, 7, and 13 years in children born preterm (<30 weeks' gestation or <1250 g birth weight). METHODS: Language function was assessed as part of a prospective longitudinal study of 224 children born preterm at 2, 5, 7, and 13 years using age-appropriate tools. Language Z-scores were generated based on a contemporaneous term-born control group. A selection of biological factors (sex, small for gestational age, bronchopulmonary dysplasia, infection, and qualitatively defined brain injury) and early socioenvironmental factors at age 2 years (primary income earner employment status and type, primary caregiver education level, English as a second language, parental mental health history, parent sensitivity and facilitation, and parent-child synchrony) was chosen a priori. Associations were assessed using univariable and multivariable linear regression models applied to outcomes at each time point. RESULTS: Higher primary caregiver education level, greater parent-child synchrony, and parent sensitivity were independently associated with better language function across childhood. Socioenvironmental factors together explained an increasing percentage of the variance (9%-18%) in language function from 2 to 13 years of age. In comparison, there was little evidence for associations between biological factors and language function, even during early childhood years. CONCLUSION: This study highlights the importance of socioenvironmental factors over biological factors for language development throughout childhood. Some of these socioenvironmental factors are potentially modifiable, and parent-based interventions addressing parenting practices and education may benefit preterm children's language development.

DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.

Neurodevelopmental outcomes in infants and children with single-suture craniosynostosis: a systematic review.

Children with single-suture craniosynostosis (SSC) are increasingly considered to be at high risk of adverse neurodevelopmental outcomes. This systematic review aimed to synthesise and critically appraise the existing literature on the neurodevelopmental features of SSC, with particular attention to methodological quality. A total of 33 articles based on 27 cohorts met inclusion criteria. In the context of variable methodological design and quality, most neurodevelopmental studies indicated that children with SSC are at increased risk for difficulties in cognitive, language, and motor domains during infancy (both pre- and post-surgery) and childhood. Limited information exists on factors influencing outcome.

Attention and social functioning in children with malformations of cortical development and stroke.

Attention and social functioning and their interrelationships have not been routinely examined in children with early brain insult (EBI). This study aimed to describe attention and social functioning in children with two types of EBI: malformations of cortical development (MCD) and stroke. Children diagnosed with MCD (n = 14, 6 males) or stroke (n = 14, 8 males) aged 8 to 14 years (M = 12 years 11 months) completed neuropsychological assessments to examine attention processes. Primary caregivers completed a questionnaire to assess executive components of children's attention and teachers completed a questionnaire to measure children's social functioning. Brain scans (MRI or CT) were coded by a pediatric neuroradiologist. Higher rates of impairments in attention and social function were found in children with EBI compared with normative expectations. Children with MCD experienced more global and clinically significant levels of impairment than children with stroke; though impairments were present in both groups. A strong association between executive components of attention and social function was observed. In addition, complex attention processes were associated with social function. The findings emphasize the reciprocity between attention, behavior and social outcomes, and the vulnerability of social function following EBI.

Attention problems in a representative sample of extremely preterm/extremely low birth weight children.

The aim of this study was to examine attention in a large, representative, contemporary cohort of children born extremely preterm (EP) and/or extremely low birth weight (ELBW). Participants included 189 of 201 surviving children born EP (<28 weeks' gestation) or ELBW (<1,000 g) in 1997 in the state of Victoria, Australia. A comparison group of 173 of 199 children born full term and normal birth weight (FT/NBW) were randomly selected matching for birth hospital, expected due date, gender, mother's country of birth, and health insurance status. Participants were assessed at 8 years of age on subtests from the Test of Everyday Attention for Children (TEA-Ch) and the Wechsler Intelligence Scale for Children-4th Edition (WISC-IV). Measures of selective attention, sustained attention, attention encoding, and executive attention (inhibition, shifting attention, and divided attention) were administered. To assess behavioral elements of inattention, the primary caregiver completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Conners' ADHD/DSM-IV Scale (CADS-P). The EP/ELBW group performed more poorly across all cognitive and behavioral measures than the FT/NBW group, with the exception of inhibition. The EP/ELBW group also had significantly elevated rates of impairment in selective, sustained, shifting and divided attention, as well as attention deficit hyperactivity disorder (ADHD) symptoms. No significant gender or gradient effects (e.g., <26 weeks' gestation vs. ≥ 26 weeks' gestation) were identified. Neonatal medical factors were not strong predictors of attention, although necrotizing enterocolitis (NEC) and cystic periventricular leukomalacia (PVL) were independent predictors of selective attention. In conclusion, our comprehensive assessment of attention provides strong evidence that children born EP/ELBW are at increased risk for attentional impairments, and as such, this population should be monitored closely during early and middle childhood with a focus on attention functioning.