Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes.

Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.

DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation.

Corpus callosum dysgenesis (CCD) is a congenital disorder that incorporates either partial or complete absence of the largest cerebral commissure. Remodelling of the interhemispheric fissure (IHF) provides a substrate for callosal axons to cross between hemispheres, and its failure is the main cause of complete CCD. However, it is unclear whether defects in this process could give rise to the heterogeneity of expressivity and phenotypes seen in human cases of CCD. We identify incomplete IHF remodelling as the key structural correlate for the range of callosal abnormalities in inbred and outcrossed BTBR mouse strains, as well as in humans with partial CCD. We identify an eight base-pair deletion in Draxin and misregulated astroglial and leptomeningeal proliferation as genetic and cellular factors for variable IHF remodelling and CCD in BTBR strains. These findings support a model where genetic events determine corpus callosum structure by influencing leptomeningeal-astroglial interactions at the IHF.

DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation.

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice.

Post-zygotic mutations that generate tissue mosaicism are increasingly associated with severe congenital defects, including those arising from failed neural tube closure. Here we report that neural fold elevation during mouse spinal neurulation is vulnerable to deletion of the VANGL planar cell polarity protein 2 (Vangl2) gene in as few as 16% of neuroepithelial cells. Vangl2-deleted cells are typically dispersed throughout the neuroepithelium, and each non-autonomously prevents apical constriction by an average of five Vangl2-replete neighbours. This inhibition of apical constriction involves diminished myosin-II localisation on neighbour cell borders and shortening of basally-extending microtubule tails, which are known to facilitate apical constriction. Vangl2-deleted neuroepithelial cells themselves continue to apically constrict and preferentially recruit myosin-II to their apical cell cortex rather than to apical cap localisations. Such non-autonomous effects can explain how post-zygotic mutations affecting a minority of cells can cause catastrophic failure of morphogenesis leading to clinically important birth defects.

Altered structural connectivity networks in a mouse model of complete and partial dysgenesis of the corpus callosum.

Corpus callosum dysgenesis (CCD) describes a collection of brain malformations in which the main fiber tract connecting the two hemispheres is either absent (complete CCD, or 'agenesis of the corpus callosum') or reduced in size (partial CCD). Humans with these neurodevelopmental disorders have a wide range of cognitive outcomes, including seemingly preserved features of interhemispheric communication in some cases. However, the structural substrates that could underlie this variability in outcome remain to be fully elucidated. Here, for the first time, we characterize the global brain connectivity of a mouse model of complete and partial CCD. We demonstrate features of structural brain connectivity that model those predicted in humans with CCD, including Probst bundles in complete CCD and heterotopic sigmoidal connections in partial CCD. Crucially, we also histologically validate the recently predicted ectopic sigmoid bundle present in humans with partial CCD, validating the utility of this mouse model for fine anatomical studies of this disorder. Taken together, this work describes a mouse model of altered structural connectivity in variable severity CCD and forms a foundation for future studies investigating the function and mechanisms of development of plastic tracts in developmental disorders of brain connectivity.

NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly.

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

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).

Astroglial-mediated remodeling of the interhemispheric midline during telencephalic development is exclusive to eutherian mammals.

The corpus callosum forms the major interhemispheric connection in the human brain and is unique to eutherian (or placental) mammals. The developmental events associated with the evolutionary emergence of this structure, however, remain poorly understood. A key step in callosal formation is the prior remodeling of the interhemispheric fissure by embryonic astroglial cells, which then subsequently act as a permissive substrate for callosal axons, enabling them to cross the interhemispheric midline. However, whether astroglial-mediated interhemispheric remodeling is unique to eutherian mammals, and thus possibly associated with the phylogenetic origin of the corpus callosum, or instead is a general feature of mammalian brain development, is not yet known. To investigate this, we performed a comparative analysis of interhemispheric remodeling in eutherian and non-eutherian mammals, whose lineages branched off before the evolution of the corpus callosum. Whole brain MRI analyses revealed that the interhemispheric fissure is retained into adulthood in marsupials and monotremes, in contrast to eutherians (mice), in which the fissure is significantly remodeled throughout development. Histological analyses further demonstrated that, while midline astroglia are present in developing marsupials, these cells do not intercalate with one another through the intervening interhemispheric fissure, as they do in developing mice. Thus, developing marsupials do not undergo astroglial-mediated interhemispheric remodeling. As remodeling of the interhemispheric fissure is essential for the subsequent formation of the corpus callosum in eutherians, our data highlight the role of astroglial-mediated interhemispheric remodeling in the evolutionary origin of the corpus callosum.

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.

Altered structural connectome in adolescent socially isolated mice.

Social experience is essential for adolescent development and plasticity of social animals. Deprivation of the experience by social isolation impairs white matter microstructures in the prefrontal cortex. However, the effect of social isolation may involve highly distributed brain networks, and therefore cannot be fully explained by a change of a single region. Here, we compared the connectomes of adolescent socially-isolated mice and normal-housed controls via diffusion magnetic resonance imaging. The isolated mice displayed an abnormal connectome, characterized by an increase in degree and reductions in measures such as modularity, small-worldness, and betweenness. The increase in degree was most evident in the dorsolateral orbitofrontal cortex, entorhinal cortex, and perirhinal cortex. In a connection-wise comparison, we revealed that most of the abnormal edges were inter-modular and inter-hemispheric connections of the dorsolateral orbitofrontal cortex. Further tractography-based analyses and histological examinations revealed microstructural changes in the forceps minor and lateral-cortical tracts that were associated with the dorsolateral orbitofrontal cortex. These changes of connectomes were correlated with fear memory deficits and hyper-locomotion activities induced by social isolation. Considering the key role of the orbitofrontal cortex in social behaviors, adolescent social isolation may primarily disrupt the orbitofrontal cortex and its neural pathways thereby contributing to an abnormal structural connectome.

EMX1 regulates NRP1-mediated wiring of the mouse anterior cingulate cortex.

Transcription factors act during cortical development as master regulatory genes that specify cortical arealization and cellular identities. Although numerous transcription factors have been identified as being crucial for cortical development, little is known about their downstream targets and how they mediate the emergence of specific neuronal connections via selective axon guidance. The EMX transcription factors are essential for early patterning of the cerebral cortex, but whether EMX1 mediates interhemispheric connectivity by controlling corpus callosum formation remains unclear. Here, we demonstrate that in mice on the C57Bl/6 background EMX1 plays an essential role in the midline crossing of an axonal subpopulation of the corpus callosum derived from the anterior cingulate cortex. In the absence of EMX1, cingulate axons display reduced expression of the axon guidance receptor NRP1 and form aberrant axonal bundles within the rostral corpus callosum. EMX1 also functions as a transcriptional activator of Nrp1 expression in vitro, and overexpression of this protein in Emx1 knockout mice rescues the midline-crossing phenotype. These findings reveal a novel role for the EMX1 transcription factor in establishing cortical connectivity by regulating the interhemispheric wiring of a subpopulation of neurons within the mouse anterior cingulate cortex.

Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes.

The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.

Determinants of patient satisfaction during receipt of radiation therapy.

PURPOSE: To evaluate the correlations and relative contributions of components of a radiation oncology-specific patient satisfaction survey to their overall satisfaction scores. METHODS AND MATERIALS: From September 2006 through August 2012, we prospectively collected data from 8069 patients receiving radiation treatments with a 26-question survey. Each question was rated on a 10-point Likert scale. We analyzed the correlation between scores for each question and the overall satisfaction question. We also dichotomized the scores to reflect satisfaction versus dissatisfaction and used logistic regression to assess the relationship between items in 4 domains (the patient-provider relationship, access and environmental issues, wait times, and educational information) and overall satisfaction. RESULTS: Scores on all questions correlated with overall patient satisfaction scores (P<.0001). Satisfaction with patient-provider relationships had the greatest influence on overall satisfaction (R(2)=0.4219), followed by wait times (R(2)=0.4000), access/environment (R(2)=0.3837), and patient education (R(2)=0.3700). The specific variables with the greatest effect on patient satisfaction were the care provided by radiation therapists (odds ratio 1.91) and pain management (odds ratio 1.29). CONCLUSIONS: We found that patients' judgment of provider relationships in an outpatient radiation oncology setting were the greatest contributors to their overall satisfaction ratings. Other measures typically associated with patient satisfaction (phone access, scheduling, and ease of the check-in process) correlated less strongly with overall satisfaction. These findings may be useful for other practices preparing to assess patient ratings of quality of care.