Neurodevelopmental outcome in preterm infants with intraventricular hemorrhages: the potential of quantitative brainstem MRI.

OBJECTIVES: This retrospective study aimed to identify quantitative magnetic resonance imaging markers in the brainstem of preterm neonates with intraventricular hemorrhages. It delves into the intricate associations between quantitative brainstem magnetic resonance imaging metrics and neurodevelopmental outcomes in preterm infants with intraventricular hemorrhage, aiming to elucidate potential relationships and their clinical implications. MATERIALS AND METHODS: Neuroimaging was performed on preterm neonates with intraventricular hemorrhage using a multi-dynamic multi-echo sequence to determine T1 relaxation time, T2 relaxation time, and proton density in specific brainstem regions. Neonatal outcome scores were collected using the Bayley Scales of Infant and Toddler Development. Statistical analysis aimed to explore potential correlations between magnetic resonance imaging metrics and neurodevelopmental outcomes. RESULTS: Sixty preterm neonates (mean gestational age at birth 26.26 ± 2.69 wk; n = 24 [40%] females) were included. The T2 relaxation time of the midbrain exhibited significant positive correlations with cognitive (r = 0.538, P < 0.0001, Pearson's correlation), motor (r = 0.530, P < 0.0001), and language (r = 0.449, P = 0.0008) composite scores at 1 yr of age. CONCLUSION: Quantitative magnetic resonance imaging can provide valuable insights into neurodevelopmental outcomes after intraventricular hemorrhage, potentially aiding in identifying at-risk neonates. Multi-dynamic multi-echo sequence sequences hold promise as an adjunct to conventional sequences, enhancing the sensitivity of neonatal magnetic resonance neuroimaging and supporting clinical decision-making for these vulnerable patients.

Prenatal diagnosis of CLCN4-related neurodevelopmental disorder in fetuses with congenital brain anomalies.

We report two male fetuses born to a healthy unrelated couple, with agenesis of the corpus callosum identified on detailed 20-week ultrasound scans and confirmed by in-utero MRI. Whole-genome sequencing identified a likely pathogenic missense variant in the CLCN4 gene, establishing this as the causative gene in the family. Pathogenic variants in the CLCN4 gene cause a neurodevelopmental disorder (also called Raynaud-Claes syndrome) inherited in an X-linked pattern. The disorder is characterised by developmental delay, intellectual disability, autism spectrum disorder, epilepsy, mental health conditions, and significant feeding difficulties, predominantly, but not exclusively, affecting males. This is the first report of a prenatal phenotype associated with variants in the CLCN4 gene. The diagnosis of the CLCN4-related neurodevelopmental disorder in this family allowed accurate genetic counseling and discussion of reproductive choices. This leaves uncertainty about the possibility of a postnatal neurodevelopmental phenotype in heterozygous females, which we discuss.

Case analysis of epilepsy, neurodevelopmental disorder, and motor disorders associated with mutations in the dehydrodolichyl diphosphate synthase gene.

The objective of this study is to analyze the role of dehydrodolichyl diphosphate synthase (DHDDS), a crucial enzyme in the mevalonate pathway, and its encoded mutations in the onset of developmental delay and seizures, with or without movement abnormalities. Its genotype-phenotype characteristics are still inconclusive. We analyzed the clinical characteristics of epilepsy, and neurodevelopmental and motor disorders related to DHDDS gene mutations and report the genotype-phenotype characteristics of a child with epilepsy caused by DHDDS gene mutation, providing a summary and a statistical analysis of epilepsy cases associated with DHDDS gene mutation up until February 2022. METHODS: Using "DHDDS; epilepsy; neurodevelopmental disorder" as the keywords, the literature relevant to DHDDS gene mutations up until February 2022 was reviewed. A total of 25 cases were retrieved, among which 21 cases with complete data were included in the chi-squared test. The clinical characteristics of DHDDS gene-related cases were summarized and analyzed. RESULTS: The onset of epilepsy caused by mutations of the DHDDS gene typically occurs during infancy. Predominantly, the mutation occurs in the locus of c.632G>A p.R211Q. Myoclonus is frequently the initial manifestation of epilepsy; it frequently coexists with neurodevelopmental disorder and intellectual disability, and patients have no specific type of motor disorder. Cranial magnetic resonance imaging (MRI) reveals no abnormalities, whereas electroencephalogram (EEG) frequently exhibits abnormalities. Valproic acid (VPA) yields good curative effects. CONCLUSION: Mutations in the DHDDS gene are associated with congenital glycosylation disorder, autosomal recessive retinitis pigmentosa, and epilepsy. According to statistical analysis using the chi-squared test, for pediatric patients with mutations in this gene locus, most of the epilepsy types are myoclonic epilepsies with intellectual disability and neurodevelopmental disorders. They have normal brain MRIs and abnormal EEGs. VPA produces beneficial therapeutic results and the differences are all statistically significant. The current diagnosis still relies on next-generation sequencing or whole-exome sequencing.

Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes.

Genomic copy number variants (CNVs) are associated with a high risk of neurodevelopmental disorders. A growing body of genetic studies suggests that these high-risk genetic variants converge in common molecular pathways and that common pathways also exist across clinically distinct disorders, such as schizophrenia and autism spectrum disorder. A key question is how common molecular mechanisms converge into similar clinical outcomes. We review emerging evidence for convergent cognitive and brain phenotypes across distinct CNVs. Multiple CNVs were shown to have similar effects on core sensory, cognitive, and motor traits. Emerging data from multisite neuroimaging studies have provided valuable information on how these CNVs affect brain structure and function. However, most of these studies examined one CNV at a time, making it difficult to fully understand the proportion of shared brain effects. Recent studies have started to combine neuroimaging data from multiple CNV carriers and identified similar brain effects across CNVs. Some early findings also support convergence in CNV animal models. Systems biology, through integration of multilevel data, provides new insights into convergent molecular mechanisms across genetic risk variants (e.g., altered synaptic activity). However, the link between such key molecular mechanisms and convergent psychiatric phenotypes is still unknown. To better understand this link, we need new approaches that integrate human molecular data with neuroimaging, cognitive, and animal model data, while taking into account critical developmental time points. Identifying risk mechanisms across genetic loci can elucidate the pathophysiology of neurodevelopmental disorders and identify new therapeutic targets for cross-disorder applications.

Scoring of brain magnetic resonance imaging and neurodevelopmental outcomes in infants with congenital heart disease.

BACKGROUND: Advances in surgical techniques to tackle critical congenital heart diseases (CHD) have enhanced the survival rates and life expectancy of children born with heart disease. Studies to better acknowledge their neurodevelopmental trajectory have paramount implications. OBJECTIVE: The aim of this study is to examine the nature of brain MRI findings in infants born with critical congenital heart diseases needing intervention in the first 6 months of life, with the help of an MRI scoring system and correlation with long term neurodevelopmental outcomes. METHODS: Brain MRI scans of eligible infants were extracted from database, reexamined to categorize, and score them into three main functional areas: cognitive/grey matter, motor/white matter, and visual. The scoring system also included stage of myelination and presence of punctate hemorrhages. The correlation of individual and total MRI scores with neurodevelopmental assessment using Bayley Scales for Infant and Toddler Development- version 3 (BSID III) were examined via logistic regression models while controlling for confounding variables. RESULT: Median (IQR) MRI score was 6 (4-7) with grey matter score of 2 (1-4). Initial BSID III scores were 80 ± 15, 80 ± 18, and 81 ± 19 for cognitive, motor and language components, respectively. The MRI cognitive score had direct correlation with respiratory index prior to surgery (cc = 0.47, p = 0.03) and cross-clamping time (cc = 0.65, p = 0.001). It displayed a significant inverse correlation with language scores for BSID III at 9 months (R = -0.42, p = 0.04) which lost significance in subsequent visits. CONCLUSION: This pilot study proved the feasibility of correlating structural brain abnormalities in MRI with later brain developmental deficits in infants with CHD. We envision establishing a standardized MRI scoring system to be performed on a large multi-center cohort that would help better predict and measure brain injury in infants with CHDs.

Connectome Analysis in an Individual with SETD1B -Related Neurodevelopmental Disorder and Epilepsy.

OBJECTIVE: Causative variants in SETD1B , encoding a lysine-specific methyltransferase, have recently been associated with a neurodevelopmental phenotype encompassing intellectual disability, autistic features, pronounced language delay, and epilepsy. It has been noted that long-term and deep phenotype data are needed to further delineate this rare condition. METHODS: In this study, we provide an in-depth clinical characterization with long-term follow-up and trio exome sequencing findings to describe one additional individual affected by SETD1B -related disorder. The diagnostic workup was complemented by a functional magnetic resonance imaging (fMRI) study. RESULTS: We report a 24-year-old male individual with an early-onset neurodevelopmental disorder with epilepsy due to the de novo missense variant c.5699A>G, p.(Tyr1900Cys) in SETD1B (NM_015048.1). He exhibited delayed speech development, autism spectrum disorder, and early-onset epilepsy with absence and generalized tonic-clonic seizures. Despite profoundly impaired communication skills, ongoing improvements regarding language production have been noted in adulthood. fMRI findings demonstrate abnormal language activation and resting-state connectivity structure. CONCLUSION: Our report expands the previously delineated phenotype of SETD1B -related disorder and provides novel insights into underlying disease mechanisms.

ConCeptCNN: A novel multi-filter convolutional neural network for the prediction of neurodevelopmental disorders using brain connectome.

BACKGROUND: Deep convolutional neural network (CNN) and its derivatives have recently shown great promise in the prediction of brain disorders using brain connectome data. Existing deep CNN methods using single global row and column convolutional filters have limited ability to extract discriminative information from brain connectome for prediction tasks. PURPOSE: This paper presents a novel deep Connectome-Inception CNN (ConCeptCNN) model, which is developed based on multiple convolutional filters. The proposed model is used to extract topological features from brain connectome data for neurological disorders classification and analysis. METHODS: The ConCeptCNN uses multiple vector-shaped filters extract topological information from the brain connectome at different levels for complementary feature embeddings of brain connectome. The proposed model is validated using two datasets: the Neuro Bureau ADHD-200 dataset and the Cincinnati Early Prediction Study (CINEPS) dataset. RESULTS: In a cross-validation experiment, the ConCeptCNN achieved a prediction accuracy of 78.7% for the detection of attention deficit hyperactivity disorder (ADHD) in adolescents and an accuracy of 81.6% for the prediction of cognitive deficits at 2 years corrected age in very preterm infants. In addition to the classification tasks, the ConCeptCNN identified several brain regions that are discriminative to neurodevelopmental disorders. CONCLUSIONS: We compared the ConCeptCNN with several peer CNN methods. The results demonstrated that proposed model improves overall classification performance of neurodevelopmental disorders prediction tasks.

Neurodevelopmental outcomes in mild and moderate isolated ventriculomegaly originating in utero.

OBJECTIVE: To determine the differences in outcomes between mild and moderate isolated ventriculomegaly (IVM). METHODS: We conducted a prospective cohort study on 94 fetuses with IVM and evaluated the neurodevelopmental outcomes at 12 months of age using the ASQ-3 and BSID-I neurodevelopmental assessment tools. Progression of VM was defined as an increase in the width of the ventricular by at least 3 mm during sequential ultrasound monitoring. The population was divided into two groups according to ventricular width: mild (10-12 mm) and moderate (12.1-15 mm), which were further evaluated for VM progression in utero separately. RESULTS: Neurodevelopmental assessments at 12 months were the main form of evaluations. Neurodevelopmental impairment (NDI) was defined as a mental development index (MDI) or psychomotor development index (PDI) < 85. There were no significant differences in NDI values between the mild and moderate groups (p = .155). Compared with the non-in utero progression group (7.6%), the rate of NDI was significantly higher (p = .004) in the group with progression (33.3%). Using linear regression and correlation, no negative correlation was found between the maximum value of atrial diameter (AD) in utero and the PDI (r = -0.021, p = .914) or MDI (r = -0.073, p = .703) score. However, the maximum change in the AD in utero was negatively correlated with both PDI (r = -0.460, p = .011) and MDI (r=-0.422, p = .020) scores. CONCLUSION: There were likely no differences in neurodevelopmental outcomes between mild and moderate IVM. In fetuses with mild to moderate VM, intrauterine progression may be a poor prognostic factor for neurodevelopmental outcomes.

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

Best Practices in Structural Neuroimaging of Neurodevelopmental Disorders.

Structural magnetic resonance imaging (sMRI) offers immense potential for increasing our understanding of how anatomical brain development relates to clinical symptoms and functioning in neurodevelopmental disorders. Clinical developmental sMRI may help identify neurobiological risk factors or markers that may ultimately assist in diagnosis and treatment. However, researchers and clinicians aiming to conduct sMRI studies of neurodevelopmental disorders face several methodological challenges. This review offers hands-on guidelines for clinical developmental sMRI. First, we present brain morphometry metrics and review evidence on typical developmental trajectories throughout adolescence, together with atypical trajectories in selected neurodevelopmental disorders. Next, we discuss challenges and good scientific practices in study design, image acquisition and analysis, and recent options to implement quality control. Finally, we discuss choices related to statistical analysis and interpretation of results. We call for greater completeness and transparency in the reporting of methods to advance understanding of structural brain alterations in neurodevelopmental disorders.

Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males.

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Relationship between the Quantitative Indicators of Cranial MRI and the Early Neurodevelopment of Preterm Infants.

AIM: To explore the relationship between the quantitative indicators (biparietal width, interhemispheric distance) of the cranial MRI for preterm infants at 37 weeks of postmenstrual age (PMA) and neurodevelopment at 6 months of corrected age. METHODS: A total of 113 preterm infants (gestational age < 37 weeks) delivered in the Obstetrics Department of the First People's Hospital of Lianyungang from September 2018 to February 2020 and directly transferred to the Neonatology Department for treatment were enrolled in this study. Based on their development quotient (DQ), the patients were divided into the normal (DQ ≥ 85, n = 76) group and the abnormal (DQ < 85, n = 37) group. Routine cranial MRI (cMRI) was performed at 37 weeks of PMA to measure the biparietal width (BPW) and interhemispheric distance (IHD). At the corrected age of 6 months, Development Screening Test (for children under six) was used to assess the participants' neurodevelopment. RESULTS: Univariate analysis showed statistically significant differences in BPW, IHD, and the incidence of bronchopulmonary dysplasia between the normal and the abnormal groups (P < 0.05), while no statistically significant differences were found in maternal complications and other clinical conditions between the two groups (P > 0.05). Binary logistic regression analysis demonstrated statistically significant differences in IHD and BPW between the normal and the abnormal groups (95% CI: 1.629-12.651 and 0.570-0.805, respectively; P = 0.004 and P < 0.001, respectively), while no significant differences were found in the incidence of bronchopulmonary dysplasia between the two groups (95% CI: 0.669-77.227, P = 0.104). Receiver operating characteristic curve revealed that the area under the curve of BPW, IHD, and the joint predictor (BPW + IHD) were 0.867, 0.805, and 0.881, respectively (95% CI: 0.800-0.933, 0.710-0.900, and 0.819-0.943, respectively; all P values < 0.001). CONCLUSION: BPW and IHD, the two quantitative indicators acquired by cMRI, could predict the neurodevelopmental outcome of preterm infants at the corrected age of 6 months. The combination of the two indicators showed an even higher predictive value.

Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients' fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.

OBJECTIVES: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. STUDY DESIGN: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. RESULTS: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. CONCLUSIONS: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

Disruptions in global network segregation and integration in adolescents and young adults with fetal alcohol spectrum disorder.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a significant public health problem that is associated with a broad range of physical, neurocognitive, and behavioral effects resulting from prenatal alcohol exposure (PAE). Magnetic resonance imaging (MRI) has been an important tool for advancing our knowledge of abnormal brain structure and function in individuals with FASD. However, whereas only a small number of studies have applied graph theory-based network analysis to resting-state functional MRI (fMRI) data in individuals with FASD additional research in this area is needed. METHODS: Resting-state fMRI data were collected from adolescent and young adult participants (ages 12-22) with fetal alcohol syndrome (FAS) or alcohol-related neurodevelopmental disorder (ARND) and neurotypically developing controls (CNTRL) from previous studies. Group independent components analysis (gICA) was applied to fMRI data to extract components representing functional brain networks. Functional network connectivity (FNC), measured by Pearson correlation of the average independent component (IC) time series, was analyzed under a graph theory framework to compare network modularity, the average clustering coefficient, characteristic path length, and global efficiency between groups. Cognitive intelligence, measured by the Wechsler Abbreviated Scale of Intelligence (WASI), was compared and correlated to global network measures. RESULTS: Group comparisons revealed significant differences in the average clustering coefficient, characteristic path length, and global efficiency. Modularity was not significantly different between groups. The FAS and ARND groups scored significantly lower than the CNTRL group on Full Scale IQ (FS-IQ) and the Vocabulary subtest, but not the Matrix Reasoning subtest. No significant associations between intelligence and graph theory measures were detected. CONCLUSION: Our results partially agree with previous studies examining global graph theory metrics in children and adolescents with FASD and suggest that the exposure to alcohol during prenatal development leads to disruptions in aspects of functional network segregation and integration.

An Examination of the Long-Term Neurodevelopmental Impact of Prenatal Zika Virus Infection in a Rat Model Using a High Resolution, Longitudinal MRI Approach.

Since Zika virus (ZIKV) first emerged as a public health concern in 2015, our ability to identify and track the long-term neurological sequelae of prenatal Zika virus (ZIKV) infection in humans has been limited. Our lab has developed a rat model of maternal ZIKV infection with associated vertical transmission to the fetus that results in significant brain malformations in the neonatal offspring. Here, we use this model in conjunction with longitudinal magnetic resonance imaging (MRI) to expand our understanding of the long-term neurological consequences of prenatal ZIKV infection in order to identify characteristic neurodevelopmental changes and track them across time. We exploited both manual and automated atlas-based segmentation of MR images in order to identify long-term structural changes within the developing rat brain following inoculation. The paradigm involved scanning three cohorts of male and female rats that were prenatally inoculated with 107 PFU ZIKV, 107 UV-inactivated ZIKV (iZIKV), or diluent medium (mock), at 4 different postnatal day (P) age points: P2, P16, P24, and P60. Analysis of tracked brain structures revealed significantly altered development in both the ZIKV and iZIKV rats. Moreover, we demonstrate that prenatal ZIKV infection alters the growth of brain regions throughout the neonatal and juvenile ages. Our findings also suggest that maternal immune activation caused by inactive viral proteins may play a role in altered brain growth throughout development. For the very first time, we introduce manual and automated atlas-based segmentation of neonatal and juvenile rat brains longitudinally. Experimental results demonstrate the effectiveness of our novel approach for detecting significant changes in neurodevelopment in models of early-life infections.

Nanoscale synapse organization and dysfunction in neurodevelopmental disorders.

Neurodevelopmental disorders such as those linked to intellectual disabilities or autism spectrum disorder are thought to originate in part from genetic defects in synaptic proteins. Single gene mutations linked to synapse dysfunction can broadly be separated in three categories: disorders of transcriptional regulation, disorders of synaptic signaling and disorders of synaptic scaffolding and structures. The recent developments in super-resolution imaging technologies and their application to synapses have unraveled a complex nanoscale organization of synaptic components. On the one hand, part of receptors, adhesion proteins, ion channels, scaffold elements and the pre-synaptic release machinery are partitioned in subsynaptic nanodomains, and the respective organization of these nanodomains has tremendous impact on synaptic function. For example, pre-synaptic neurotransmitter release sites are partly aligned with nanometer precision to postsynaptic receptor clusters. On the other hand, a large fraction of synaptic components is extremely dynamic and constantly exchanges between synaptic domains and extrasynaptic or intracellular compartments. It is largely the combination of the exquisitely precise nanoscale synaptic organization of synaptic components and their high dynamic that allows the rapid and profound regulation of synaptic function during synaptic plasticity processes that underlie adaptability of brain function, learning and memory. It is very tempting to speculate that genetic defects that lead to neurodevelopmental disorders and target synaptic scaffolds and structures mediate their deleterious impact on brain function through perturbing synapse nanoscale dynamic organization. We discuss here how applying super-resolution imaging methods in models of neurodevelopmental disorders could help in addressing this question.

Microstructural Measures of the Inferior Longitudinal Fasciculus Predict Later Cognitive and Language Development in Infants Born With Extremely Low Birth Weight.

OBJECTIVE: Extremely preterm children are at high risk for adverse neurodevelopmental outcomes. Identifying predictors of discrete developmental outcomes early in life would allow for targeted neuroprotective therapies when neuroplasticity is at its peak. Our goal was to examine whether diffusion magnetic resonance imaging (MRI) metrics of the inferior longitudinal and uncinate fasciculi early in life could predict later cognitive and language outcomes. STUDY DESIGN: In this pilot study, 43 extremely low-birth-weight preterm infants were scanned using diffusion MRI at term-equivalent age. White matter tracts were assessed via diffusion tensor imaging metrics of fractional anisotropy and mean diffusivity. The Language and Cognitive subscale scores of the Bayley Scales of Infant & Toddler Development-III at 18-22 months corrected age were our outcomes of interest. Multiple linear regression models were created to assess diffusion metrics of the inferior longitudinal and uncinate fasciculi as predictors of Bayley scores. We controlled for brain injury score on structural MRI, maternal education, birth weight, and age at MRI scan. RESULTS: Of the 43 infants, 36 infants had high-quality diffusion tensor imaging and returned for developmental testing. The fractional anisotropy of the inferior longitudinal fasciculus was associated with Bayley-III scores in univariate analyses and was an independent predictor of Bayley-III cognitive and language development over and above known predictors in multivariable analyses. CONCLUSIONS: Incorporating new biomarkers such as the fractional anisotropy of the inferior longitudinal fasciculus with structural MRI findings could enhance accuracy of neurodevelopment predictive models. Additional research is needed to validate our findings in a larger cohort.

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities.

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and ßIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and ßIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.