The Pediatric Neurology 2020 Research Workforce Survey: Optimism in a Time of Challenge.

BACKGROUND: The past decades have seen a transformational shift in the understanding and treatment for neurological diseases affecting infants and children. These advances have been driven in part by the pediatric neurology physician-scientist workforce and its efforts. However, pediatric neurology research faces substantial challenges from internal and external forces including work-life balance demands, COVID-19 pandemic effects, and research funding. Understanding the impact of these challenges on the perceptions, planning, and careers of pediatric neurology physician-scientists is needed to guide the research mission. METHODS: Our objective was to survey the research challenges, goals, and priorities of pediatric neurologists. In 2020 we conducted a cross-sectional, 28-question survey emailed to 1,775 members of the Child Neurology Society. RESULTS: One hundred fifty-one individuals responded to the survey. Most respondents were grant investigators (52%) and conducted clinical research (69%). Research areas included epilepsy (23%), neurodevelopmental and autism (16%), neurocritical care and stroke (11%), neurogenetics and neurometabolics (9%), neonatal neurology (8%), and others. The most common funding source was the National Institutes of Health (37%). Shared major research concerns were funding, utilization of remote technology, overcoming disparities, natural history and multicenter studies, global neurology, and diversification of the research portfolio. Commitment to continuing and increasing research efforts was evident. CONCLUSIONS: Our survey demonstrates obstacles for physician-scientist researchers in pediatric neurology, but it also shows optimism about continued opportunity. Creative approaches to address challenges will benefit the research mission, maximize the current and future pool of researchers, and help improve the lives of children with neurological disorders.

Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2.

Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human CLN2, in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort (P < 0.04) and European natural history cohort (P < 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy.

Pediatric Neurology Research in the Twenty-First Century: Status, Challenges, and Future Directions Post-COVID-19.

BACKGROUND: The year 2020 marked a fundamental shift in the pediatric neurology field. An impressive positive trajectory of advances in patient care and research faced sudden global disruptions by the coronavirus disease 2019 pandemic and by an international movement protesting racial, socioeconomic, and health disparities. The disruptions revealed obstacles and fragility within the pediatric neurology research mission. However, renewed commitment offers unique opportunities for the pediatric neurology research community to enhance and prioritize research directions for the coming decades. METHODS: The Research Committee of the Child Neurology Society evaluated the challenges and opportunities facing the pediatric neurology research field, including reviewing published literature, synthesizing publically available data, and conducting a survey of pediatric neurologists. RESULTS: We identified three priority domains for the research mission: funding levels, active guidance, and reducing disparities. Funding levels: to increase funding to match the burden of pediatric neurological disease; to tailor funding mechanisms and strategies to support clinical trial efforts unique to pediatric neurology; and to support investigators across their career trajectory. Active guidance: to optimize infrastructure and strategies, to leverage novel therapeutics, enhance data collection, and improve inclusion of children in clinical trials. Reducing disparities: to reduce health disparities in children with neurological disease, to develop proactive measures to enhance workforce diversity and inclusion, and increase avenues to balance work-life obligations for investigators. CONCLUSIONS: In this uniquely challenging epoch, the pediatric neurology research community has a timely and important mission to re-engage the public and government, advancing the health of children with neurological conditions.

Autonomic dysfunction following mild traumatic brain injury.

PURPOSE OF REVIEW: Between 1.6 and 3.6 million concussions, or mild traumatic brain injuries (mTBI), occur each year, nearly half of which go unreported and untreated. Despite the high incidence, practitioners currently lack both objective gold-standard diagnostic tools and evidence-based treatments to enable optimal care of concussed individuals. RECENT FINDINGS: This article aims to review recent research on the topic, emphasizing the role of the autonomic nervous system (ANS) in concussion. Current data suggests that ANS dysfunction is often evident following mTBI and accounts for many of the symptoms commonly seen in concussed patients. This link suggests several objective biomarkers that could be used to diagnose and monitor recovery following mTBI. Contrary to conventional wisdom, symptoms and biomarkers of ANS function improve when individuals are exposed to a program of graded exercise as treatment within the first week following concussion. SUMMARY: ANS dysfunction contributes to concussion symptomatology, an effect likely mediated through diffuse axonal injury, including brainstem structures and pathways mediating normal cerebrovascular autoregulation. Exercise, which enhances ANS function, is a well tolerated and effective method of treatment for both acute concussion patients and those suffering from postconcussion syndrome (PCS). The relationship between the ANS, exercise, and concussion creates an opportunity for the identification of objective biomarkers that can facilitate the diagnosis and treatment of mTBI.

Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease).

Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare lysosomal storage disorder caused by a monogenetic deficiency of tripeptidyl peptidase-1 (TPP1). Despite knowledge that lipofuscin is the hallmark disease product, the relevant TPP1 substrate and its role in neuronal physiology/pathology is unknown. We hypothesized that untargeted metabolite profiling of cerebrospinal fluid (CSF) could be used as an effective tool to identify disease-associated metabolic disruptions in CLN2 disease, offering the potential to identify biomarkers that inform on disease severity and progression. Accordingly, a mass spectrometry-based untargeted metabolite profiling approach was employed to differentiate CSF from normal vs. CLN2 deficient individuals. Of 1,433 metabolite features surveyed, 29 linearly correlated with currently employed disease severity scores. With tandem mass spectrometry 8 distinct metabolite identities were structurally confirmed based on retention time and fragmentation pattern matches, vs. standards. These putative CLN2 biomarkers include 7 acetylated species - all attenuated in CLN2 compared to controls. Because acetate is the major bioenergetic fuel for support of mitochondrial respiration, deficient acetylated species in CSF suggests a brain energy defect that may drive neurodegeneration. Targeted analysis of these metabolites in CSF of CLN2 patients offers a powerful new approach for monitoring CLN2 disease progression and response to therapy.

Accuracy of Reported Community Diagnosis of Autism Spectrum Disorder.

To compare community diagnoses of Autism Spectrum Disorder (ASD) reported by parents to consensus diagnoses made using standardized tools plus clinical observation. 87 participants (85% male, average age 7.4 years), with reported community diagnosis of ASD were evaluated using the Autism Diagnostic Observation Schedule) (ADOS-2), Differential Ability Scale (DAS-II), and Vineland Adaptive Behavior Scales (VABS-II). Detailed developmental and medical history was obtained from all participants. Diagnosis was based on clinical consensus of at least two expert clinicians, using test results, clinical observations, and parent report. 23% of participants with a reported community diagnosis of ASD were classified as non-spectrum based on our consensus diagnosis. ASD and non-spectrum participants did not differ on age at evaluation and age of first community diagnosis. Non-verbal IQ scores and Adaptive Behavior Composite scores were significantly higher in the non-spectrum group compared to the ASD group (104.5 ± 21.7 vs. 80.1 ± 21.6, p < .01; 71.1 ± 15 versus 79.5 ± 17.6, p < .05, respectively). Participants enrolled with community diagnosis of PDD-NOS were significantly more likely to be classified as non-spectrum on the study consensus diagnosis than Participants with Autism or Asperger (36% versus 9.5%, Odds Ratio = 5.4, p < .05). This study shows suboptimal agreement between community diagnoses of ASD and consensus diagnosis using standardized instruments. These findings are based on limited data, and should be further studied, taking into consideration the influence of DSM 5 diagnostic criteria on ASD prevalence.

Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study.

BACKGROUND: Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients. METHODS: We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death. FINDINGS: In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years. INTERPRETATION: In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies. FUNDING: EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathan's Battle Foundation, Cures Within Reach Foundation, Noah's Hope Foundation, Hope4Bridget Foundation.

Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure.

Children and adolescents affected by prenatal exposure to alcohol who have brain damage that is manifested in functional impairments of neurocognition, self-regulation, and adaptive functioning may most appropriately be diagnosed with neurobehavioral disorder associated with prenatal exposure. This Special Article outlines clinical implications and guidelines for pediatric medical home clinicians to identify, diagnose, and refer children regarding neurobehavioral disorder associated with prenatal exposure. Emphasis is given to reported or observable behaviors that can be identified as part of care in pediatric medical homes, differential diagnosis, and potential comorbidities. In addition, brief guidance is provided on the management of affected children in the pediatric medical home. Finally, suggestions are given for obtaining prenatal history of in utero exposure to alcohol for the pediatric patient.

Guiding Principles for a Pediatric Neurology ICU (neuroPICU) Bedside Multimodal Monitor: Findings from an International Working Group.

BACKGROUND: Physicians caring for children with serious acute neurologic disease must process overwhelming amounts of physiological and medical information. Strategies to optimize real time display of this information are understudied. OBJECTIVES: Our goal was to engage clinical and engineering experts to develop guiding principles for creating a pediatric neurology intensive care unit (neuroPICU) monitor that integrates and displays data from multiple sources in an intuitive and informative manner. METHODS: To accomplish this goal, an international group of physicians and engineers communicated regularly for one year. We integrated findings from clinical observations, interviews, a survey, signal processing, and visualization exercises to develop a concept for a neuroPICU display. RESULTS: Key conclusions from our efforts include: (1) A neuroPICU display should support (a) rapid review of retrospective time series (i.e. cardiac, pulmonary, and neurologic physiology data), (b) rapidly modifiable formats for viewing that data according to the specialty of the reviewer, and (c) communication of the degree of risk of clinical decline. (2) Specialized visualizations of physiologic parameters can highlight abnormalities in multivariable temporal data. Examples include 3-D stacked spider plots and color coded time series plots. (3) Visual summaries of EEG with spectral tools (i.e. hemispheric asymmetry and median power) can highlight seizures via patient-specific "fingerprints." (4) Intuitive displays should emphasize subsets of physiology and processed EEG data to provide a rapid gestalt of the current status and medical stability of a patient. CONCLUSIONS: A well-designed neuroPICU display must present multiple datasets in dynamic, flexible, and informative views to accommodate clinicians from multiple disciplines in a variety of clinical scenarios.

Clinical features and biomarkers of concussion and mild traumatic brain injury in pediatric patients.

There has been increasing awareness of the incidence and potential long-term consequences of mild traumatic brain injury (mTBI) in children and young adults. While parents, school systems, and athletic programs are clamoring for evidence-based guidelines, the field remains primitive in understanding the factors resulting in a spectrum of individual outcomes, most of which are complete, but some of which are not. In this article, we discuss the definition, epidemiology, clinical presentation, course, and outcomes of mTBI, with a focus on the pediatric population as the context for reviewing the mechanisms and pathophysiology mediating, and biomarkers reflective of, more significant concussion-induced brain injury. Our goal is to present a general overview of the features of mTBI in the pediatric population in order to provide a conceptual model for pediatricians and pediatric subspecialists. This model emphasizes the importance of establishing actionable, noninvasive biomarkers that are reflective of brain injury and that may identify those pediatric patients who can benefit from earlier and more aggressive interventions. We will focus on the specific features of mTBI in pediatric patients; although given the relative lack of research in the pediatric population, we will also extrapolate from research on adults.

Structural brain imaging in children and adolescents following prenatal cocaine exposure: preliminary longitudinal findings.

The brain morphometry of 21 children, who were followed from birth and underwent structural brain magnetic resonance imaging at 8-10 years, was studied. This cohort included 11 children with prenatal cocaine exposure (CE) and 10 noncocaine-exposed children (NCE). We compared the CE versus NCE groups using FreeSurfer to automatically segment and quantify the volume of individual brain structures. In addition, we created a pediatric atlas specifically for this population and demonstrate the enhanced accuracy of this approach. We found an overall trend towards smaller brain volumes among CE children. The volume differences were significant for cortical gray matter, the thalamus and the putamen. Here, reductions in thalamic and putaminal volumes showed a robust inverse correlation with exposure levels, thus highlighting effects on dopamine-rich brain regions that form key components of brain circuitry known to play important roles in behavior and attention. Interestingly, head circumferences (HCs) at birth as well as at the time of imaging showed a tendency for smaller size among CE children. HCs at the time of imaging correlated well with the cortical volumes for all subjects. In contrast, HCs at birth were predictive of the cortical volume only for the CE group. A subgroup of these subjects (6 CE, 4 NCE) was also scanned at 13-15 years of age. In subjects who were scanned twice, we found that the trend for smaller structures continued into teenage years. We found that the differences in structural volumes between the CE and NCE groups are largely diminished when the HCs are controlled for or matched by study design. Participants in this study were drawn from a unique longitudinal cohort and, while the small sample size precludes strong conclusions regarding the longitudinal findings reported, the results point to reductions in HCs and in specific brain structures that persist through teenage years in children who were exposed to cocaine in utero.

Effects of prenatal exposure to cocaine on brain structure and function.

Drug abuse during pregnancy affects the mother and has adverse effects on the unborn child. This chapter highlights our recent findings at the neuroanatomical, molecular, and behavioral levels in a prenatal cocaine exposure mouse model. In the embryonic brains of prenatally cocaine-exposed mice, we observed a delay in the tangential migration of GABA neurons to the cerebral cortex as a result of a significant but transient decrease in the expression of the neurotrophin brain-derived neurotrophic factor (BDNF). These developmental changes lead to lasting deficits in the numerical density of GABA neurons in the mature medial prefrontal cortex (mPFC). In adult prenatally cocaine-exposed mice, we observed a behavioral deficit in the recall of an extinguished cue-conditioned fear, which was rescued by administration of exogenous recombinant BDNF protein directly into the infralimbic cortex of the mPFC, which may result from altered activity-driven transcriptional regulation of BDNF.

Effects of prenatal cocaine exposure on social development in mice.

Prenatal cocaine exposure (PCE) in humans and animals has been shown to impair social development. Molecules that mediate synaptic plasticity and learning in the medial prefrontal cortex (mPFC), specifically brain-derived neurotrophic factor (BDNF) and its downstream signaling molecule, early growth response protein 1 (egr1), have been shown to affect the regulation of social interactions (SI). In this study we determined the effects of PCE on SI and the corresponding ultrasonic vocalizations (USVs) in developing mice. Furthermore, we studied the PCE-induced changes in the constitutive expression of BDNF, egr1 and their transcriptional regulators in the mPFC as a possible molecular mechanism mediating the altered SI. In prenatal cocaine-exposed (PCOC) mice we identified increased SI and USV production at postnatal day (PD) 25, and increased SI but not USVs at PD35. By PD45 the expression of both social behaviors normalized in PCOC mice. At the molecular level, we found increased BDNF exon IV and egr1 mRNA in the mPFC of PCOC mice at PD30 that normalized by PD45. This was concurrent with increased EGR1 protein in the mPFC of PCOC mice at PD30, suggesting a role of egr1 in the enhanced SI observed in juvenile PCOC mice. Additionally, by measuring the association of acetylation of histone 3 at lysine residues 9 and 14 (acH3K9,14) and MeCP2 at the promoters of BDNF exons I and IV and egr1, our results provide evidence of promoter-specific alterations in the mPFC of PCOC juvenile mice, with increased association of acH3K9,14 only at the BDNF exon IV promoter. These results identify a potential PCE-induced molecular alteration as the underlying neurobiological mechanism mediating the altered social development in juvenile mice.

Multimodal monitoring in the pediatric intensive care unit: new modalities and informatics challenges.

We review several newer modalities to monitor the brain in children with acute neurologic disease in the pediatric intensive care unit, such as partial brain tissue oxygen tension (PbtO2), jugular venous oxygen saturation (SjvO2), near infrared spectroscopy (NIRS), thermal diffusion measurement of cerebral blood flow, cerebral microdialysis, and EEG. We then discuss the informatics challenges to acquire, consolidate, analyze, and display the data. Acquisition includes multiple data types: discrete, waveform, and continuous. Consolidation requires device interoperability and time synchronization. Analysis could include pressure reactivity index and quantitative EEG. Displays should communicate the patient's current status, longitudinal and trend information, and critical alarms.

Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero.

Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC) mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC) and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF) protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it's phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals.

Spectrum of ocular manifestations in CLN2-associated batten (Jansky-Bielschowsky) disease correlate with advancing age and deteriorating neurological function.

BACKGROUND: Late infantile neuronal ceroid lipofuscinosis (LINCL), one form of Batten's disease is a progressive neurodegenerative disorder resulting from a CLN2 gene mutation. The spectrum of ophthalmic manifestations of LINCL and the relationship with neurological function has not been previously described. METHODS: Patients underwent ophthalmic evaluations, including anterior segment and dilated exams, optical coherence tomography, fluorescein and indocyanine green angiography. Patients were also assessed with the LINCL Neurological Severity Scale. Ophthalmic findings were categorized into one of five severity scores, and the association of the extent of ocular disease with neurological function was assessed. RESULTS: Fifty eyes of 25 patients were included. The mean age at the time of exam was 4.9 years (range 2.5 to 8.1). The mean ophthalmic severity score was 2.6 (range 1 to 5). The mean neurological severity score was 6.1 (range 2 to 11). Significantly more severe ophthalmic manifestations were observed among older patients (p<0.005) and patients with more severe neurological findings (p<0.03). A direct correlation was found between the Ophthalmic Severity Scale and the Weill Cornell Neurological Scale (p<0.002). A direct association was also found between age and the ophthalmic manifestations (p<0.0002), with older children having more severe ophthalmic manifestations. CONCLUSIONS: Ophthalmic manifestations of LINCL correlate closely with the degree of neurological function and the age of the patient. The newly established LINCL Ophthalmic Scale may serve as an objective marker of LINCL severity and disease progression, and may be valuable in the evaluation of novel therapeutic strategies for LINCL, including gene therapy.

Cup of Joe: a brain development "no"?

Treating pregnant mice with adenosine receptor antagonists including caffeine results in delayed migration of cortical γ-aminobutyric acid neurons and altered brain development in mouse offspring (Silva et al.).

Markers of Celiac Disease and Gluten Sensitivity in Children with Autism.

OBJECTIVE: Gastrointestinal symptoms are a common feature in children with autism, drawing attention to a potential association with celiac disease or gluten sensitivity. However, studies to date regarding the immune response to gluten in autism and its association with celiac disease have been inconsistent. The aim of this study was to assess immune reactivity to gluten in pediatric patients diagnosed with autism according to strict criteria and to evaluate the potential link between autism and celiac disease. METHODS: Study participants included children (with or without gastrointestinal symptoms) diagnosed with autism according to both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n = 37), their unaffected siblings (n = 27), and age-matched healthy controls (n = 76). Serum specimens were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2 (TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -DQ8 alleles. RESULTS: Children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls (p<0.01). The IgG levels were also higher compared to the unaffected siblings, but did not reach statistical significance. The IgG anti-gliadin antibody response was significantly greater in the autistic children with gastrointestinal symptoms in comparison to those without them (p<0.01). There was no difference in IgA response to gliadin across groups. The levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between patients and controls. An association between increased anti-gliadin antibody and presence of HLA-DQ2 and/or -DQ8 was not observed. CONCLUSIONS: A subset of children with autism displays increased immune reactivity to gluten, the mechanism of which appears to be distinct from that in celiac disease. The increased anti-gliadin antibody response and its association with GI symptoms points to a potential mechanism involving immunologic and/or intestinal permeability abnormalities in affected children.

Prenatal-onset neurodevelopmental disorders secondary to toxins, nutritional deficiencies, and maternal illness.

Neurodevelopmental disorders result from an inordinate number of genetic and environmental causes during the embryological and fetal periods of life. In the clinical setting, deciphering precise etiological diagnoses is often difficult. Newer screening technologies allow a gradual shift from traditional nature-versus-nurture debates toward the focused analysis of gene-by-environment interactions (G X E). Further understanding of developmental adaptation and plasticity requires consideration of epigenetic processes such as maternal nutritional status, environmental toxins, maternal illnesses, as well as genetic determinants, alone or in combination. Appreciation of specific G X E mechanisms of neurodevelopmental pathogenesis should lead to better risk-modifying or preventive strategies. We provide a brief overview of clinical and experimental observations that link prenatal-onset toxic exposures, metabolic disturbances, and maternal illnesses to certain neurodevelopmental disorders.