Neurodevelopment*
Date/Time: Sunday, September 10, 2023 - 3:30 PM – 5:00 PM
Track: Cross-Cutting Special Interest Group (SIG)
Room: Conference Room 404 (4th Floor)
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Description:
Session Evaluation Form: https://myana.org/form/ana2023-sessionevaluation-neuro
Chair: Jodi Lindsey, MD
Co-Chair: Miya Asato, MD
Exposure science is increasingly considered in the pathogenesis of neurological disease occurring during development and across the lifespan. As complex exposures interact with the body and nervous system, candidate critical time periods of development may shed light on potential mechanisms that result in CNS disease across the lifespan, such as mitochondrial disorders and Parkinson’s disease. Insights into exposure effects on the body may identify points of intervention and prevention opportunities.
Learning Objectives:
- Following this session, learners will be able to better take an exposure history to identify potential candidate environmental exposures
- Following this session, learners will understand the importance of genetic susceptibility for commonly encountered disorders that may be compounded by exposomic mechanisms.
- Following this session, learners will initiate and engage in ongoing efforts to contribute to data collection to better characterize and define classification of disorders and exposures.
The Role of Exposomes in Neurodevelopment and CNS Disease
Speaker: J. William Gaynor, MD
This presentation will discuss the impact of environmental exposures and the exposome on neurodevelopmental outcomes for patients with congenital heart defects.
Gene-Environment Interaction in Neurodevelopmental Disorders
Speaker: Ashley Song, PhD
This talk with review current and emerging findings on environmental factors and neurodevelopmental disorders and discuss research strategies and provide examples of the study of genes and environment jointly in neurodevelopmental outcomes.
Lessons from Researching the ALS Exposome
Speaker: Stephen Goutman, MD, MS
Amyotrophic lateral sclerosis (ALS) results from a combination of genetic and non-genetic risk factors. A clearer understanding of this relationship may unlock therapeutic targets and risk factor modification strategies. Here the presenter will briefly share concepts learned by studying the ALS exposome and how such lessons could be applied to other neurodegenerative diseases.
Early Disruption of Epigenetic and Transcriptomic Organization after Prenatal Hypoxia Predicts Persistent Functional Deficits in Glutamatergic Neurons
Oral Abstract Presenter: Ana Cristancho, MD, PhD
Prenatal hypoxic injury affects over a million births annually, leading to neurodevelopmental disability in one-third of those children. Yet, we lack targeted interventions for improving outcomes. A limitation toward developing therapeutics is that we lack understanding of the multifaceted, cell type-specific molecular consequences of this transient insult on the developing brain. To address this gap, we performed joint single nucleus RNA-sequencing and assay for transposase-accessible chromatin sequencing from the cortex of mice immediately after prenatal hypoxia exposure (8 hours, 5% inspired oxygen at embryonic day 17.5). This animal model phenocopies mild hypoxic injury seen in children. Over 140,000 nuclei were sequenced from 16 total samples evenly divided between normoxia and hypoxia and by sex. We identified clusters of known neuronal and glial cell populations. Prenatal hypoxia led to a slight increase in endothelial cells but no further changes in cell number for other cell types. We found several cell type-specific disruptions in gene expression and regions of chromatin organization after prenatal hypoxia. Many of the cell type-specific genes dysregulated by hypoxia were associated with pathogenic variants that cause neurodevelopmental disabilities or neurodegenerative disorders. Remarkably, we discovered that hypoxic glutamatergic neurons had a selective disassociation between global chromatin organization and gene expression. Glutamatergic neurons, which develop synapses postnatally, also demonstrated dysregulation of genes associated with neuron structure and synapse function after prenatal hypoxia. To test whether these changes in the fetal brain suggested which cells and pathways may be disrupted by transient hypoxia in mature neurons, we used Golgi staining and whole-cell patch-clamp electrophysiology in juvenile mice to examine glutamatergic neuron structure and function. We found that these neurons had decreased dendritic spine density and prolonged action potential hyperpolarization one month after the insult. Notably, many of the potassium channels associated with hyperpolarization were not expressed in fetal glutamatergic neurons at baseline, but about 80% of these genes had abnormalities in nearby chromatin accessibility after prenatal hypoxia. Together, these findings suggest that prenatal hypoxia disrupts the organization of chromatin and the transcriptome in glutamatergic neurons, leading to persistent disruption of neuronal maturation and structure that may contribute to lasting behavioral deficits. Ongoing analyses will test (1) whether the shifts in the chromatin organization after prenatal hypoxia are persistent in juvenile mice and (2) which motifs are present at sites of differential accessibility that may suggest pathways that are amenable for intervention to improve outcomes.
Gross Motor Function in Pediatric Onset TUBB4A-Related Leukodystrophy: GMFM-88 Performance and Validation of GMFC-MLD Use
Oral Abstract Presenter: Francesco Gavazzi, MD, PhD
Objective: TUBB4A pathogenic variants are associated with a spectrum of neurologic conditions, including movement disorders and leukodystrophy. With the development of targeted therapies in preclinical models, there is an urgent unmet need for validated tools to measure mobility limitations in children with this disease. The objective is to explore gross motor function in a pediatric-onset TUBB4A-related leukodystrophy cohort with existing outcome tools. Methods: The Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function Classification System (GMFCS), and Gross Motor Function Classification-Metachromatic Leukodystrophy (GMFC-MLD) were selected for use by a panel of experts through face validity. The GMFM-88 is comprised of five dimensions (A-E) measuring increasingly complex motor function. Subjects with a confirmed molecular and clinical diagnosis of TUBB4A-related leukodystrophy were enrolled. Participants’ sex, age, genotype, and age at disease onset were collected, together with GMFM-88 and concurrent GMFCS and GMFC-MLD scores. Performances on each measure were compared. A GMFM-88 floor effect was defined as a total score below 20%. Correlative statistics included the Spearman’s Rank Correlation Coefficient and the Pearson’s Rank Correlation Coefficient. Results: A total of 35 subjects participated in motor outcome assessments. At the time of the GMFM-88 testing and classification system scoring, the mean chronologic age of patients was 8.36 years [median: 7.56; standard deviation: 5.17; interquartile range (IQR): 8.73]. The median performance on the GMFM-88 was 16.24% [range: 0-97.31%; IQR: 47.02], and 42.9% (n=15) of individuals performed above the floor effect threshold. In Dimension A, which evaluates lying and rolling, 82.9% (n=29/35) of participants performed above the floor threshold. In all other GMFM-88 dimensions, >50% of the population scored below the floor threshold. All levels of the Classification Scales were represented, except for the GMFC-MLD level ‘0.’ Evaluation by GMFM-88 was strongly correlated with the Classification Scales [Spearman Correlations: GMFCS:GMFM-88 r=0.90, p<0.0001; GMFC-MLD:GMFM-88 r=0.88, p<0.0001; GMFCS:GMFC-MLD: r=0.92, p<0.0001]. Conclusions: Despite overall observation of a floor effect, the GMFM-88 accurately captures performance of individuals with attenuated phenotypes. GMFM-88 Dimension A shows no floor effect. The GMFC-MLD shows a strong correlation with the GMFCS and GMFM-88, supporting its use as an age-independent functional classification in TUBB4A-related leukodystrophy.