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Exploring the Landscape of Pre- and Post-Synaptic Pediatric Disorders with Epilepsy: A Narrative Review on Molecular
Giovanna Scorrano1, Ludovica Di Francesco2, Armando Di Ludovico1
1Department of Pediatrics, University of Chieti-Pescara, Sant'Annunziata Hospital, 66100 Chieti, Italy.
Insights
Neurodevelopmental disorders (NDDs) and epilepsy are linked to genetic defects affecting brain cell communication. This review explores molecular mechanisms in SNAREopathies and AMPA-related synaptopathies.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Neurodevelopmental disorders (NDDs) encompass conditions like intellectual disability (ID), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD), often co-occurring with epilepsy and other comorbidities.
- These disorders present heterogeneous clinical features and variable severity, impacting brain development and function.
Purpose of the Study:
- To review and dissect molecular mechanisms underlying NDDs and epilepsy, focusing on defects in synaptic transmission.
- To highlight recently identified genetic variants and their roles in pre- and post-synaptic function.
Main Methods:
- This narrative review analyzes current literature on genetic variants associated with NDDs and epilepsy.
- Focus is placed on next-generation sequencing (NGS) findings related to synaptic proteins.
Main Results:
- NGS has identified numerous pathogenic gene variants linked to NDDs and epilepsy in affected children.
- These variants affect proteins crucial for synaptic homeostasis, including SNARE proteins (pre-synaptic release) and ionotropic glutamate receptors (post-synaptic transmission).
Conclusions:
- Defects in pre- and post-synaptic transmission, particularly in SNAREopathies and AMPA-related synaptopathies, are key molecular mechanisms in NDDs and epilepsy.
- Understanding these genetic underpinnings is crucial for advancing diagnostics and therapeutics for these complex neurological conditions.
Abstract:
Neurodevelopmental disorders (NDDs) are a group of conditions affecting brain development, with variable degrees of severity and heterogeneous clinical features. They include intellectual disability (ID), autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), often coexisting with epilepsy, extra-neurological comorbidities, and multisystemic involvement. In recent years, next-generation sequencing (NGS) technologies allowed the identification of several gene pathogenic variants etiologically related to these disorders in a large cohort of affected children. These genes encode proteins involved in synaptic homeostasis, such as SNARE proteins, implicated in calcium-triggered pre-synaptic release of neurotransmitters, or channel subunit proteins, such as post-synaptic ionotropic glutamate receptors involved in the brain's fast excitatory neurotransmission. In this narrative review, we dissected emerged molecular mechanisms related to NDDs and epilepsy due to defects in pre- and post-synaptic transmission. We focused on the most recently discovered SNAREopathies and AMPA-related synaptopathies.
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