Objective:

To provide an overview of recent advances in neurogenetics and precision-based therapies for severe childhood-onset neurological disorders, with a particular emphasis on metabolic epilepsies.

Key Findings:

• Single-gene mutations disrupt neuronal signaling and network stability, leading to complex seizure phenotypes and multisystem involvement.
• Traditional antiseizure therapies often fail to address underlying genetic mechanisms.
• Emerging therapies include gene replacement, modulation, and RNA-based strategies.

Interpretation:

The evolving understanding of metabolic epilepsies necessitates a shift from symptom control to disease-modifying therapies that target genetic causes.

Limitations:

• Challenges in delivering therapies within the central nervous system.
• Safety considerations for new genetic and molecular therapies.
• Need for long-term follow-up in clinical trials and standardized outcome measures.

Conclusion:

Advancements in neurogenetics are paving the way for more effective treatments for metabolic epilepsies, emphasizing the importance of understanding genetic mechanisms in developing these therapies.