Precision Medicine in Genetic Epilepsy and Developmental Encephalopathies (DEEs)

Precision medicine in neurodevelopmental and epileptic encephalopathies (DEEs) seeks to direct pharmacological treatment towards the pathophysiological and molecular mechanism underlying the patient's genetic variant, avoiding ineffective or harmful therapies.

Epilepsy-related genetic conditions displaying potential specific therapeutic approaches
Figure: Genetic conditions associated with epilepsy and their specific precision therapeutic approaches (Adapted from Beltrán-Corbellini et al., Front. Neurol. 2022).

Clinical Breakdown of Therapeutic Approaches Represented

The main molecular categories and therapeutic targets represented in the table are detailed below:

1. Sodium and Potassium Channelopathies

  • SCN1A (Dravet Syndrome – Loss of Function): Precision approach with fenfluramine, cannabidiol, stiripentol, clobazam and valproate. Accuracy alert: Sodium channel blockers (carbamazepine, phenytoin, lamotrigine) are formally contraindicated due to the risk of severe worsening and refractory seizures.
  • SCN2A and SCN8A (Gain of Function Variants in early debut): Preferential indication of sodium channel blockers at high doses (phenytoin, carbamazepine), which restore membrane hyperexcitability.
  • KCNQ2 / KCNQ3 (Kv7.2/Kv7.3 Potassium Channels): Selective opening of K+ channels through retigabine (ezogabine) and favorable response to sodium blockers such as carbamazepine in early phases.
  • KCNT1 (Na+-dependent potassium channels): Use of quinidine as a specific off-label modulator in refractory childhood migrant focal epilepsies.

2. Metabolic and Brain Transport Disorders

  • SLC2A1 (Brain Glucose Transporter GLUT1 Deficiency): Mandatory substitution therapy Ketogenic Diet early, providing ketone bodies as an alternative brain energy substrate to glucose.
  • ALDH7A1 / PNPO (Pyridoxine-dependent epilepsies): Specific lifelong supplementation with pyridoxine (vitamin B6) o pyridoxal 5′-phosphate (PLP).

3. mTORopathies and Proliferation/Signalling Pathways

  • TSC1/TSC2 (Tuberous Sclerosis Complex) and DEPDC5/NPRL2/NPRL3 (GATOR1 Complex): Hyperactivation of the intracellular mTOR cascade. Targeted approach with mTOR inhibitors (Everolimus, Sirolimus) for the control of seizures and associated focal cortical dysplasias.

4. Modulators of Receptors and Synaptic Pathways

  • GRIN2A / GRIN2B (NMDA Receptor Subunits): Allosteric modulation and blockade of NMDA receptors through memantine in variants with gain of function.
  • PCDH19 (Protocadherin 19): Neurosteroid modulating therapies (ganaxolone) and specific hormonal protocols.

Literature

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1.
Beltrán-Corbellini Á, Aledo-Serrano Á, Møller RS, Pérez-Palma E, García-Morales I, Toledano R, et al. Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies. Front Neurol [Internet]. 2022 Feb 17 [cited 2026 June 15];13. Available from: https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.777115/full