DEPDC5-related epilepsy: A comprehensive review.

Area of Science:

• Neurogenetics
• Epileptology
• Molecular Neuroscience

Background:

• DEPDC5-related epilepsy is a focal epilepsy associated with pathogenic variants in the DEPDC5 gene, leading to enhanced mTORC1 pathway activity.
• This condition encompasses familial focal epilepsy with variable foci (FFEVF) and sporadic nonlesional focal epilepsy, and is linked to infantile spasms and SUDEP.
• DEPDC5 variants are found in individuals with brain abnormalities, blurring the lines between lesional and nonlesional epilepsies.

Purpose of the Study:

• To review the current understanding of DEPDC5-related epilepsy, its genetic basis, and clinical spectrum.
• To highlight the potential of mTOR inhibitors as precision therapeutics for DEPDC5-related epilepsy.
• To identify areas requiring further research, including variant functional impact and therapeutic development.

Main Methods:

• Literature review and synthesis of existing research on DEPDC5 gene variants and epilepsy.
• Analysis of clinical data and genetic findings in patients with DEPDC5-related epilepsy.
• Review of preclinical studies on mTOR inhibitors in relevant epilepsy models.

Main Results:

• DEPDC5 variants are a significant cause of focal epilepsy, often associated with mTORC1 hyperactivity.
• While intelligence is typically preserved, associated conditions include intellectual disability, autism spectrum disorder, and psychiatric issues.
• Phenotypic rescue in animal models supports the therapeutic potential of mTOR inhibitors.

Conclusions:

• DEPDC5-related epilepsy presents a unique genetic epilepsy syndrome with a clear molecular target for therapy.
• Precision therapeutics using mTOR inhibitors show promise for DEPDC5-related epilepsy and potentially other mTOR-dysregulated neurological disorders.
• Further research is crucial to elucidate variant effects, epileptogenesis mechanisms, and clinical translation of precision therapies.