Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture

Area of Science:

• Neuroscience
• Genetics
• Epilepsy Research

Background:

• Familial mesial temporal lobe epilepsy (FMTLE) is a significant focal epilepsy syndrome with an unknown molecular genetic basis.
• Clinical presentations of FMTLE range from mild déjà vu to severe phenotypes involving febrile seizures and hippocampal sclerosis.

Purpose of the Study:

• To refine the phenotype of FMTLE through analysis of a large patient cohort.
• To investigate whether common risk variants for focal epilepsy and febrile seizures, assessed by polygenic risk scores (PRS), are enriched in FMTLE individuals.

Main Methods:

• Studied 134 families with at least two relatives diagnosed with temporal lobe epilepsy and mesial ictal semiology.
• Calculated PRS for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls.

Main Results:

• FMTLE onset ranged from 2.5 to 70 years, with déjà vu being the most frequent symptom (62%).
• FMTLE cases exhibited a higher mean focal epilepsy PRS compared to population controls (OR=1.24, P=0.007).
• No enrichment for febrile seizure PRS was found in FMTLE cases.

Conclusions:

• FMTLE is typically a mild, drug-responsive syndrome characterized by déjà vu.
• Molecular data support a polygenic basis for FMTLE, contrasting with dominant monogenic focal epilepsy syndromes.
• Polygenic risk score data indicate that common single nucleotide polymorphisms associated with focal epilepsy are significant risk variants for FMTLE.