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

Rebekah V Harris¹, Karen L Oliver^{1

2

3}, Piero Perucca^{1

4

5

6

7}, Pasquale Striano^{8

9}, Angelo Labate^{10

11}, Antonella Riva^{8

9}, Bronwyn E Grinton¹, Joshua Reid¹, Jessica Hutton^{1

5

6

7}, Marian Todaro^{5

6

7}, Terence J O'Brien^{5

6

7}, Patrick Kwan^{5

6

7}, Lynette G Sadleir¹², Saul A Mullen^{1

4}, Emanuela Dazzo¹³, Douglas E Crompton^{1

14}, Ingrid E Scheffer^{1

4

15

16}, Melanie Bahlo^{2

3}, Carlo Nobile¹², Antonio Gambardella^{10

11}, Samuel F Berkovic^{1

4}

Affiliations

¹ Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia.
² Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
³ Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
⁴ Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
⁵ Departments of Medicine and Neurology, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ Department of Neurology, Alfred Health, Melbourne, Victoria, Australia.
⁷ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁸ IRCCS Istituto Giannina Gaslini, Member of ERN-Epicare, Genoa, Italy.
⁹ Departments of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal, and Child Health, University of Genoa, Genoa, Italy.
¹⁰ Neurophysiopatology and Movement Disorders Clinic, University of Messina, Messina, Italy.
¹¹ Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
¹² Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
¹³ The CNR Institute of Neuroscience (CNR-IN), National Research Council of Italy, Padova, Italy.
¹⁴ Department of Neurology, Northern Health, Epping, Victoria, Australia.
¹⁵ Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
¹⁶ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.

PMID: 37597255
PMCID: PMC10952415
DOI: 10.1002/ana.26765

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

Rebekah V Harris et al. Ann Neurol. 2023 Nov.

. 2023 Nov;94(5):825-835.

doi: 10.1002/ana.26765. Epub 2023 Aug 31.

Authors

Affiliations

¹ Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia.
² Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
³ Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
⁴ Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
⁵ Departments of Medicine and Neurology, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ Department of Neurology, Alfred Health, Melbourne, Victoria, Australia.
⁷ Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁸ IRCCS Istituto Giannina Gaslini, Member of ERN-Epicare, Genoa, Italy.
⁹ Departments of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal, and Child Health, University of Genoa, Genoa, Italy.
¹⁰ Neurophysiopatology and Movement Disorders Clinic, University of Messina, Messina, Italy.
¹¹ Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
¹² Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
¹³ The CNR Institute of Neuroscience (CNR-IN), National Research Council of Italy, Padova, Italy.
¹⁴ Department of Neurology, Northern Health, Epping, Victoria, Australia.
¹⁵ Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
¹⁶ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.

PMID: 37597255
PMCID: PMC10952415
DOI: 10.1002/ana.26765

Abstract

Objective: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE.

Methods: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls.

Results: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed.

Interpretation: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.

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Conflict of interest statement

Nothing to report.

Figures

**Figure 1**
Process of review and inclusion of families to this study. FS = febrile seizure; FMTLE = familial mesial temporal lobe epilepsy; MTLE = mesial temporal lobe epilepsy; TLE = temporal lobe epilepsy.

**Figure 2**
Comparison of mean PRS for focal epilepsy across affected individuals from FMTLE families, their unaffected relatives, and population controls. (A) Normalized distributions of focal epilepsy PRS. (B) Shown are the means of the normalized PRS values with 95% CIs for the FMTLE cases, their relatives, and population controls. CI = confidence interval; FMTLE = familial mesial temporal lobe epilepsy; PRS = polygenic risk score. [Color figure can be viewed at www.annalsofneurology.org]

**Figure 3**
Comparison of mean PRS for FS across affected individuals from FMTLE families, their unaffected relatives and population controls. (A) Normalized distributions of FS‐PRS, showing standard deviation (SD). (B) Shown are the means of the normalized PRS values with 95% CIs for the affected cases from FMTLE families, their unaffected relatives, and population controls. CI = confidence interval; FMTLE = familial mesial temporal lobe epilepsy; FS = febrile seizure; PRS = polygenic risk score. [Color figure can be viewed at www.annalsofneurology.org]

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources

Full Text Sources