Rebekah V. Harris BSc (Hons), Karen L. Oliver MSc, Piero Perucca MD, PhD, Pasquale Striano MD, PhD, Angelo Labate MD, Antonella Riva MD, Bronwyn E. Grinton BSc (Hons), Joshua Reid BSc, Jessica Hutton GradDip (Psych), Marian Todaro PhD, Terence J. O'Brien MD, Patrick Kwan MD, PhD, Lynette G. Sadleir MBChB, MD, Saul A. Mullen MBBS, PhD, Emanuela Dazzo PhD, Douglas E. Crompton MBBS, PhD, Ingrid E. Scheffer MBBS, PhD, Melanie Bahlo PhD, Carlo Nobile PhD, Antonio Gambardella MD, Samuel F. Berkovic MD, FRS
{"title":"家族性颞叶间叶癫痫：多基因结构的临床谱和遗传学证据。","authors":"Rebekah V. Harris BSc (Hons), Karen L. Oliver MSc, Piero Perucca MD, PhD, Pasquale Striano MD, PhD, Angelo Labate MD, Antonella Riva MD, Bronwyn E. Grinton BSc (Hons), Joshua Reid BSc, Jessica Hutton GradDip (Psych), Marian Todaro PhD, Terence J. O'Brien MD, Patrick Kwan MD, PhD, Lynette G. Sadleir MBChB, MD, Saul A. Mullen MBBS, PhD, Emanuela Dazzo PhD, Douglas E. Crompton MBBS, PhD, Ingrid E. Scheffer MBBS, PhD, Melanie Bahlo PhD, Carlo Nobile PhD, Antonio Gambardella MD, Samuel F. Berkovic MD, FRS","doi":"10.1002/ana.26765","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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, <i>p</i> = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>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</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"94 5","pages":"825-835"},"PeriodicalIF":8.1000,"publicationDate":"2023-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26765","citationCount":"0","resultStr":"{\"title\":\"Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture\",\"authors\":\"Rebekah V. Harris BSc (Hons), Karen L. Oliver MSc, Piero Perucca MD, PhD, Pasquale Striano MD, PhD, Angelo Labate MD, Antonella Riva MD, Bronwyn E. Grinton BSc (Hons), Joshua Reid BSc, Jessica Hutton GradDip (Psych), Marian Todaro PhD, Terence J. O'Brien MD, Patrick Kwan MD, PhD, Lynette G. Sadleir MBChB, MD, Saul A. Mullen MBBS, PhD, Emanuela Dazzo PhD, Douglas E. Crompton MBBS, PhD, Ingrid E. Scheffer MBBS, PhD, Melanie Bahlo PhD, Carlo Nobile PhD, Antonio Gambardella MD, Samuel F. Berkovic MD, FRS\",\"doi\":\"10.1002/ana.26765\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>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, <i>p</i> = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Interpretation</h3>\\n \\n <p>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. 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Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture
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
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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