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

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2023-08-19 DOI:10.1002/ana.26765

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

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引用次数: 0

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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家族性颞叶间叶癫痫：多基因结构的临床谱和遗传学证据。

目的：家族性近中颞叶癫痫（FMTLE）是一种重要的局灶性癫痫综合征；其分子遗传学基础尚不清楚。FMTLE的临床描述各不相同，既有明显似曾相识的轻度综合征，也有伴有高热惊厥和海马硬化的更严重表型。我们的目的是通过分析一大群患者来完善FMTLE的表型，并询问通过多基因风险评分（PRS）测量的局灶性癫痫和/或热性癫痫的常见风险变体是否在FMTLE患者中富集。方法：我们研究了134个≥ 2名颞叶癫痫的一级或二级亲属，至少有一人需要明确的近中发作症状学。计算了227例FMTLE病例、124例未受影响的亲属和16077例人群对照的PRS。结果：FMTLE患者的发病年龄在2.5至70岁之间年（中位数 = 18，四分位间距 = 13-28 年）。最常见的局灶性癫痫症状是似曾相识（62%的病例），其次是上腹部感觉上升（34%）和恐惧或焦虑（22%）。临床谱包括罕见的耐药和/或海马硬化症病例。FMTLE病例的平均局灶性癫痫PRS高于对照组（优势比 = 1.24,95%置信区间 = 1.06,1.46，p = 0.007）；相反，没有观察到热性惊厥PRS的富集。解释：FMTLE是一种通常较轻的药物反应综合征，似曾相识是最常见的症状。与显性单基因局灶性癫痫综合征相反，我们的分子数据支持FMTLE的多基因基础。此外，PRS数据表明，亚基因组范围内显著的局灶性癫痫全基因组关联研究单核苷酸多态性是FMTLE的重要风险变异。神经网络2023；94:825-835。

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

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.