Gertler Tracy, Bearden David, Bhattacharjee Arin, Carvill Gemma
Department of Pediatrics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois
Department of Neurology, Division of Child Neurology, University of Rochester School of Medicine, Rochester, New York
related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months. ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals with -related ADNFLE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems than individuals with ADNFLE resulting from other causes. Less common seizure phenotypes in individuals with related epilepsy include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy and/or leukoencephalopathy, focal epilepsy, and multifocal epilepsy. Additional neurologic features include hypotonia, microcephaly developing by age 12 months, strabismus, profound developmental delay, and additional movement disorders. Other systemic manifestations including pulmonary hemorrhage caused by prominent systemic-to-pulmonary collateral arteries or cardiac arrhythmia have been reported.
DIAGNOSIS/TESTING: The diagnosis of -related epilepsy is established in a proband with intractable epilepsy and a heterozygous pathogenic variant in identified by molecular genetic testing.
-related epilepsy is often refractory to conventional anticonvulsants; stiripentol, benzodiazepines, levetiracetam, and the ketogenic diet have all been well tolerated with limited success; quinidine has been used as an off-label anticonvulsant with success in some individuals; in rare cases of pulmonary hemorrhage as a result of systemic pulmonary collaterals, embolization has been recommended; developmental support is appropriate. EEG at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen; monitoring of development. For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights). For women with ADNFLE, a discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before conception. Transitioning to a lower-risk medication prior to pregnancy may be possible
-related epilepsy is inherited in an autosomal dominant manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a pathogenic variant. The proportion of cases caused by a pathogenic variant varies by phenotype. All individuals diagnosed with -related epilepsy of infancy with migrating focal seizures (EIMFS) have the disorder as the result of a pathogenic variant or an inherited variant from an unaffected parent with somatic and/or germline mosaicism. Some individuals diagnosed with -related autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have an affected parent. Each child of an individual with -related epilepsy has a 50% chance of inheriting the pathogenic variant, and intrafamilial clinical variability and reduced penetrance have been reported. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family is known.
相关癫痫最常与两种表型相关：婴儿期迁移性局灶性癫痫发作（EIMFS）和常染色体显性遗传性夜间额叶癫痫（ADNFLE）。EIMFS的特征为癫痫发作，通常为局灶性且不同步，始于生命的前六个月，并伴有发育停滞或倒退。自主神经表现（如口周发绀、潮红、呼吸暂停）很常见。癫痫发作对多种抗惊厥药无效，到6至9个月大时会发展为几乎持续发作。ADNFLE的特征为夜间成串的运动性癫痫发作，从简单的觉醒到具有强直或张力障碍特征的运动过多事件不等。与相关ADNFLE患者相比，由其他原因导致ADNFLE的患者更可能在年轻时发病，伴有认知合并症，并出现精神和行为问题。相关癫痫患者中较不常见的癫痫表型包括韦斯特综合征、大田原综合征、早期肌阵挛性脑病、脑白质营养不良和/或脑白质病、局灶性癫痫和多灶性癫痫。其他神经学特征包括肌张力减退、12个月大时出现小头畸形、斜视、严重发育迟缓以及其他运动障碍。还报告了其他全身表现，包括由明显的体肺侧支动脉引起的肺出血或心律失常。
诊断/检测：通过分子遗传学检测在难治性癫痫先证者中发现 中的杂合致病变异，从而确立相关癫痫的诊断。
相关癫痫通常对传统抗惊厥药难治；司替戊醇、苯二氮䓬类药物、左乙拉西坦和生酮饮食耐受性均良好，但效果有限；奎尼丁已作为一种未获批准的抗惊厥药使用，在一些个体中取得了成功；在因体肺侧支导致肺出血的罕见情况下，建议进行栓塞治疗；提供发育支持是合适的。根据癫痫发作频率和进展情况定期进行脑电图检查，以评估新出现的不自主运动或生命体征不明原因的阵发性变化，或在调整抗惊厥药治疗方案后进行检查；监测发育情况。对于ADNFLE患者，应避免从事突然意识丧失可能导致受伤或死亡的活动（如洗澡、游泳、驾驶或在高处工作/玩耍）。对于患有ADNFLE的女性，理想情况下应在受孕前讨论在孕期使用特定抗癫痫药物的风险和益处。在怀孕前可能可以改用风险较低的药物。
相关癫痫以常染色体显性方式遗传。大多数受影响个体为单发病例（即家族中仅有一例发病），由 致病变异引起。由 致病变异导致的病例比例因表型而异。所有被诊断为婴儿期迁移性局灶性癫痫发作（EIMFS）相关癫痫的个体均因 致病变异或来自未受影响父母的具有体细胞和/或生殖细胞镶嵌现象的遗传变异而患病。一些被诊断为常染色体显性遗传性夜间额叶癫痫（ADNFLE）相关癫痫的个体有患病的父母。相关癫痫患者的每个孩子都有50%的机会继承致病变异，并且已报告家族内存在临床变异性和较低的外显率。如果家族中的致病变异已知，则对高风险妊娠进行产前检测和植入前基因检测是可行的。
