[Early infantile epileptic encephalopathy caused by PACS2 gene variation: three cases report and literature review].

Objective: To explore the clinical features of three early-onset infantile epileptic encephalopathy (EIEE) patients with variations in phosphofurin acidic cluster sorting protein 2 (PACS2) gene and to review related literature. Methods: The clinical data and genetic features of three early infantile epileptic encephalopathy 66 (EIEE66) patients with a PACS2 gene variant diagnosed by the Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2019 to January 2020 were retrospectively analyzed. A literature search with "PACS2 gene" "PACS2" "epileptic encephalopathy, early infantile, 66" and"early infantile epileptic encephalopathy 66" as key words was conducted at PubMed, China National Knowledge Infrastructure (CNKI), and Wanfang Data Knowledge Service Platform (up to July 2020). Case reports of patients with PACS2 gene variants and related clinical data were chosen and reviewed. Results: Case 1, a girl aged 2 years and 2 months was hospitalized because of repetitive seizures within more than two years and 6 convulsions within 2 days due to fever. The seizures occurred at the age of 7 days, characterized by focal seizures and generalized tonic-clonic seizures. Sometimes, the frequency of seizures increased with high fever. Regular treatment had not been implemented in the early stage, later seizures were controlled by valproic acid treatment. Case 2, a female 5 months of age, was admitted due to recurrent convulsions in nearly five months. Focal seizures occured at the age of 5 days. And the brain magnetic resonance imaging (MRI) confirmed abnormal cerebellar hemispheres and cerebellar vermis, as well as cerebellar dysplasia. Several antiepileptic drugs and ketogenic diet were ineffective in the early months, and later seizures were controlled with the treatment with levetiracetam and valproic acid. Case 3, a five-month-old girl, was admitted because of recurrent convulsions for nearly five months. At the age of 3 days, she had tonic seizures, and showed good response to levetiracetam and valproic acid. All the three cases were accompanied by development delay and dysmorphic facial appearance, and got seizure-free with the treatment with valproic acid. All copy-number variant analysis and trio whole exome sequencing revealed a recurrent heterozygous missense variant (c.625G>A) in PACS2 gene. No related reports were found in Chinese journals, while 4 reports were found in English literature, describing 17 patients in total. With these 3 patients included, 20 cases had only two missense PACS2 gene variants, in whom 19 cases carried the variant c. 625G>A (p.Glu209Lys) and 1 case carried the variant c. 631G>A (p.Glu211Lys). Epilepsy was the first reported symptom in all patients, and 17 cases had seizures during the first week of life. Out of the various seizure types observed, focal seizures were the predominant types (13 cases), whereas tonic, clonic, tonic-clonic seizures and non-motor seizures (such as facial flushing) were also reported. Almost all patients showed facial dysmorphism and developmental delay to different degrees. Total of 16 patients had abnormal brain MRI recordings, and 13 cases had cerebellar hypoplasia. More specifically, 7 cases showed inferior vermian hypoplasia, and 3 cases showed hypothalamic fusion anomaly. The treatment was mainly aimed to control the symptoms. And the recommended effective treatment for epilepsy has not been reported yet. Conclusions: PACS2-related early infantile epileptic encephalopathy is an autosomal dominant disease, characterized by seizure onset within the first week of life in most cases, dysmorphic facial appearance, and various degrees of developmental retardation. Treatment with valproic acid showed good effect.目的： 探讨磷酸弗林蛋白酶酸性氨基酸簇分选2（PACS2）基因变异致早发癫痫性脑病（EIEE）患儿的临床特点。 方法： 回顾性总结2019年1月至2020年1月就诊于华中科技大学同济医学院附属武汉儿童医院神经内科的3例PACS2基因变异所致EIEE66患儿的病例资料。分别以“PACS2基因”“早发癫痫性脑病66型”“PACS2”“epileptic encephalopathy，early infantile，66”“early infantile epileptic encephalopathy 66”为检索词检索Pubmed、中国知网、万方医学网等数据库（建库至2020年7月），选取有PACS2基因变异及相关临床资料的文献进行复习，总结PACS2基因变异所致EIEE66患儿的临床特点。 结果：例1 女，2岁2月龄，主因“间断抽搐2年余，发热2 d内抽搐6次”就诊，生后第7天出现抽搐，表现为局灶性发作和全面性强直阵挛发作，偶在发热时抽搐频次增多；早期未规律服药，后期丙戊酸治疗发作控制。例2 女，5月龄，主因“间断抽搐近5个月”就诊，生后第5天出现局灶性癫痫发作，病程中头颅磁共振成像（MRI）示小脑半球及小脑蚓部改变、小脑发育不良；癫痫早期多药难治，生酮饮食无效，予左乙拉西坦、丙戊酸治疗后发作控制。例3 女，5月龄，主因“间断抽搐近5个月”就诊，出生后第3天出现抽搐，表现为强直发作，左乙拉西坦、丙戊酸治疗后发作控制。3例患儿均存在发育迟缓和面容异常，使用丙戊酸治疗后癫痫发作控制。拷贝数变异（CNV）和全外显子测序结果均发现PACS2基因c.625G>A（p.Glu209Lys）新发杂合变异。检索符合条件的中文文献0篇、英文文献4篇共17例患儿。包括本组3例在内，共20例患儿纳入分析，共发现2个PACS2基因错义变异，其中19例携带变异c.625G>A （p.Glu209Lys）、1例携带变异c.631G>A （p.Glu211Lys）。20例患儿均以癫痫起病，17例在生后1周内起病，有多种癫痫发作类型，以局灶性发作为主（13例），也可见强直、阵挛、强直-阵挛发作和非运动性发作（面色潮红等）；所有患儿具有面容异常和不同程度的发育落后。16例患儿头颅MRI结果异常，13例表现为小脑发育不全，其中7例表现为小脑蚓部发育不全，3例表现为下丘脑融合异常。治疗主要为对症治疗，文献尚无推荐有效抗癫痫治疗药物。 结论： PACS2基因变异相关EIEE呈常染色体显性遗传，多在生后1周内以癫痫起病，伴有面容异常和不同程度发育落后。丙戊酸治疗有效率较高。.