热性惊厥相关性癫痫中的孤独症及其与精神运动发育迟滞和SCN1A突变的相关性研究
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摘要
【目的】研究孤独症在热性惊厥相关性癫痫中的患病率、特征及与癫痫临床特征、精神运动发育迟滞、SCN1A基因突变的相互关系。
【研究对象和方法】通过对1997-2008年间来我院癫痫中心的6040个癫痫患者进行随访分析,根据国际抗癫痫联盟分类诊断标准(1981,1989)诊断FS, Dravet综合症, MAE;根据国际上认可的标准诊断GEFS+, SMEB;另根据临床只有部分性发作诊断为PEFS+。根据DSM-IV和ICD-10诊断孤独症,ABC作为筛查量表,CARS作为辅助诊断量表。为评估患者的智力及发育情况,6岁及以上的患者使用中国儿童韦氏智力量表测试,6岁以下患者使用Gesell儿童发育诊断量表。收集患者的临床资料包括癫痫发作起病年龄、家族史、癫痫发作类型和频率、神经系统检查、对抗癫痫药物的反应、影像学、脑电图和家系资料加以分析。收集热性惊厥相关性癫痫患者及其可能的家系成员血样,提取基因组DNA,应用DHPLE技术筛查SCN1A基因全部外显子,对发现异常洗脱峰者进行测序并分析结果。
【结果】共103例资料详细并成功采取血样的患者,其中GEFS+39例(男25例), PEFS+26例(男16例), Dravet综合症(DS)(包括14例SMEI和23例SMEB)37例(男27例)和MAE 1例(男性)。有热性惊厥或癫痫家族史者42例,占40.8%。这些患者中的癫痫发作形式多样,全面性发作有强直阵挛、肌阵挛、失神、强直和失张力;部分性发作有CPS, SPS, sGTCS和偏侧阵挛发作。94.9%的GEFS+患者有GTCS, 88.5%的PEFS+患者有CPS, 23.1%的PEFS+患者有SPS,而在DS患者GTCS (占86.5%,包括sGTCS)和CPS (59.5%)是最常见的癫痫发作类型。70.3%的DS患者有癫痫持续状态。共11例患者被诊断为孤独症(9例孤独症障碍,2例PDD-NOS),其中包括1例(2.6%) GEFS+患者、1例(3.8%) PEFS+患者和9例(24.3%) DS(4例SMEI和5例SMEB)。在DS患者中,所有孤独症患者均有口头语言发育延迟、无感情互动和兴趣狭窄,而在非孤独症组中口头语言发育延迟、脾气暴躁和兴趣狭窄所占的比例分别是89.3%, 46.4%,和39.9%。全部103例患者均进行了IQ或DQ的测试, 1例MAE智力正常, 46.2%的GEFS+患者和30.8%的PEFS+患者智力正常,其余的GEFS+患者和PEFS+患者均有不同程度的精神运动发育迟滞(MR); 94.6%的DS患者有精神运动发育迟滞。伴孤独症的DS患者中极重度MR的比率更高,而非孤独症的DS患者轻至中度MR的比率更高。103例患者SCN1A基因筛查发现突变31个(30例患者,其中1例PEFS+患者有2个突变),其中GEFS+有8个突变,突变率20.5%, PEFS+有8个突变,突变率30.8%, DS有15个突变,突变率40.5%。1例MAE患者未查出突变。1例GEFS+的孤独症患者未发现SCN1A突变,1例PEFS+的孤独症患者发现SCN1A突变。有SCN1A突变的15例GEFS+、PEFS+患者中,智力正常的共6例,占40%,轻中度精神运动发育迟滞的8例,占53.3%,极重度精神运动发育迟滞的1例,占6.7%。15例有SCN1A突变的DS患者中,有5例孤独症,而22例未发现SCN1A突变的DS患者中有4孤独症,两组之间没有统计学差异。其中60%(3/5)的孤独症患者有极重度MR,80%(8/10)的非孤独症患者为轻至中度MR。
【结论】孤独症与PEFS+和SCN1A突变的相关性尚不清楚。虽然目前对孤独症和Dravet综合症之间的关系了解有限,孤独症在Dravet综合症中的患病率明显高于在其他的癫痫综合症中,以及孤独症性的行为在Dravet综合症中的出现率高均提示我们在临床上要高度注意。除治疗癫痫以外,心理干预措施亦要加以考虑。伴孤独症的Dravet综合症患者有更严重的精神运动发育迟滞,有SCN1A突变者的精神运动发育迟滞比未发现突变者更严重。Dravet综合症和孤独症可能有共同的分子机制——SCN1A基因突变。大样本的临床研究和对潜在的病理生理机制的进一步的基础研究是必要的。
Purpose To study autism in febrile seizures related epilepsy: prevalence, features, and relationship to the clinical characteristics of epilepsy, mental retardation and SCN1A mutation.
Methods The patients were recruited from 6040 epilepsy patients (including 2033 children) visiting our hospital’s Epilepsy Center between 1997 and 2008. According to the criteria of the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) (1981, 1989), FS, Dravet syndrome(DS), MAE were diagnosed; according to international criteria, GEFS+, SMEB were diagnosed,and the diagnosis of PEFS+ was made based on the partial seizures. Autism was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and the International Classification of Diseases, 10th edition(ICD-10). The Autism Behavior Checklist (ABC) was completed, as a screening tool, by the parents under the supervision of a psychiatrist, and the Childhood Autism Rating Scale (CARS) by a psychiatrist for assistance in diagnosis. For evaluation of mental retardation, the Chinese Wechsler Intelligence Scale for Children (C-WISC) was administered by qualified psychologists to the children aged 6 years or above. Gesell Developmental Scales were used for the children less than 6 years old. Clinical data were collected, including the onset age of seizures, family history, seizure types and frequency, neurological examination, and response to anti-epileptic drugs (AEDs). Brain magnetic resonance imaging (MRI) and electroencephalography (EEG) were performed. DNA of the febrile related epilepsy patients were extracted from peripheral blood. All exons of SCN1A gene were screened with denaturing high performance liquid chromatography (DHPLC) technology, and then sequence analysis was performed on those with abnormal elution peak.
Result One hundred and three patients were studied, among them there were 39 (25male) patients with GEFS+, 26 (16 male) patients with PEFS+, 37 (27 male) patients with DS (14 SMEI and 23 SMEB) and 1 patient with MAE (male). Forty-two patients (40.8%) had family history of febrile seizures or epilepsy. Seizure types were multiple, generalized seizures included GTCS, myoclonic, absence, tonic and atonic seizures; partial seizures included CPS, SPS, sGTCS and unilateral clonic seizures. GTCS occurred in 94.9% of patients with GEFS+, CPS in 88.5% of patients with PEFS+, SPS in 23.1% of patients with PEFS+; and in patients with DS, GTCS (86.5%, including secondary GTCS) and complex partial seizures (59.5%) were the most common seizure types. Status epilepticus (SE) occurred in 70.3% of patients with DS. All of 11 patients were diagnosed with autism, including 9 autism disorder and 2 PDD-NOS. One (2.6%) patient with GEFS+, one (3.8%) patient with PEFS+ and 9 (24.3%) patients with DS (4 SMEI and 5 SMEB) were diagnosed with autism. In DS, all patients with autism showed speech delay, no emotional reciprocity, and narrow interest, whereas speech delay, short temper, and narrow interest, respectively, appeared in 89.3%, 46.4%, and 39.9% of patients without autism. IQ/DQ was obtained from all 103 patients, 1 MAE was normal, 46.2% GEFS+ and 30.8% PEFS+ were normal, the remaining of GEFS+ and PEFS+ showed MR; only 2 patients with DS (one with autism and one without autism) showed borderline MR, 94.6% of patients with DS showed MR. Patients with DS with autism had a higher proportion of profound MR, and patients without autism had a higher percentage of mild and moderate MR. SCN1A gene was screened in 103 patients, 8 mutations were found in patients with GEFS+, the percentage of mutation was 20.5%, 8 mutations in patients with PEFS+, the percentage was 30.8%, 15 mutations in patients with DS, the percentage was 40.5%. No mutation was found in the patient with MAE. One SCN1A mutation was found in one patient with PEFS+ with autism. Among 15 patients with DS with SCN1A mutation, there were 5 patients with autism, and 22 patients with DS without SCN1A mutation, there were 4 patients with autism, there was no statistical deference between these two groups. Among 15 patients with DS with SCN1A mutation, 3 patients with autism (60% in patients with autism) had profound MR, 8 patients without autism (80% in patients without autism) had mild to moderate MR.
Conclusions The relationship between autism, PEFS+ and SCN1A mutation is still unclear. Although the current understanding of the association between autism and DS is limited, the high prevalence of autistic behaviors in DS suggests a need for clinical attention. Besides the treatment of epilepsy, measures for psychological intervention should be considered. Patients with DS with autism exhibit more severe mental retardation. DS and autism might share the common molecular mechanisms ----SCN1A mutation. Further clinical studies with large sample sizes and basic research on the underlying pathogenesis mechanism are needed.
【研究对象和方法】通过对1997-2008年间来我院癫痫中心的6040个癫痫患者进行随访分析,根据国际抗癫痫联盟分类诊断标准(1981,1989)诊断FS, Dravet综合症, MAE;根据国际上认可的标准诊断GEFS+, SMEB;另根据临床只有部分性发作诊断为PEFS+。根据DSM-IV和ICD-10诊断孤独症,ABC作为筛查量表,CARS作为辅助诊断量表。为评估患者的智力及发育情况,6岁及以上的患者使用中国儿童韦氏智力量表测试,6岁以下患者使用Gesell儿童发育诊断量表。收集患者的临床资料包括癫痫发作起病年龄、家族史、癫痫发作类型和频率、神经系统检查、对抗癫痫药物的反应、影像学、脑电图和家系资料加以分析。收集热性惊厥相关性癫痫患者及其可能的家系成员血样,提取基因组DNA,应用DHPLE技术筛查SCN1A基因全部外显子,对发现异常洗脱峰者进行测序并分析结果。
【结果】共103例资料详细并成功采取血样的患者,其中GEFS+39例(男25例), PEFS+26例(男16例), Dravet综合症(DS)(包括14例SMEI和23例SMEB)37例(男27例)和MAE 1例(男性)。有热性惊厥或癫痫家族史者42例,占40.8%。这些患者中的癫痫发作形式多样,全面性发作有强直阵挛、肌阵挛、失神、强直和失张力;部分性发作有CPS, SPS, sGTCS和偏侧阵挛发作。94.9%的GEFS+患者有GTCS, 88.5%的PEFS+患者有CPS, 23.1%的PEFS+患者有SPS,而在DS患者GTCS (占86.5%,包括sGTCS)和CPS (59.5%)是最常见的癫痫发作类型。70.3%的DS患者有癫痫持续状态。共11例患者被诊断为孤独症(9例孤独症障碍,2例PDD-NOS),其中包括1例(2.6%) GEFS+患者、1例(3.8%) PEFS+患者和9例(24.3%) DS(4例SMEI和5例SMEB)。在DS患者中,所有孤独症患者均有口头语言发育延迟、无感情互动和兴趣狭窄,而在非孤独症组中口头语言发育延迟、脾气暴躁和兴趣狭窄所占的比例分别是89.3%, 46.4%,和39.9%。全部103例患者均进行了IQ或DQ的测试, 1例MAE智力正常, 46.2%的GEFS+患者和30.8%的PEFS+患者智力正常,其余的GEFS+患者和PEFS+患者均有不同程度的精神运动发育迟滞(MR); 94.6%的DS患者有精神运动发育迟滞。伴孤独症的DS患者中极重度MR的比率更高,而非孤独症的DS患者轻至中度MR的比率更高。103例患者SCN1A基因筛查发现突变31个(30例患者,其中1例PEFS+患者有2个突变),其中GEFS+有8个突变,突变率20.5%, PEFS+有8个突变,突变率30.8%, DS有15个突变,突变率40.5%。1例MAE患者未查出突变。1例GEFS+的孤独症患者未发现SCN1A突变,1例PEFS+的孤独症患者发现SCN1A突变。有SCN1A突变的15例GEFS+、PEFS+患者中,智力正常的共6例,占40%,轻中度精神运动发育迟滞的8例,占53.3%,极重度精神运动发育迟滞的1例,占6.7%。15例有SCN1A突变的DS患者中,有5例孤独症,而22例未发现SCN1A突变的DS患者中有4孤独症,两组之间没有统计学差异。其中60%(3/5)的孤独症患者有极重度MR,80%(8/10)的非孤独症患者为轻至中度MR。
【结论】孤独症与PEFS+和SCN1A突变的相关性尚不清楚。虽然目前对孤独症和Dravet综合症之间的关系了解有限,孤独症在Dravet综合症中的患病率明显高于在其他的癫痫综合症中,以及孤独症性的行为在Dravet综合症中的出现率高均提示我们在临床上要高度注意。除治疗癫痫以外,心理干预措施亦要加以考虑。伴孤独症的Dravet综合症患者有更严重的精神运动发育迟滞,有SCN1A突变者的精神运动发育迟滞比未发现突变者更严重。Dravet综合症和孤独症可能有共同的分子机制——SCN1A基因突变。大样本的临床研究和对潜在的病理生理机制的进一步的基础研究是必要的。
Purpose To study autism in febrile seizures related epilepsy: prevalence, features, and relationship to the clinical characteristics of epilepsy, mental retardation and SCN1A mutation.
Methods The patients were recruited from 6040 epilepsy patients (including 2033 children) visiting our hospital’s Epilepsy Center between 1997 and 2008. According to the criteria of the Commission on Classification and Terminology of the International League Against Epilepsy (ILAE) (1981, 1989), FS, Dravet syndrome(DS), MAE were diagnosed; according to international criteria, GEFS+, SMEB were diagnosed,and the diagnosis of PEFS+ was made based on the partial seizures. Autism was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and the International Classification of Diseases, 10th edition(ICD-10). The Autism Behavior Checklist (ABC) was completed, as a screening tool, by the parents under the supervision of a psychiatrist, and the Childhood Autism Rating Scale (CARS) by a psychiatrist for assistance in diagnosis. For evaluation of mental retardation, the Chinese Wechsler Intelligence Scale for Children (C-WISC) was administered by qualified psychologists to the children aged 6 years or above. Gesell Developmental Scales were used for the children less than 6 years old. Clinical data were collected, including the onset age of seizures, family history, seizure types and frequency, neurological examination, and response to anti-epileptic drugs (AEDs). Brain magnetic resonance imaging (MRI) and electroencephalography (EEG) were performed. DNA of the febrile related epilepsy patients were extracted from peripheral blood. All exons of SCN1A gene were screened with denaturing high performance liquid chromatography (DHPLC) technology, and then sequence analysis was performed on those with abnormal elution peak.
Result One hundred and three patients were studied, among them there were 39 (25male) patients with GEFS+, 26 (16 male) patients with PEFS+, 37 (27 male) patients with DS (14 SMEI and 23 SMEB) and 1 patient with MAE (male). Forty-two patients (40.8%) had family history of febrile seizures or epilepsy. Seizure types were multiple, generalized seizures included GTCS, myoclonic, absence, tonic and atonic seizures; partial seizures included CPS, SPS, sGTCS and unilateral clonic seizures. GTCS occurred in 94.9% of patients with GEFS+, CPS in 88.5% of patients with PEFS+, SPS in 23.1% of patients with PEFS+; and in patients with DS, GTCS (86.5%, including secondary GTCS) and complex partial seizures (59.5%) were the most common seizure types. Status epilepticus (SE) occurred in 70.3% of patients with DS. All of 11 patients were diagnosed with autism, including 9 autism disorder and 2 PDD-NOS. One (2.6%) patient with GEFS+, one (3.8%) patient with PEFS+ and 9 (24.3%) patients with DS (4 SMEI and 5 SMEB) were diagnosed with autism. In DS, all patients with autism showed speech delay, no emotional reciprocity, and narrow interest, whereas speech delay, short temper, and narrow interest, respectively, appeared in 89.3%, 46.4%, and 39.9% of patients without autism. IQ/DQ was obtained from all 103 patients, 1 MAE was normal, 46.2% GEFS+ and 30.8% PEFS+ were normal, the remaining of GEFS+ and PEFS+ showed MR; only 2 patients with DS (one with autism and one without autism) showed borderline MR, 94.6% of patients with DS showed MR. Patients with DS with autism had a higher proportion of profound MR, and patients without autism had a higher percentage of mild and moderate MR. SCN1A gene was screened in 103 patients, 8 mutations were found in patients with GEFS+, the percentage of mutation was 20.5%, 8 mutations in patients with PEFS+, the percentage was 30.8%, 15 mutations in patients with DS, the percentage was 40.5%. No mutation was found in the patient with MAE. One SCN1A mutation was found in one patient with PEFS+ with autism. Among 15 patients with DS with SCN1A mutation, there were 5 patients with autism, and 22 patients with DS without SCN1A mutation, there were 4 patients with autism, there was no statistical deference between these two groups. Among 15 patients with DS with SCN1A mutation, 3 patients with autism (60% in patients with autism) had profound MR, 8 patients without autism (80% in patients without autism) had mild to moderate MR.
Conclusions The relationship between autism, PEFS+ and SCN1A mutation is still unclear. Although the current understanding of the association between autism and DS is limited, the high prevalence of autistic behaviors in DS suggests a need for clinical attention. Besides the treatment of epilepsy, measures for psychological intervention should be considered. Patients with DS with autism exhibit more severe mental retardation. DS and autism might share the common molecular mechanisms ----SCN1A mutation. Further clinical studies with large sample sizes and basic research on the underlying pathogenesis mechanism are needed.
引文
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[46] Kanai K, Hirose S, Oguni H, et al. Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity. Neurology. 2004;63(2):329-34.
[47] Zucca C, Redaelli F, Epifanio R,et al. Cryptogenic epileptic syndromes related to SCN1A: twelve novel mutations identified. Arch Neurol. 2008;65(4):489-94.
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