热性惊厥相关性癫痫的疾病谱分析及其基因遗传研究
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摘要
【目的】分析我国热性惊厥相关性癫痫的临床疾病谱特征,筛查160个患者的SCN1A, SCN2A, SCN1B, GABRG2基因,探讨热性惊厥相关性癫痫表型与基因型之间的关系。
【研究对象和方法】通过对2004-2007年间来我院癫痫门诊的2659个癫痫病人进行随访分析,根据国际抗癫痫联盟的分类标准诊断FS, SMEI, MAE;根据国际上认可的标准诊断GEFS+, SMEB, ICEGTC;另根据临床有部分性发作诊断为PEFS+,并详细收集患者的临床表现、脑电图、影像学、精神智力发育、治疗转归及家系资料加以分析。收集热性惊厥相关性癫痫病人及其可能的家系成员血样,提取基因组DNA,应用DHPLC技术筛查SCN1A, SCN2A, SCN1B, GABRG2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】共收集并成功采取血标本160例患者,其中SME(包括SMEI12例, SMEB12个)24例(男20例,女4例), GEFS+34例(男21例,女13例), PEFS+85例(男50例,女35例), FS15例(男6例,女9例), MAE2例(男、女各1例),总男女比例1.58:1。有热性惊厥或癫痫家族史者共71例,占44.4%, SME中7例, 29.2%; GEFS+中15例, 44.1%; PEFS+中39例, 45.9%; FS中9例, 60%; MAE中1例, 50%。患者有多种发作形式,全面性发作有强直阵挛、肌阵挛、失神、强直、失张力发作,部分性发作有CPS、sGTCS、SPS、半侧阵挛发作。部分患者有不同程度精神智力发育迟滞,部分有影像学异常,药物治疗以丙戊酸、托吡酯、氯硝安定的疗效最好,拉莫三嗪和卡马西平疗效多样,或有效或加重。对这160例病人的SCN1A, SCN2A, SCN1B, GABRG2基因筛查发现SCN1A突变20例, SCN2A突变1例,其中SME有8个突变,突变率33.3%,为最高, PEFS+有10个突变,突变率11.7%, FS有2个突变,突变率6.7%, GEFS+有1个突变,突变率2.9%,在MAE病人中无查出突变。SCN1B, GABRG2基因未发现有异常者。在2个先证者为PEFS+并有SCN1A突变的家系中发现为父亲嵌合突变遗传。
【结论】热性相关性癫痫是一个涵盖多种癫痫综合征的疾病,从预后良好的FS到预后恶劣的SME,临床表型复杂多样,几乎包括了所有的癫痫发作类型。而从筛查的4个基因可看出,热性相关性癫痫与SCN1A基因关系最密切,其中又以在SME中的突变率最高,应该是该恶性癫痫脑病的主要致病基因。
Purpose To study the clinical features of febrile seizures related epilepsy, screen SCN1A, SCN2A, SCN1B, GABRG2 genes mutation in 160 Chinese probands and explore the possible relationship between the phenotype and genotype.
Methods Study was done in 2659 patients with epilepsy visiting our epileptic clinic during 2004-2007. According to criteria of the International League against Epilepsy (ILAE), FS, SMEI, MAE were diagnosed; according to international criteria, GEFS+, SMEB, ICEGTC were diagnosed; and the diagnosis of PEFS+ was made based on the partial seizures. The information of clinical manifestation, EEG, brain imaging, psychiatric development, treatment and prognosis were collected and analyzed. DNA of the febrile related epilepsy patients were extracted from peripheral blood. All exons of SCN1A, SCN2A, SCN1B and GABRG2 genes were screened with denaturing high performance liquid chromatography (DHPLC) technology, and then sequence analysis was performed on those with abnormal elution peak.
Results 160 patients were collected, among these there were 24 (male 20, female 4) SME (12 SMEI and 12 SMEB), 34(male 31, female 13) GEFS+, 85(male 50, female 35) PEFS+, 15(male 6, female 9) FS and 2(male 1, female 1) MAE, the sex ration between male and female was 1.58:1. 71 patients had family history of febrile seizures or epilepsy, which was 44.4%, 7 in SME, 29.2%; 15 in GEFS+, 44.1%; 39 in PEFS+, 45.9%; 9 in FS, 60%; 1 in MAE, 50%. All patients had multiple seizure types, generalized seizures included tonic-clonic, myoclonic, absence, tonic and atonic seizures. Parital seizures included CPS, sGTCS, SPS and unilateral clonic seizures. Some of the patients had different degrees of mental developing retardation, some had abnormality on brain imaging. On medicine treatment, VPA, TPM and CNZ were the most effective medicines. LTG and CBZ could be beneficial or aggravated. The screening of SCN1A, SCN2A, SCN1B, GABRG2 genes among these 60 patients found out that 20 mutations in SCN1A, 1 mutation in SCN2A. 8 mutations were found in SME patients, percentage of mutation was 33.3%, 10 mutations in PEFS+ patients, percentage was 11.7%, 2 mutation in FS patients, percentage was 6.7%, 1 mutation in GEFS+, percentage was 2.9%. No mutation was found in MAE patients. There was no abnormality on SCN1B and GABRG2 screening。In 2 PEFS+ probands with SCN1A mutation, mosaic mutation was found in the fathers.
Conclusions Febrile related epilepsy is a disease covers wide range of many epileptic syndromes, from the benign FS to malignant SME, and the clinical phenotype is multiple, includes almost all the epileptic seizures types. From the screening result of 4 genes, SCN1A is the most closed related gene with febrile related epilepsy, and the highest mutation percentage was in SME patients, suggested that SCN1A should be the main pathogenic gene to SME.
【研究对象和方法】通过对2004-2007年间来我院癫痫门诊的2659个癫痫病人进行随访分析,根据国际抗癫痫联盟的分类标准诊断FS, SMEI, MAE;根据国际上认可的标准诊断GEFS+, SMEB, ICEGTC;另根据临床有部分性发作诊断为PEFS+,并详细收集患者的临床表现、脑电图、影像学、精神智力发育、治疗转归及家系资料加以分析。收集热性惊厥相关性癫痫病人及其可能的家系成员血样,提取基因组DNA,应用DHPLC技术筛查SCN1A, SCN2A, SCN1B, GABRG2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】共收集并成功采取血标本160例患者,其中SME(包括SMEI12例, SMEB12个)24例(男20例,女4例), GEFS+34例(男21例,女13例), PEFS+85例(男50例,女35例), FS15例(男6例,女9例), MAE2例(男、女各1例),总男女比例1.58:1。有热性惊厥或癫痫家族史者共71例,占44.4%, SME中7例, 29.2%; GEFS+中15例, 44.1%; PEFS+中39例, 45.9%; FS中9例, 60%; MAE中1例, 50%。患者有多种发作形式,全面性发作有强直阵挛、肌阵挛、失神、强直、失张力发作,部分性发作有CPS、sGTCS、SPS、半侧阵挛发作。部分患者有不同程度精神智力发育迟滞,部分有影像学异常,药物治疗以丙戊酸、托吡酯、氯硝安定的疗效最好,拉莫三嗪和卡马西平疗效多样,或有效或加重。对这160例病人的SCN1A, SCN2A, SCN1B, GABRG2基因筛查发现SCN1A突变20例, SCN2A突变1例,其中SME有8个突变,突变率33.3%,为最高, PEFS+有10个突变,突变率11.7%, FS有2个突变,突变率6.7%, GEFS+有1个突变,突变率2.9%,在MAE病人中无查出突变。SCN1B, GABRG2基因未发现有异常者。在2个先证者为PEFS+并有SCN1A突变的家系中发现为父亲嵌合突变遗传。
【结论】热性相关性癫痫是一个涵盖多种癫痫综合征的疾病,从预后良好的FS到预后恶劣的SME,临床表型复杂多样,几乎包括了所有的癫痫发作类型。而从筛查的4个基因可看出,热性相关性癫痫与SCN1A基因关系最密切,其中又以在SME中的突变率最高,应该是该恶性癫痫脑病的主要致病基因。
Purpose To study the clinical features of febrile seizures related epilepsy, screen SCN1A, SCN2A, SCN1B, GABRG2 genes mutation in 160 Chinese probands and explore the possible relationship between the phenotype and genotype.
Methods Study was done in 2659 patients with epilepsy visiting our epileptic clinic during 2004-2007. According to criteria of the International League against Epilepsy (ILAE), FS, SMEI, MAE were diagnosed; according to international criteria, GEFS+, SMEB, ICEGTC were diagnosed; and the diagnosis of PEFS+ was made based on the partial seizures. The information of clinical manifestation, EEG, brain imaging, psychiatric development, treatment and prognosis were collected and analyzed. DNA of the febrile related epilepsy patients were extracted from peripheral blood. All exons of SCN1A, SCN2A, SCN1B and GABRG2 genes were screened with denaturing high performance liquid chromatography (DHPLC) technology, and then sequence analysis was performed on those with abnormal elution peak.
Results 160 patients were collected, among these there were 24 (male 20, female 4) SME (12 SMEI and 12 SMEB), 34(male 31, female 13) GEFS+, 85(male 50, female 35) PEFS+, 15(male 6, female 9) FS and 2(male 1, female 1) MAE, the sex ration between male and female was 1.58:1. 71 patients had family history of febrile seizures or epilepsy, which was 44.4%, 7 in SME, 29.2%; 15 in GEFS+, 44.1%; 39 in PEFS+, 45.9%; 9 in FS, 60%; 1 in MAE, 50%. All patients had multiple seizure types, generalized seizures included tonic-clonic, myoclonic, absence, tonic and atonic seizures. Parital seizures included CPS, sGTCS, SPS and unilateral clonic seizures. Some of the patients had different degrees of mental developing retardation, some had abnormality on brain imaging. On medicine treatment, VPA, TPM and CNZ were the most effective medicines. LTG and CBZ could be beneficial or aggravated. The screening of SCN1A, SCN2A, SCN1B, GABRG2 genes among these 60 patients found out that 20 mutations in SCN1A, 1 mutation in SCN2A. 8 mutations were found in SME patients, percentage of mutation was 33.3%, 10 mutations in PEFS+ patients, percentage was 11.7%, 2 mutation in FS patients, percentage was 6.7%, 1 mutation in GEFS+, percentage was 2.9%. No mutation was found in MAE patients. There was no abnormality on SCN1B and GABRG2 screening。In 2 PEFS+ probands with SCN1A mutation, mosaic mutation was found in the fathers.
Conclusions Febrile related epilepsy is a disease covers wide range of many epileptic syndromes, from the benign FS to malignant SME, and the clinical phenotype is multiple, includes almost all the epileptic seizures types. From the screening result of 4 genes, SCN1A is the most closed related gene with febrile related epilepsy, and the highest mutation percentage was in SME patients, suggested that SCN1A should be the main pathogenic gene to SME.
引文
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2. Scheffer IE and Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997; 120:479-490.
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4. Singh R, Scheffer IE, Crossland K, et al. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann Neurol 1999; 45:75-81.
5. Fujiwara T, Sugawara T, Mazaki-Miyazaki E, et al. Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic clonic seizures. Brain 2003; 126:531-546.
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8. Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 1998; 19:366-370
9. Wallace RH, Scheffer IE, Parasivam G, et al. Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. Neurology 2002; 58:1426-1429.
10. Audenaert D, Claes L, Ceulemans B, et al. A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology 2003;61:854-856.
11. Scheffer IE, Harkin LA, Grinton BE, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain 2006; 27:1093-1103.
12. Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA (A) receptor dysfunction in epilepsy: a mutation in the g2 subunit gene. Nature Genet 2001; 28: 46-8.
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14. Harkin LA, Browser DN, Dibbens LM, et al. Tuncation of the GABAA-receptorγ2 subunit in family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet. 2002; 70: 530-536.
15. Kananura C, Haug K, Sander T, et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsion. Arch Neurol 2002; 59: 1137-41.
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17. Xiu W, Mei X and Li D. Association analysis ofγ2 subunit ofγ-aminobutyric acid (GABA) type A receptor and voltage-gated sodium channel typeⅡα-polypeptide gene mutation in southern Chinese children with febrile seizures. J Child Neurology 2007; 22(6): 714-719.
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20. Berg AT, Shinnar S. Unprovoked seizures in children with febrile seizures: Short-term outcome [J]. Neurology 1996;47:562-8.
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22. Hirokazu O, Fukuyama Y, Tanaka T, et al. Myoclonic-astatic epilepsy of earlychildhood-clinical and EEG analysis of myoclonic-astatic seizures, and discussions on the nosology of the syndrome. Brain & Development 23 2001,757-764.
23. Ito M, Nagafuji H, Okazawa H, et al. Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (NaC)-channel a1 subunit gene, SCN1A. Epilepsy Res 2002, 48:15-23.
24. Bonanni P,Malcarne M,Moro F,et al. Generalized epilepsy with febrile seizures plus(GEFS+):clinical spectrum in seven Italian families unrelated to SCN1A,SCN1B,and GABRG2 gene mutatins[J].Epilepsia,2004,25:149-158.
25. Janszky J, Ra′sonyi G, Hala′sz P, et al. Disabling Erratic Myoclonus during Lamotrigine Therapy with High Serum Level—Report of Two Cases. Clin. Neuropharmacol, 2000: 23(2); 86-89
26. Guerrini R, Dravet C, Genton P et al. Lamotrigine and Seizure Aggravation in Severe Myoclonic Epilepsy. Epilepsia, 1998:39(5): 508-512,
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28. Vinod KY, Subhash MN. Lamotrigine induced selective changes in 5-HT1A receptor–mediated response in rat brain. Neurochem Int 2002; 40:315–9.
29. Huang CW, Chao-Ching H, Liu YC, et al. Inhibitory Effect of Lamotrigine on A-type Potassium Current in Hippocampal Neuron–Derived H19-7 Cells. Epilepsia, 2004, 45(7): 729–736.
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2. Scheffer IE and Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997; 120:479-490.
3. Abou-Khalil B, Ge Q, Desai R, et al. Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation. Neurology 2001; 57:2265-2272.
4. Singh R, Scheffer IE, Crossland K, et al. Generalized epilepsy with febrile seizures plus: a common childhood-onset genetic epilepsy syndrome. Ann Neurol 1999; 45:75-81.
5. Fujiwara T, Sugawara T, Mazaki-Miyazaki E, et al. Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic clonic seizures. Brain 2003; 126:531-546.
6. Singh R, Andermann E, Whitehouse WP, et al. Severe myoclonic epilepsy of infancy: extended spectrum of GEFS+? Epilepsia 2001; 42:837–44.
7. Karsten Haug a, Kerstin Hallmann a, Johannes Rebstock b,et al. The voltage-gated sodium channel gene SCN2A and idiopathic generalized epilepsy [J]. Epilepsy Research 47 (2002) 243–246.
8. Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 1998; 19:366-370
9. Wallace RH, Scheffer IE, Parasivam G, et al. Generalized epilepsy with febrile seizures plus: mutation of the sodium channel subunit SCN1B. Neurology 2002; 58:1426-1429.
10. Audenaert D, Claes L, Ceulemans B, et al. A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology 2003;61:854-856.
11. Scheffer IE, Harkin LA, Grinton BE, et al. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain 2006; 27:1093-1103.
12. Baulac S, Huberfeld G, Gourfinkel-An I, et al. First genetic evidence of GABA (A) receptor dysfunction in epilepsy: a mutation in the g2 subunit gene. Nature Genet 2001; 28: 46-8.
13. Wallace RH, Marini C, Petrou S, et al. Mutant GABA (A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 2001a; 28:49-52.
14. Harkin LA, Browser DN, Dibbens LM, et al. Tuncation of the GABAA-receptorγ2 subunit in family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet. 2002; 70: 530-536.
15. Kananura C, Haug K, Sander T, et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsion. Arch Neurol 2002; 59: 1137-41.
16. Audenaert D, Schwartz E, Claeys KG, et al. A novel GABRG2 mutation associated with febrile seizures. Neurology 2006; 67: 687-690.
17. Xiu W, Mei X and Li D. Association analysis ofγ2 subunit ofγ-aminobutyric acid (GABA) type A receptor and voltage-gated sodium channel typeⅡα-polypeptide gene mutation in southern Chinese children with febrile seizures. J Child Neurology 2007; 22(6): 714-719.
18. Ito M, Shirasaka Y, Hirose S, et al. Seizure phenotypes of a family with missense mutations in SCN2A. Pediatr Neurol. 2004 Aug; 31(2):150-2.
19. Baulac S, Gourfinkel-An I, Nabbout R, et al. Fever, genes and epilepsy. Lancet, 2004,3:421-430
20. Berg AT, Shinnar S. Unprovoked seizures in children with febrile seizures: Short-term outcome [J]. Neurology 1996;47:562-8.
21. Scheffer IE,Harkin LA,Dibbens LM,et al. Neonatal Epilepsy of Syndromes and Generalized Epilepsy with Febrile Seizures Plus(GEFS+. Epilepsia 2005,46(Suppl.10):41- 47.
22. Hirokazu O, Fukuyama Y, Tanaka T, et al. Myoclonic-astatic epilepsy of earlychildhood-clinical and EEG analysis of myoclonic-astatic seizures, and discussions on the nosology of the syndrome. Brain & Development 23 2001,757-764.
23. Ito M, Nagafuji H, Okazawa H, et al. Autosomal dominant epilepsy with febrile seizures plus with missense mutations of the (NaC)-channel a1 subunit gene, SCN1A. Epilepsy Res 2002, 48:15-23.
24. Bonanni P,Malcarne M,Moro F,et al. Generalized epilepsy with febrile seizures plus(GEFS+):clinical spectrum in seven Italian families unrelated to SCN1A,SCN1B,and GABRG2 gene mutatins[J].Epilepsia,2004,25:149-158.
25. Janszky J, Ra′sonyi G, Hala′sz P, et al. Disabling Erratic Myoclonus during Lamotrigine Therapy with High Serum Level—Report of Two Cases. Clin. Neuropharmacol, 2000: 23(2); 86-89
26. Guerrini R, Dravet C, Genton P et al. Lamotrigine and Seizure Aggravation in Severe Myoclonic Epilepsy. Epilepsia, 1998:39(5): 508-512,
27. Xiong ZG, Chu XP, MacDonald JF. Effect of lamotrigine on the Ca2+-sensing cation current in cultured hippocampal neurons. J Neurophysiol 2001; 86:2520–6.
28. Vinod KY, Subhash MN. Lamotrigine induced selective changes in 5-HT1A receptor–mediated response in rat brain. Neurochem Int 2002; 40:315–9.
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