基因检测对儿童癫痫性脑病的检出率_Journal of Epilepsy

Authors：

 Mercimek-MahmutogluS , PatelJ , CordeiroD , HewsonS , CallenD , DonnerEJ , HahnCD , KannuP , KobayashiJ , MinassianBA , MoharirM , SiriwardenaK , WeissSK , WeksbergR , SneadOC , 童馨 , 慕洁

Corresponding author：

Mercimek-MahmutogluS, Email: saadet.Mahmutoglu@sickkids.Ca

Keywords：

癫痫; 基因; 代谢障碍; 染色体; 分子遗传学

DOI：

10.7507/2096-0247.20160093

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

癫痫是儿童期常见的神经系统疾病,为了明确癫痫性脑病的基因检出率,对一个癫痫遗传诊所进行了一项回顾性队列研究。2012年1月-2014年6月,在一个癫痫遗传诊所纳入了所有兼有难治性癫痫、整体性发育迟滞和认知功能障碍的患者。通过回顾电子病历,获得了患者的临床特征、神经影像、生化检验及分子遗传学资料,包括对癫痫性脑病基因的第二代目的基因测序。在110例患者中,发现28%是有基因异常的:7%有遗传性代谢障碍,包括由ALDH7A1变异引起的吡哆醇依赖性癫痫、Menkes病、吡哆醇-5-磷酸氧化酶缺乏、钴胺素G缺乏、亚甲基四氢叶酸还原酶缺乏、I型葡萄糖载体缺陷、甘氨酸脑病和丙酮酸脱氢酶复合体缺陷;21%有其他的基因病因,包括遗传性综合征、在阵列比较基因组杂交上的致病性拷贝数变异,以及与SCN1A、SCN2A、SCN8A、KCNQ2、STXBP1、PCDH19和SLC9A6基因变异相关的癫痫性脑病。4.5%的患者得到了由第二代目的基因测序的癫痫性脑病面板作出的基因诊断。值得注意的是,4.5%的患者有可治的遗传性代谢性疾病。该研究为首个将遗传性代谢障碍和癫痫性脑病的其他遗传病因结合起来的研究。第二代目的基因测序面板将癫痫性脑病患者的基因诊断检出率从＜10%增加到＞25%。

Citation： Mercimek-MahmutogluS, PatelJ, CordeiroD, HewsonS, CallenD, DonnerEJ, HahnCD, KannuP, KobayashiJ, MinassianBA, MoharirM, SiriwardenaK, WeissSK, WeksbergR, SneadOC, 童馨, 慕洁. 基因检测对儿童癫痫性脑病的检出率. Journal of Epilepsy, 2016, 2(6): 527-534. doi: 10.7507/2096-0247.20160093 Copy

1.	Wiebe S, Bellhouse DR, Fallahay C, et al. Burden of epilepsy:the Ontario Health Survey. Can J Neurol Sci, 1999, 26(11):263-270.
2.	Kwan P, Brodie MJ. Early identification of refractory epilepsy. N EnglJ Med,2000, 342(8):314-319.
3.	Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies:report of the ILAE Commission on Classification and Terminology, 2005-2009.Epilepsia,2010, 51(7):676-685.
4.	Chawla S, Aneja S, Kashyap R, et al. Etiology and clinical predictors of intractable epilepsy. Pediatr Neurol,2002, 27(3):186-191.
5.	Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants arean important cause of epileptic encephalopathies. Ann Neurol,2011, 70(11):974-985.
6.	Lemke JR, Riesch E, Scheurenbrand T, et al. Targeted next generationsequencing as a diagnostic tool in epileptic disorders. Epilepsia,2012, 21(5):1387-1398.
7.	Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet,2014, 23(6):3200-3211.
8.	Jain-Ghai S, Mishra N, Hahn C, et al. Fetal onset ventriculomegalyand subependymal cysts in a pyridoxine dependent epilepsy patient.Pediatrics,2014, 133(11):e1092-e1096.
9.	Guerin A, Aziz AS, Mutch C, et al. Pyridox(am)ine-5-phosphateoxidase deficiency treatable cause of neonatal epileptic encephalopathy with burst suppression:case report and review of theliterature. J Child Neurol, 2014, 27(10):829.
10.	Munoz T, Patel J, Badilla-Porras R, et al. Severe scoliosis in a patientwith severe methylenetetrahydrofolate reductase deficiency. BrainDev, 2014,37(6):168-170.
11.	Mercimek-Mahmutoglu S, Cordeiro D, Nagy L, et al. Lysine restricteddiet and mild cerebral serotonin deficiency in a patient with pyridoxinedependent epilepsy caused by ALDH7A1 genetic defect. Mol GenetMetab Rep,2014, 1(7):124-128.
12.	Olson H, Shen Y, Avallone J, et al. Copy number variation plays animportant role in clinical epilepsy. Ann Neurol,2014, 75(7):943-958.
13.	Wang D, Pascual JM, De Vivo D. Glucose transporter type 1deficiency syndrome. In Pagon RA, Adam MP, Ardinger HH, Bird TD,Dolan CR, Fong CT, Smith RJH, Stephens K (Eds) GeneReviews. Seattle, WA:University of Washington, Seattle; 1993:1-256.
14.	Kodera H, Mitsuhiro K, Nord AS, et al. Targed capture andsequencing for detection of mutation causing early onset epilepticencephalopathy. Epilepsia,2013, 54(3):1262-1269.
15.	Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing inepileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet,2013, 45(4):825-830.
16.	Della Mina E, Ciccone R, Brustia F, et al. Improving moleculardiagnosis in epilepsy by a dedicated high-throughput sequencingplatform. Eur J Hum Genet,2015, 23(8):354-362.
17.	Wang J, Gotway G, Pascual JM, et al. Diagnostic yield of clinicalnext-generation sequencing panels for epilepsy. JAMA Neurol,2014, 71(10):650-651.
18.	Veeramah KR, Johnstone L, Karafet TM, et al. Exome sequencingreveals new causal mutations in children with epilepticencephalopathies. Epilepsia,2013, 54(7):1270-1281.
19.	Dyment DA, Tetreault M, Beaulieu CL, et al. Whole-exomesequencing broadens the phenotypic spectrum of rare pediatricepilepsy:a retrospective study. Clin Genet, 2014, 21(7):12464.
20.	Michaud JL, Lachance M, Hamdan FF, et al. The genetic landscape ofinfantile spasms. Hum Mol Genet,2014, 23(5):4846-4858.
21.	Allen AS,Berkovic SF. De novo mutations in epileptic encephalopathies.Nature,2013, 501(11):217-221.
22.	Euro-epinomics-res Consortium, Epilepsy Phenome/Genome Project, Epileptic Consortium. De novo mutations in synaptictransmission genes including DNM1 cause epileptic encephalopathies.Am J Hum Genet, 2014, 95(6):360-370.
23.	Depienne C, LeGuern E. PCDH19-related infantile epileptic encephalopathy:an unusual X-linked inheritance disorder. Hum Mutat, 2012, 33(7):627-634.
24.	Milh M, Villeneuve N, Chouchane M, et al. Epileptic and nonepilepticfeatures in patients with early onset epileptic encephalopathy andSTXBP1 mutations. Epilepsia, 2011, 52(7):1828-1834.
25.	Deprez L, Weckhuysen S, Holmgren P, et al. Clinical spectrum ofearly-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology,2010, 75(8):1159-1165.
26.	Miller IO, Sotero de Menezes MA. SCN1A-related seizure disorders.In Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT,Smith RJH, Stephens K (Eds) GeneReviews. Seattle, WA:University of Washington, Seattle; 1993-2014, 2007, 29[updated2014 May 15].
27.	Nakamura K, Kato M, Osaka H, et al. Clinical spectrum ofSCN2A mutations expanding to ohtahara syndrome. Neurology, 2013, 81(10):992-998.
28.	Veeramah KR, O'Brien JE, Meisler MH, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a familyquartet affected by infantile epileptic encephalopathy and SUDEP. AmJ Hum Gene, 2012, 90(4):502-510.
29.	Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia, 2014, 55(3):994-1000.
30.	Milh M, Boutry-Kryza N, Sutera-Sardo J, et al. Similar earlycharacteristics but variable neurological outcome of patients with a denovo mutation of KCNQ2. Orphanet J Rare Dis, 2013, 8(2):80.
31.	Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy:emerging phenotype of a neonatal epileptic encephalopathy. AnnNeurol, 2012, 71(8):15-25.
32.	Wolf NI, Bast T, Surtees R. Epilepsy in inborn errors of metabolism.Epileptic Disord, 2005, 7(2):67-81.
33.	Weber YG, Storch A, Wuttke TV, et al. GLUT1 mutations are a causeof paroxysmal exertion-induced dyskinesias and induce hemolyticanemia by a cation leak. J Clin Invest, 2008, 118(3):2157-2168.
34.	Wilson A, Leclerc D, Saberi F, et al. Functionally null mutations inpatients with the cblg-variant form of methionine synthase deficiency.Am J Hum Genet, 1998, 63(2):409-414.
35.	Urreizti R, Moya-Garc AA, Pino-Angeles A, et al. Molecularcharacterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clin Genet, 2010, 78(1):441-448.
36.	Auranen M, Vanhala R, Vosman M, et al. MECP2 gene analysis inclassical Rett syndrome and in patients with Rett-like features.Neurology, 2001, 56(3):611-617.
37.	Morris-Rosendahl DJ, Najm J, Lachmeijer AM, et al. Refining thephenotype of alpha-1a Tubulin (TUBA1A) mutation in patients withclassical lissencephaly. Clin Genet, 2008, 74(4):425-433.
38.	Marini C, Mei D, Temudo T, et al. Idiopathic epilepsies with seizuresprecipitated by fever and SCN1A abnormalities. Epilepsia, 2007, 48(7):1678-1685.
39.	Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1 Agene mutations associated with Dravet syndrome:analysis of 333patients. J Med Genet, 2009, 46(5):183-191.

1. Wiebe S, Bellhouse DR, Fallahay C, et al. Burden of epilepsy:the Ontario Health Survey. Can J Neurol Sci, 1999, 26(11):263-270.
2. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N EnglJ Med,2000, 342(8):314-319.
3. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies:report of the ILAE Commission on Classification and Terminology, 2005-2009.Epilepsia,2010, 51(7):676-685.
4. Chawla S, Aneja S, Kashyap R, et al. Etiology and clinical predictors of intractable epilepsy. Pediatr Neurol,2002, 27(3):186-191.
5. Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants arean important cause of epileptic encephalopathies. Ann Neurol,2011, 70(11):974-985.
6. Lemke JR, Riesch E, Scheurenbrand T, et al. Targeted next generationsequencing as a diagnostic tool in epileptic disorders. Epilepsia,2012, 21(5):1387-1398.
7. Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet,2014, 23(6):3200-3211.
8. Jain-Ghai S, Mishra N, Hahn C, et al. Fetal onset ventriculomegalyand subependymal cysts in a pyridoxine dependent epilepsy patient.Pediatrics,2014, 133(11):e1092-e1096.
9. Guerin A, Aziz AS, Mutch C, et al. Pyridox(am)ine-5-phosphateoxidase deficiency treatable cause of neonatal epileptic encephalopathy with burst suppression:case report and review of theliterature. J Child Neurol, 2014, 27(10):829.
10. Munoz T, Patel J, Badilla-Porras R, et al. Severe scoliosis in a patientwith severe methylenetetrahydrofolate reductase deficiency. BrainDev, 2014,37(6):168-170.
11. Mercimek-Mahmutoglu S, Cordeiro D, Nagy L, et al. Lysine restricteddiet and mild cerebral serotonin deficiency in a patient with pyridoxinedependent epilepsy caused by ALDH7A1 genetic defect. Mol GenetMetab Rep,2014, 1(7):124-128.
12. Olson H, Shen Y, Avallone J, et al. Copy number variation plays animportant role in clinical epilepsy. Ann Neurol,2014, 75(7):943-958.
13. Wang D, Pascual JM, De Vivo D. Glucose transporter type 1deficiency syndrome. In Pagon RA, Adam MP, Ardinger HH, Bird TD,Dolan CR, Fong CT, Smith RJH, Stephens K (Eds) GeneReviews. Seattle, WA:University of Washington, Seattle; 1993:1-256.
14. Kodera H, Mitsuhiro K, Nord AS, et al. Targed capture andsequencing for detection of mutation causing early onset epilepticencephalopathy. Epilepsia,2013, 54(3):1262-1269.
15. Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing inepileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet,2013, 45(4):825-830.
16. Della Mina E, Ciccone R, Brustia F, et al. Improving moleculardiagnosis in epilepsy by a dedicated high-throughput sequencingplatform. Eur J Hum Genet,2015, 23(8):354-362.
17. Wang J, Gotway G, Pascual JM, et al. Diagnostic yield of clinicalnext-generation sequencing panels for epilepsy. JAMA Neurol,2014, 71(10):650-651.
18. Veeramah KR, Johnstone L, Karafet TM, et al. Exome sequencingreveals new causal mutations in children with epilepticencephalopathies. Epilepsia,2013, 54(7):1270-1281.
19. Dyment DA, Tetreault M, Beaulieu CL, et al. Whole-exomesequencing broadens the phenotypic spectrum of rare pediatricepilepsy:a retrospective study. Clin Genet, 2014, 21(7):12464.
20. Michaud JL, Lachance M, Hamdan FF, et al. The genetic landscape ofinfantile spasms. Hum Mol Genet,2014, 23(5):4846-4858.
21. Allen AS,Berkovic SF. De novo mutations in epileptic encephalopathies.Nature,2013, 501(11):217-221.
22. Euro-epinomics-res Consortium, Epilepsy Phenome/Genome Project, Epileptic Consortium. De novo mutations in synaptictransmission genes including DNM1 cause epileptic encephalopathies.Am J Hum Genet, 2014, 95(6):360-370.
23. Depienne C, LeGuern E. PCDH19-related infantile epileptic encephalopathy:an unusual X-linked inheritance disorder. Hum Mutat, 2012, 33(7):627-634.
24. Milh M, Villeneuve N, Chouchane M, et al. Epileptic and nonepilepticfeatures in patients with early onset epileptic encephalopathy andSTXBP1 mutations. Epilepsia, 2011, 52(7):1828-1834.
25. Deprez L, Weckhuysen S, Holmgren P, et al. Clinical spectrum ofearly-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology,2010, 75(8):1159-1165.
26. Miller IO, Sotero de Menezes MA. SCN1A-related seizure disorders.In Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT,Smith RJH, Stephens K (Eds) GeneReviews. Seattle, WA:University of Washington, Seattle; 1993-2014, 2007, 29[updated2014 May 15].
27. Nakamura K, Kato M, Osaka H, et al. Clinical spectrum ofSCN2A mutations expanding to ohtahara syndrome. Neurology, 2013, 81(10):992-998.
28. Veeramah KR, O'Brien JE, Meisler MH, et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a familyquartet affected by infantile epileptic encephalopathy and SUDEP. AmJ Hum Gene, 2012, 90(4):502-510.
29. Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia, 2014, 55(3):994-1000.
30. Milh M, Boutry-Kryza N, Sutera-Sardo J, et al. Similar earlycharacteristics but variable neurological outcome of patients with a denovo mutation of KCNQ2. Orphanet J Rare Dis, 2013, 8(2):80.
31. Weckhuysen S, Mandelstam S, Suls A, et al. KCNQ2 encephalopathy:emerging phenotype of a neonatal epileptic encephalopathy. AnnNeurol, 2012, 71(8):15-25.
32. Wolf NI, Bast T, Surtees R. Epilepsy in inborn errors of metabolism.Epileptic Disord, 2005, 7(2):67-81.
33. Weber YG, Storch A, Wuttke TV, et al. GLUT1 mutations are a causeof paroxysmal exertion-induced dyskinesias and induce hemolyticanemia by a cation leak. J Clin Invest, 2008, 118(3):2157-2168.
34. Wilson A, Leclerc D, Saberi F, et al. Functionally null mutations inpatients with the cblg-variant form of methionine synthase deficiency.Am J Hum Genet, 1998, 63(2):409-414.
35. Urreizti R, Moya-Garc AA, Pino-Angeles A, et al. Molecularcharacterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clin Genet, 2010, 78(1):441-448.
36. Auranen M, Vanhala R, Vosman M, et al. MECP2 gene analysis inclassical Rett syndrome and in patients with Rett-like features.Neurology, 2001, 56(3):611-617.
37. Morris-Rosendahl DJ, Najm J, Lachmeijer AM, et al. Refining thephenotype of alpha-1a Tubulin (TUBA1A) mutation in patients withclassical lissencephaly. Clin Genet, 2008, 74(4):425-433.
38. Marini C, Mei D, Temudo T, et al. Idiopathic epilepsies with seizuresprecipitated by fever and SCN1A abnormalities. Epilepsia, 2007, 48(7):1678-1685.
39. Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1 Agene mutations associated with Dravet syndrome:analysis of 333patients. J Med Genet, 2009, 46(5):183-191.

Previous Article
核磁共振图像后处理技术在癫痫术前评估中的应用
Next Article
癫痫动物模型中的神经系统影像学新方法——癫痫神经生物工作组报告

Journal of Epilepsy

基因检测对儿童癫痫性脑病的检出率

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content