基因檢測對兒童癲癇性腦病的檢出率_Journal of Epilepsy

Authors：

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

Corresponding?author：

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

Keywords：

癲癇; 基因; 代謝障礙; 染色體; 分子遺傳學

DOI：

10.7507/2096-0247.20160093

Video：

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癲癇是兒童期常見的神經系統疾病,為了明確癲癇性腦病的基因檢出率,對一個癲癇遺傳診所進行了一項回顧性隊列研究。2012年1月-2014年6月,在一個癲癇遺傳診所納入了所有兼有難治性癲癇、整體性發育遲滯和認知功能障礙的患者。通過回顧電子病歷,獲得了患者的臨床特征、神經影像、生化檢驗及分子遺傳學資料,包括對癲癇性腦病基因的第二代目的基因測序。在110例患者中,發現28%是有基因異常的:7%有遺傳性代謝障礙,包括由ALDH7A1變異引起的吡哆醇依賴性癲癇、Menkes病、吡哆醇-5-磷酸氧化酶缺乏、鈷胺素G缺乏、亞甲基四氫葉酸還原酶缺乏、I型葡萄糖載體缺陷、甘氨酸腦病和丙酮酸脫氫酶復合體缺陷;21%有其他的基因病因,包括遺傳性綜合征、在陣列比較基因組雜交上的致病性拷貝數變異,以及與SCN1A、SCN2A、SCN8A、KCNQ2、STXBP1、PCDH19和SLC9A6基因變異相關的癲癇性腦病。4.5%的患者得到了由第二代目的基因測序的癲癇性腦病面板作出的基因診斷。值得注意的是,4.5%的患者有可治的遺傳性代謝性疾病。該研究為首個將遺傳性代謝障礙和癲癇性腦病的其他遺傳病因結合起來的研究。第二代目的基因測序面板將癲癇性腦病患者的基因診斷檢出率從＜10%增加到＞25%。

Citation： Mercimek-MahmutogluS, PatelJ, CordeiroD, HewsonS, CallenD, DonnerEJ, HahnCD, KannuP, KobayashiJ, MinassianBA, MoharirM, SiriwardenaK, WeissSK, WeksbergR, SneadOC, 童馨, 慕潔. 基因檢測對兒童癲癇性腦病的檢出率. 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.

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基因檢測對兒童癲癇性腦病的檢出率

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