常染色体显性遗传夜间额叶癫痫的基因学研究现状_Journal of Epilepsy

Authors：

张欣 ,  林卫红

吉林大学第一医院神经内科（长春 130012）;

Corresponding author：

林卫红, Email: linweihong321@126.com

Keywords：

常染色体显性遗传夜间额叶癫痫; 致病基因; 基因测序技术

DOI：

10.7507/2096-0247.20190021

Video：

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常染色体显性遗传夜间额叶癫痫（Autosomal dominant nocturnal frontal lobe epilepsy，ADNFLE）首先由 Lugaresi 等描述，是第一个发现致病基因的癫痫综合征。迄今为止，已鉴定出的可能致病基因有CHRNA4、CHRNB2、CHRNA2、KCNT1、DEPDC5、CRH、CABP4，外显率 70%～80%，但已发现的基因仅能解释部分患者的病因，不同种族仍具有较大的遗传异质性。文章回顾了 ADNFLE 近几年的流行病学、临床体征、致病基因研究及基因测序技术等，为已发现的致病基因提供解释，并为未来寻找新的基因提供方向。

Citation： 张欣, 林卫红. 常染色体显性遗传夜间额叶癫痫的基因学研究现状. Journal of Epilepsy, 2019, 5(2): 116-119. doi: 10.7507/2096-0247.20190021 Copy

1.	Wang X, Marcuse LV, Jin L, et al. Sleep-related hypermotor epilepsy activated by rapid eye movement sleep. Epileptic Disord, 2018, 20(1): 65-69.
2.	Tinuper P. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology, 2016, 86(19): 1834-1842.
3.	周霞, 张诚. 额叶癫痫的临床特点及脑电图分析. 中国实用神经疾病杂志, 2016, 19(22): 10-11.
4.	Raju GP, Sarco DP, Poduri A, et al. Oxcarbazepine in children with nocturnal frontal-lobe epilepsy. Pediatric Neurol, 2007, 37(5): 345-349.
5.	O'Reilly C, Chapotot F, Pittau F, et al. Nicotine increases sleep spindle activity. J Sleep Res, 2018: e12800.
6.	Milligan CJ, Li M, Gazina E, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol, 2014, 75(4): 581-590.
7.	Mullen SA, Carney PW, Roten A, et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology, 2018, 90(1): e67-72.
8.	Puligheddu M, Melis M, Pillolla G, et al. Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy. Epilepsia, 2017, 58(10): 1762-1770.
9.	Mangiardi M, Alfano G. A clinical efficacy experience of lacosamide on sleep quality in patients with nocturnal frontal lobe epilepsy (NFLE). Acta Biomed, 2018, 89(3): 397-399.
10.	Samarasekera SR, Berkovic SF, Scheffer IE. A case series of lacosamide as adjunctive therapy in refractory sleep-related hypermotor epilepsy (previously nocturnal frontal lobe epilepsy). J Sleep Res, 2018, 27(5): e12669.
11.	Indurthi DC, Qudah T, Liao VW, et al. Revisiting autosomal dominant nocturnal frontal lobe epilepsy(ADNFLE) mutations in the nicotinic acetylcholine receptor reveal an increase in efficacy regardless of stochiometry. Pharmacol Res, 2019, 139: 215-227.
12.	Steinlein O, Smigrodzki R, Lindstrom J, et al. Refinement of the localization of the gene for neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) to human chromosome 20q13.2-q13.3. Genomics, 1994, 22(2): 493-495.
13.	Steinlein OK, Magnusson A, Stoodt J, et al. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet, 1997, 6(6): 943-947.
14.	Hirose S, Iwata H, Akiyoshi H, et al. A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 1999, 53(8): 1749-1753.
15.	Phillipsc HA, C. Marini MD, Scheffer IE, et al A de novo mutation in sporadic nocturnal frontal lobe epilepsy. Ann Neurol, 2010, 48(2): 264-267.
16.	Steinlein OK, Stoodt J, Mulley J, et al. Independent occurrence of the CHRNA4 Ser 248 Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy. Epilepsia, 2000, 41(5): 529-535.
17.	Pascual FT, Wierenga KJ, Ng YT. Contiguous deletion of KCNQ2 and CHRNA4 may cause a different disorder from benign familial neonatal seizures. Epilep Behav Case Rep, 2013, 1: 35-38.
18.	Chen Y, Wu L. A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy. Epilepsy Res, 2009, 83(2): 152-156.
19.	Rempel N, Heyers S, Engels H, et al. The structures of the human neuronal nicotinic acetylcholine receptor β2- and α3-subunit genes (CHRNB2 and CHRNA3). Hum Genet, 1998, 103(6): 645-653.
20.	de Fusco M, Becchetti A, Patrignani A, et al. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genetics, 2000, 26(3): 275-276.
21.	Bertrand D, Elmslie F, Hughes E, et al. The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits. Neurobiol Dis, 2005, 20(3): 799-804.
22.	Díaz-Otero F, Quesada M, Moralescorraliza J, et al. Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene. Epilepsia, 2010, 49(3): 516-520.
23.	Shiba Y, Mori F, Yamada J, et al. Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor. Neurosci Res, 2015, 100: 46-54.
24.	Aridon P, Marini C, Di Resta C, et al. Increased sensitivity of the neuronal nicotinic receptor α2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet, 2006, 79(2): 342-350.
25.	Conti V, Aracri P, Chiti L, et al. Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology, 2015, 84(15): 1520-1528.
26.	Villa C, Colombo G, Meneghini S, et al. CHRNA2 and nocturnal frontal lobe epilepsy: identification and characterization of a novel loss of function mutation. Front Mol Neurosci, 2019, 12: 17.
27.	Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet, 2012, 44(11): 1188-1190.
28.	Lim CX, Ricos MG, Dibbens LM, et al. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet, 2016, 53(4): 217-225.
29.	Bhattacharjee A, Kaczmarek LK. For K⁺ channels, Na⁺ is the new Ca²⁺. Trends Neurosci, 2005, 28(8): 422-428.
30.	Møller RS, Heron SE, Larsen LH, et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia, 2015, 56(9): e114-120.
31.	Lim CX, Ricos MG, Dibbens LM, et al. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet, 2016, 53(4): 217-225.
32.	Evely KM, Pryce KD, Bhattacharjee A. The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype. Neuroscience, 2017, 351: 65-70.
33.	Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 2014, 82(23): 2101-2106.
34.	Baulac S. Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5. Prog Brain Res, 2014, 213: 123-139.
35.	Steinlein OK. Genetic heterogeneity in familial nocturnal frontal lobe epilepsy. Prog Brain Res, 2014, 213: 1-15.
36.	Adam MP, Ardinger HH, Pagon RA, et al. DEPDC5-related epilepsy. Gene Reviews, Seattle (WA): University of Washington, 2016: 1993-2019.
37.	Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nature Genetics, 2013, 45(5): 552-555.
38.	Martin C, Meloche C, Rioux MF, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the french-canadian population. Clin Genet, 2014, 86(6): 570-574.
39.	Combi R, Dalprà L, Ferinistrambi L, et al. Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene. Ann Neurol, 2005, 58(6): 899.
40.	Sansoni V, Forcella M, Mozzi A, et al. Functional characterization of a CRH missense mutation identified in an ADNFLE family. PLoS One, 2013, 8(4): 265-280.
41.	陈志红. 中国南方人群常染色体显性遗传夜发额叶癫痫的CHRNB2基因突变筛查. 广州: 南方医科大学, 硕士毕业论文, 2010.
42.	陈前. 中国人群常染色体显性遗传夜发额叶癫痫的nAChR基因突变筛查及cSNP研究. 广州: 南方医科大学, 硕士毕业论文, 2012.
43.	Chen ZH, Wang C, Zhuo MQ, et al. Exome sequencing identified a novel missense mutation c.464G>A (p.G155D) in Ca²⁺-binding protein 4(CABP4) in a Chinese pedigree with autosomal dominant nocturnal frontal lobe epilepsy. Oncotarget, 2017, 8(45): 78940-78947.
44.	Haeseleer F, Sokal I, Verlinde CLMJ, et al. Five members of a novel Ca²⁺-binding protein (CABP) subfamily with similarity to calmodulin. J Biol Chem, 2000, 275(2): 1247-1260.
45.	Sanger F, Coulson AR. A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J Mol Biol, 1975, 94(3): 441-448.
46.	Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA, 1977, 74(12): 5463-5467.
47.	Fedurco M, Romieu A, Williams S, et al. BTA, a novel reagent for DNA attachment on glass and efficient generation of solid-phase amplified DNA colonies. Nucleic Acids Res, 2006, 34(3): e22.
48.	Harris TD, Buzby PR, Babcock H, et al. Single-molecule DNA sequencing of a viral genome. Science, 2008, 320(5872): 106-109.
49.	Jain M, Olsen HE, Paten B, et al. The oxford nanopore minION: delivery of nanopore sequencing to the genomics community. Genome Biol, 2016, 17(1): 239.

1. Wang X, Marcuse LV, Jin L, et al. Sleep-related hypermotor epilepsy activated by rapid eye movement sleep. Epileptic Disord, 2018, 20(1): 65-69.
2. Tinuper P. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology, 2016, 86(19): 1834-1842.
3. 周霞, 张诚. 额叶癫痫的临床特点及脑电图分析. 中国实用神经疾病杂志, 2016, 19(22): 10-11.
4. Raju GP, Sarco DP, Poduri A, et al. Oxcarbazepine in children with nocturnal frontal-lobe epilepsy. Pediatric Neurol, 2007, 37(5): 345-349.
5. O'Reilly C, Chapotot F, Pittau F, et al. Nicotine increases sleep spindle activity. J Sleep Res, 2018: e12800.
6. Milligan CJ, Li M, Gazina E, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol, 2014, 75(4): 581-590.
7. Mullen SA, Carney PW, Roten A, et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology, 2018, 90(1): e67-72.
8. Puligheddu M, Melis M, Pillolla G, et al. Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy. Epilepsia, 2017, 58(10): 1762-1770.
9. Mangiardi M, Alfano G. A clinical efficacy experience of lacosamide on sleep quality in patients with nocturnal frontal lobe epilepsy (NFLE). Acta Biomed, 2018, 89(3): 397-399.
10. Samarasekera SR, Berkovic SF, Scheffer IE. A case series of lacosamide as adjunctive therapy in refractory sleep-related hypermotor epilepsy (previously nocturnal frontal lobe epilepsy). J Sleep Res, 2018, 27(5): e12669.
11. Indurthi DC, Qudah T, Liao VW, et al. Revisiting autosomal dominant nocturnal frontal lobe epilepsy(ADNFLE) mutations in the nicotinic acetylcholine receptor reveal an increase in efficacy regardless of stochiometry. Pharmacol Res, 2019, 139: 215-227.
12. Steinlein O, Smigrodzki R, Lindstrom J, et al. Refinement of the localization of the gene for neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4) to human chromosome 20q13.2-q13.3. Genomics, 1994, 22(2): 493-495.
13. Steinlein OK, Magnusson A, Stoodt J, et al. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet, 1997, 6(6): 943-947.
14. Hirose S, Iwata H, Akiyoshi H, et al. A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 1999, 53(8): 1749-1753.
15. Phillipsc HA, C. Marini MD, Scheffer IE, et al A de novo mutation in sporadic nocturnal frontal lobe epilepsy. Ann Neurol, 2010, 48(2): 264-267.
16. Steinlein OK, Stoodt J, Mulley J, et al. Independent occurrence of the CHRNA4 Ser 248 Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy. Epilepsia, 2000, 41(5): 529-535.
17. Pascual FT, Wierenga KJ, Ng YT. Contiguous deletion of KCNQ2 and CHRNA4 may cause a different disorder from benign familial neonatal seizures. Epilep Behav Case Rep, 2013, 1: 35-38.
18. Chen Y, Wu L. A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy. Epilepsy Res, 2009, 83(2): 152-156.
19. Rempel N, Heyers S, Engels H, et al. The structures of the human neuronal nicotinic acetylcholine receptor β2- and α3-subunit genes (CHRNB2 and CHRNA3). Hum Genet, 1998, 103(6): 645-653.
20. de Fusco M, Becchetti A, Patrignani A, et al. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genetics, 2000, 26(3): 275-276.
21. Bertrand D, Elmslie F, Hughes E, et al. The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits. Neurobiol Dis, 2005, 20(3): 799-804.
22. Díaz-Otero F, Quesada M, Moralescorraliza J, et al. Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene. Epilepsia, 2010, 49(3): 516-520.
23. Shiba Y, Mori F, Yamada J, et al. Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor. Neurosci Res, 2015, 100: 46-54.
24. Aridon P, Marini C, Di Resta C, et al. Increased sensitivity of the neuronal nicotinic receptor α2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet, 2006, 79(2): 342-350.
25. Conti V, Aracri P, Chiti L, et al. Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology, 2015, 84(15): 1520-1528.
26. Villa C, Colombo G, Meneghini S, et al. CHRNA2 and nocturnal frontal lobe epilepsy: identification and characterization of a novel loss of function mutation. Front Mol Neurosci, 2019, 12: 17.
27. Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet, 2012, 44(11): 1188-1190.
28. Lim CX, Ricos MG, Dibbens LM, et al. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet, 2016, 53(4): 217-225.
29. Bhattacharjee A, Kaczmarek LK. For K⁺ channels, Na⁺ is the new Ca²⁺. Trends Neurosci, 2005, 28(8): 422-428.
30. Møller RS, Heron SE, Larsen LH, et al. Mutations in KCNT1 cause a spectrum of focal epilepsies. Epilepsia, 2015, 56(9): e114-120.
31. Lim CX, Ricos MG, Dibbens LM, et al. KCNT1 mutations in seizure disorders: the phenotypic spectrum and functional effects. J Med Genet, 2016, 53(4): 217-225.
32. Evely KM, Pryce KD, Bhattacharjee A. The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype. Neuroscience, 2017, 351: 65-70.
33. Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 2014, 82(23): 2101-2106.
34. Baulac S. Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5. Prog Brain Res, 2014, 213: 123-139.
35. Steinlein OK. Genetic heterogeneity in familial nocturnal frontal lobe epilepsy. Prog Brain Res, 2014, 213: 1-15.
36. Adam MP, Ardinger HH, Pagon RA, et al. DEPDC5-related epilepsy. Gene Reviews, Seattle (WA): University of Washington, 2016: 1993-2019.
37. Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nature Genetics, 2013, 45(5): 552-555.
38. Martin C, Meloche C, Rioux MF, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the french-canadian population. Clin Genet, 2014, 86(6): 570-574.
39. Combi R, Dalprà L, Ferinistrambi L, et al. Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene. Ann Neurol, 2005, 58(6): 899.
40. Sansoni V, Forcella M, Mozzi A, et al. Functional characterization of a CRH missense mutation identified in an ADNFLE family. PLoS One, 2013, 8(4): 265-280.
41. 陈志红. 中国南方人群常染色体显性遗传夜发额叶癫痫的CHRNB2基因突变筛查. 广州: 南方医科大学, 硕士毕业论文, 2010.
42. 陈前. 中国人群常染色体显性遗传夜发额叶癫痫的nAChR基因突变筛查及cSNP研究. 广州: 南方医科大学, 硕士毕业论文, 2012.
43. Chen ZH, Wang C, Zhuo MQ, et al. Exome sequencing identified a novel missense mutation c.464G>A (p.G155D) in Ca²⁺-binding protein 4(CABP4) in a Chinese pedigree with autosomal dominant nocturnal frontal lobe epilepsy. Oncotarget, 2017, 8(45): 78940-78947.
44. Haeseleer F, Sokal I, Verlinde CLMJ, et al. Five members of a novel Ca²⁺-binding protein (CABP) subfamily with similarity to calmodulin. J Biol Chem, 2000, 275(2): 1247-1260.
45. Sanger F, Coulson AR. A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J Mol Biol, 1975, 94(3): 441-448.
46. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA, 1977, 74(12): 5463-5467.
47. Fedurco M, Romieu A, Williams S, et al. BTA, a novel reagent for DNA attachment on glass and efficient generation of solid-phase amplified DNA colonies. Nucleic Acids Res, 2006, 34(3): e22.
48. Harris TD, Buzby PR, Babcock H, et al. Single-molecule DNA sequencing of a viral genome. Science, 2008, 320(5872): 106-109.
49. Jain M, Olsen HE, Paten B, et al. The oxford nanopore minION: delivery of nanopore sequencing to the genomics community. Genome Biol, 2016, 17(1): 239.

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常染色体显性遗传夜间额叶癫痫的基因学研究现状

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