癫痫共患孤独症谱系障碍的分子遗传学研究进展_Journal of Epilepsy

Authors：

康天 ^1,2 ,  张月华 ²

1. ;
2. ;

Corresponding author：

张月华, Email: zhangyhdr@126.com

Keywords：

癫痫; 孤独症谱系障碍; 共患病; 分子遗传学

DOI：

10.7507/2096-0247.20200053

Video：

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Abstract Full text Figures/Tables Video References Cited by

癫痫与孤独症谱系障碍（Autism spectrum disorder，ASD）是十分常见的具有高共患病几率的两组神经系统疾病。近年来，癫痫-ASD 共患病的发病率高于癫痫与 ASD 单独的发病率，且癫痫 ASD 共患病的发病率逐年升高，提示癫痫与 ASD 之间存在相关性，引起了人们的广泛重视。目前对癫痫-ASD 共患病的研究有限，其发病原因及具体机制尚不明确。已知的癫痫和 ASD 病例中约半数具有遗传基础。染色体检查、全基因组、外显子组测序加深了临床对癫痫-ASD 共患病的分子遗传学病因的认识。此文总结了癫痫-ASD 共患病常见的 3 种染色体异常和 17 种基因突变，从分子遗传学角度结合临床症状、体征、辅助检查等深入探讨，了解该共患病的共同遗传基础。

Citation： 康天, 张月华. 癫痫共患孤独症谱系障碍的分子遗传学研究进展. Journal of Epilepsy, 2020, 6(4): 329-336. doi: 10.7507/2096-0247.20200053 Copy

1.	Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology, 2017, 88(3): 296-303.
2.	Hurt E, Arnold LE, Lofthouse N. Quantitative EEG neurofeedback for the treatment of pediatric attention-deficit/hyperactivity disorder, autism spectrum disorders, learning disorders, and epilepsy. Child Adolesc Psychiatr Clin N Am, 2014, 23(3): 465-486.
3.	Berg AT, Plioplys S, Tuchman R. Risk and correlates of autism spectrum disorder in children with epilepsy: a community based study. J Child Neurol, 2011, 26(5): 540-547.
4.	Fisher B, Dezort C, Nordli DR, et al. Routine developmental and autism screening in an epilepsy care setting. Epilepsy Behav, 2012, 24(4): 488-492.
5.	Amiet C, Gourfinkel-An I, Laurent C, et al. Epilepsy in simplex autism pedigrees is much lower than the rate in multiplex autism pedigrees. Biol Psychiatry, 2013, 74(3): e3-e4.
6.	Hughes JR, Melyn M. EEG and seizures in autistic children and adolescents: further findings with therapeutic implications. Clin EEG Neurosci, 2005, 36(1): 15-20.
7.	Berg AT, Plioplys S. Epilepsy and autism: Is there a special relationship? Epilepsy Behav, 2012, 23(3): 193-198.
8.	杨志仙, 刘晓燕, 张月华, 等. Angelman 综合征临床及脑电图特点. 中国实用儿科杂志, 2011, 26(7): 519-523.
9.	中华医学会儿科学分会内分泌遗传代谢学组. 中国Prader-Willi综合征诊治专家共识(2015). 中华儿科杂志, 2015, 53(6): 419-421.
10.	Soppa U, Schumacher J, Florencio Ortiz V, et al. The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation. Cell Cycle, 2014, 13(13): 2084-2100.
11.	Arya R, Kabra M, Gulati S. Epilepsy in children with Down syndrome. Epileptic Disord, 2011, 13(1): 1-7.
12.	Wilson HL, Wong AC, Shaw SR, et al. Molecular characterization of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet, 2003, 40(8): 575-584.
13.	Delahanty RJ, Zhang Y, Bichell TJ, et al. Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation. Cell Rep, 2016, 17(12): 3115-3124.
14.	Andrew G. McKechanie, Sonya Campbell, Sarah E. A. Eley, et al Autism in Fragile X Syndrome; A Functional MRI Study of Facial Emotion-Processing. Genes, 2019, 10(12): 1052.
15.	Blackmon K, Bluvstein J, MacAllister WS, et al. Treatment Resistant Epilepsy in Autism Spectrum Disorder: Increased Risk for Females. Autism Res, 2016, 9(2): 311-320.
16.	Bernardo Pia; Cobb Stuart; Coppola Antonietta, et al. Neurophysiological Signatures of Motor Impairment in Patients with Rett Syndrome. Annals of neurology, 2020, 87: 763-773.
17.	梅道启; 符娜; 秦炯. 结节性硬化症TSC1、TSC2基因型与临床表型研究进展. 中国实用儿科杂志, 2019, 34(4): 309-313.
18.	田小娟, 张月华, 杨小玲, 等. 家族性Dravet综合征家系临床表型特点和基因突变研究. 中华实用儿科杂志, 2016, 31(20): 1531-1535.
19.	曾琦, 张月华, 杨小玲, 等. 良性家族性婴儿癫痫的致病基因谱研究. 中华实用儿科临床杂志, 2017, 32(24): 1866-1872.
20.	刘爱杰, 许小菁, 孙丹, 等. 原钙黏蛋白19基因相关癫痫的遗传特点及临床表型谱研究. 癫痫杂志, 2017, 3(4): 283-291.
21.	Dedek K, Fusco L, Teloy N, et al. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res, 2003, 54(1): 21-27.
22.	Saitsu Hirotomo, Kato Mitsuhiro, Koide Ayaka, et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Annals of neurology, 2012, 72(2): 298-300.
23.	曾琦, 张月华, 杨小玲, 等. KCNQ2基因突变相关癫痫的临床表型谱研究. 癫痫杂志, 2019, 5(4): 244-256.
24.	Tao J, Van Esch H, Hagedorn-Greiwe M, et al. Mutations in the X-linked cyclin-dependent kinase-like 5(CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet, 2004, 75(6): 1149-54.
25.	Bahi-Buisson N, Nectoux J, Rosas-Vargas H, et al. Key clinical features to identify girls with CDKL5 mutations. Brain, 2008, 131(Pt 10): 2647-2661.
26.	章清萍, 赵澄, 包新华, 等. 早发性癫痫脑病患儿的CDKL5基因突变特点与临床特征. 中华医学遗传学杂志, 2016, 33(3): 404-407.
27.	Yang Y, Shen W, Ni Y, et al. Impaired Interneuron Development after Foxg1 Disruption. Cereb Cortex, 2017, 27(1): 793-808.
28.	G Lesca, G Rudolf, A Labalme, et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: Genomic dissection makes thelink with autism. Epilepsia, 2012, 53(9): 1526-1538.
29.	Viscidi EW, Triche EW, Pcscosolido MF, et al. Clinical characteristics of children with autism spectrum disorder and cooccurring epilepsy. PloS one, 2013, 8(7): e67797.
30.	Chénier S, Yoon G. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. J Neurodev Disord, 2014, 6(1): 9.
31.	Lund C, Brodtkorb E, Øye AM, et al. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav, 2014, 33: 18-21.
32.	Carvill GL, Heavin SB. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genetics, 2013, 45(7): 825-830.
33.	Suls A, Jaehn JA, Kecskés A, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. American Journal of Human Genetics, 2013, 93(5): 967-975.
34.	Neeraj Singh, Anthony Ritaccio. Juvenile myoclonic epilepsy mimic associated with CHD2 gene mutation. Epilepsy & behavior reports, 2020, 13: 100355.
35.	Iossifov I, O'Roak BJ. The contribution of de novo CO2Ding mutations to autism spectrum disorder. Nature, 2014, 515(7526): 216-221.
36.	Valik D, Miner PT, Jones JD. First U.S. case of adenylosuccinate lyase deficiency with severe hypotonia. Pediatr Neurol, 1997, 16(3): 252-255.
37.	Macchiaiolo M, Barresi S, Cecconi F, et al. A mild form of adenylosuccinate lyase deficiency in absence of typical brain MRI features diagnosed by whole exome sequencing. Ital J Pediatr, 2017, 43(1): 65.
38.	Pérez-Dueñas B, Sempere A, Campistol J, et al. Novel features in the evolution of adenylosuccinate lyase deficiency. Eur J Paediatr Neurol, 2012, 16(4): 343-348.
39.	Edery P, Chabrier S, Ceballos-Picot I, et al. Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients. Am J Med Genet A, 2003, 120(2): 185-190.
40.	Jurecka A, Jurkiewicz E, Tylki-Szymanska A. Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature. Eur J Pediatric, 2012, 171(1): 131-138.
41.	康天, 陈娇阳, 张月华. 腺苷琥珀酸裂解酶缺乏症3例报告并文献复习. 中国实用儿科杂志, 2020, 35(4): 315-318.
42.	Berryer MH, Hamdan FF, Klitten LL, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat, 2013, 34(2): 385-394.
43.	Mignot C, von Stülpnagel C, Nava C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet, 2016, 53(8): 511-522.
44.	von Stülpnagel C, Claudia Funke, Caroline Haberl, et al. SYNGAP1 mutation in focal and generalized epilepsy: a literature overview and a case report with special aspects of the EEG. Neuropediatrics, 2015, 46(4): 287-291.
45.	Miyake K, Hirasawa T, Koide T, et al. Epigenetics in autism and other neurodevelopmental diseases. Adv Exp Med Biol, 2012, 724: 91-98.
46.	张仪, 姚如恩, 胥雨菲. CASK基因变异1例临床特征分析. 临床儿科杂志, 2019, 37(9): 693-696.
47.	Getz SA, DeSpenza T Jr, Li M, et al. Rapamycin prevents, but does not reverse, aberrant migration in PTEN knockout neurons. Neurobiol Dis, 2016, 93: 12-20.
48.	He X, Thacker S, Romigh T, et al. Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits. Mol Autism, 2016, 3(7): 14.
49.	陆颖, 张晨, 易正辉, 等. PTEN基因在神经疾病发病机制中作用的研究进展. 精神医学杂志, 2016, 29(5): 388-391.

1. Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology, 2017, 88(3): 296-303.
2. Hurt E, Arnold LE, Lofthouse N. Quantitative EEG neurofeedback for the treatment of pediatric attention-deficit/hyperactivity disorder, autism spectrum disorders, learning disorders, and epilepsy. Child Adolesc Psychiatr Clin N Am, 2014, 23(3): 465-486.
3. Berg AT, Plioplys S, Tuchman R. Risk and correlates of autism spectrum disorder in children with epilepsy: a community based study. J Child Neurol, 2011, 26(5): 540-547.
4. Fisher B, Dezort C, Nordli DR, et al. Routine developmental and autism screening in an epilepsy care setting. Epilepsy Behav, 2012, 24(4): 488-492.
5. Amiet C, Gourfinkel-An I, Laurent C, et al. Epilepsy in simplex autism pedigrees is much lower than the rate in multiplex autism pedigrees. Biol Psychiatry, 2013, 74(3): e3-e4.
6. Hughes JR, Melyn M. EEG and seizures in autistic children and adolescents: further findings with therapeutic implications. Clin EEG Neurosci, 2005, 36(1): 15-20.
7. Berg AT, Plioplys S. Epilepsy and autism: Is there a special relationship? Epilepsy Behav, 2012, 23(3): 193-198.
8. 杨志仙, 刘晓燕, 张月华, 等. Angelman 综合征临床及脑电图特点. 中国实用儿科杂志, 2011, 26(7): 519-523.
9. 中华医学会儿科学分会内分泌遗传代谢学组. 中国Prader-Willi综合征诊治专家共识(2015). 中华儿科杂志, 2015, 53(6): 419-421.
10. Soppa U, Schumacher J, Florencio Ortiz V, et al. The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation. Cell Cycle, 2014, 13(13): 2084-2100.
11. Arya R, Kabra M, Gulati S. Epilepsy in children with Down syndrome. Epileptic Disord, 2011, 13(1): 1-7.
12. Wilson HL, Wong AC, Shaw SR, et al. Molecular characterization of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J Med Genet, 2003, 40(8): 575-584.
13. Delahanty RJ, Zhang Y, Bichell TJ, et al. Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation. Cell Rep, 2016, 17(12): 3115-3124.
14. Andrew G. McKechanie, Sonya Campbell, Sarah E. A. Eley, et al Autism in Fragile X Syndrome; A Functional MRI Study of Facial Emotion-Processing. Genes, 2019, 10(12): 1052.
15. Blackmon K, Bluvstein J, MacAllister WS, et al. Treatment Resistant Epilepsy in Autism Spectrum Disorder: Increased Risk for Females. Autism Res, 2016, 9(2): 311-320.
16. Bernardo Pia; Cobb Stuart; Coppola Antonietta, et al. Neurophysiological Signatures of Motor Impairment in Patients with Rett Syndrome. Annals of neurology, 2020, 87: 763-773.
17. 梅道启; 符娜; 秦炯. 结节性硬化症TSC1、TSC2基因型与临床表型研究进展. 中国实用儿科杂志, 2019, 34(4): 309-313.
18. 田小娟, 张月华, 杨小玲, 等. 家族性Dravet综合征家系临床表型特点和基因突变研究. 中华实用儿科杂志, 2016, 31(20): 1531-1535.
19. 曾琦, 张月华, 杨小玲, 等. 良性家族性婴儿癫痫的致病基因谱研究. 中华实用儿科临床杂志, 2017, 32(24): 1866-1872.
20. 刘爱杰, 许小菁, 孙丹, 等. 原钙黏蛋白19基因相关癫痫的遗传特点及临床表型谱研究. 癫痫杂志, 2017, 3(4): 283-291.
21. Dedek K, Fusco L, Teloy N, et al. Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2. Epilepsy Res, 2003, 54(1): 21-27.
22. Saitsu Hirotomo, Kato Mitsuhiro, Koide Ayaka, et al. Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Annals of neurology, 2012, 72(2): 298-300.
23. 曾琦, 张月华, 杨小玲, 等. KCNQ2基因突变相关癫痫的临床表型谱研究. 癫痫杂志, 2019, 5(4): 244-256.
24. Tao J, Van Esch H, Hagedorn-Greiwe M, et al. Mutations in the X-linked cyclin-dependent kinase-like 5(CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet, 2004, 75(6): 1149-54.
25. Bahi-Buisson N, Nectoux J, Rosas-Vargas H, et al. Key clinical features to identify girls with CDKL5 mutations. Brain, 2008, 131(Pt 10): 2647-2661.
26. 章清萍, 赵澄, 包新华, 等. 早发性癫痫脑病患儿的CDKL5基因突变特点与临床特征. 中华医学遗传学杂志, 2016, 33(3): 404-407.
27. Yang Y, Shen W, Ni Y, et al. Impaired Interneuron Development after Foxg1 Disruption. Cereb Cortex, 2017, 27(1): 793-808.
28. G Lesca, G Rudolf, A Labalme, et al. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: Genomic dissection makes thelink with autism. Epilepsia, 2012, 53(9): 1526-1538.
29. Viscidi EW, Triche EW, Pcscosolido MF, et al. Clinical characteristics of children with autism spectrum disorder and cooccurring epilepsy. PloS one, 2013, 8(7): e67797.
30. Chénier S, Yoon G. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. J Neurodev Disord, 2014, 6(1): 9.
31. Lund C, Brodtkorb E, Øye AM, et al. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav, 2014, 33: 18-21.
32. Carvill GL, Heavin SB. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genetics, 2013, 45(7): 825-830.
33. Suls A, Jaehn JA, Kecskés A, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. American Journal of Human Genetics, 2013, 93(5): 967-975.
34. Neeraj Singh, Anthony Ritaccio. Juvenile myoclonic epilepsy mimic associated with CHD2 gene mutation. Epilepsy & behavior reports, 2020, 13: 100355.
35. Iossifov I, O'Roak BJ. The contribution of de novo CO2Ding mutations to autism spectrum disorder. Nature, 2014, 515(7526): 216-221.
36. Valik D, Miner PT, Jones JD. First U.S. case of adenylosuccinate lyase deficiency with severe hypotonia. Pediatr Neurol, 1997, 16(3): 252-255.
37. Macchiaiolo M, Barresi S, Cecconi F, et al. A mild form of adenylosuccinate lyase deficiency in absence of typical brain MRI features diagnosed by whole exome sequencing. Ital J Pediatr, 2017, 43(1): 65.
38. Pérez-Dueñas B, Sempere A, Campistol J, et al. Novel features in the evolution of adenylosuccinate lyase deficiency. Eur J Paediatr Neurol, 2012, 16(4): 343-348.
39. Edery P, Chabrier S, Ceballos-Picot I, et al. Intrafamilial variability in the phenotypic expression of adenylosuccinate lyase deficiency: a report on three patients. Am J Med Genet A, 2003, 120(2): 185-190.
40. Jurecka A, Jurkiewicz E, Tylki-Szymanska A. Magnetic resonance imaging of the brain in adenylosuccinate lyase deficiency: a report of seven cases and a review of the literature. Eur J Pediatric, 2012, 171(1): 131-138.
41. 康天, 陈娇阳, 张月华. 腺苷琥珀酸裂解酶缺乏症3例报告并文献复习. 中国实用儿科杂志, 2020, 35(4): 315-318.
42. Berryer MH, Hamdan FF, Klitten LL, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat, 2013, 34(2): 385-394.
43. Mignot C, von Stülpnagel C, Nava C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet, 2016, 53(8): 511-522.
44. von Stülpnagel C, Claudia Funke, Caroline Haberl, et al. SYNGAP1 mutation in focal and generalized epilepsy: a literature overview and a case report with special aspects of the EEG. Neuropediatrics, 2015, 46(4): 287-291.
45. Miyake K, Hirasawa T, Koide T, et al. Epigenetics in autism and other neurodevelopmental diseases. Adv Exp Med Biol, 2012, 724: 91-98.
46. 张仪, 姚如恩, 胥雨菲. CASK基因变异1例临床特征分析. 临床儿科杂志, 2019, 37(9): 693-696.
47. Getz SA, DeSpenza T Jr, Li M, et al. Rapamycin prevents, but does not reverse, aberrant migration in PTEN knockout neurons. Neurobiol Dis, 2016, 93: 12-20.
48. He X, Thacker S, Romigh T, et al. Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits. Mol Autism, 2016, 3(7): 14.
49. 陆颖, 张晨, 易正辉, 等. PTEN基因在神经疾病发病机制中作用的研究进展. 精神医学杂志, 2016, 29(5): 388-391.

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癫痫共患孤独症谱系障碍的分子遗传学研究进展

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