线粒体病与癫痫的研究进展_Journal of Epilepsy

Authors：

杨夏鑫 ,  赵秀鹤

山东大学齐鲁医院神经内科（济南 250012）;

Corresponding author：

赵秀鹤, Email: zhaoxiuhe@126.com

Keywords：

线粒体病; 癫痫; 脑电图; 发病机制

DOI：

10.7507/2096-0247.20180039

Video：

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线粒体病是指由于线粒体 DNA（mitochondrial DNA，mtDNA）或核 DNA（nuclear DNA，nDNA）缺陷引起线粒体呼吸链氧化磷酸化功能障碍的一组遗传性疾病，临床表现多样，其中癫痫发作是线粒体病常见的神经系统表现。线粒体病中癫痫的发生机制极其复杂，迄今为止广为接受的机制包括离子机制、神经递质机制、氧化应激损伤和能量机制等；反之，癫痫反复发作可加重线粒体损伤，形成线粒体病-癫痫发作之间的恶性循环。在线粒体病中，不同的癫痫发作类型均有可能发生，甚至可能是各种癫痫发作类型的组合。线粒体病患者的脑电图多数可出现异常，表现为背景节律慢化或癫痫样放电。现文章旨在结合文献分析常见线粒体病中癫痫发作的临床及电生理特点，并探讨其可能的病理生理机制，以深入理解线粒体功能障碍在癫痫的发生发展过程中的作用及线粒体病的癫痫发作特性，为临床诊治伴癫痫发作的线粒体病提供更好的方向。

Citation： 杨夏鑫, 赵秀鹤. 线粒体病与癫痫的研究进展. Journal of Epilepsy, 2018, 4(3): 224-228. doi: 10.7507/2096-0247.20180039 Copy

1.	袁云, 崔丽英, 赵重波, 等. 中国神经系统线粒体病的诊治指南. 中华神经科杂志, 2015, 48(12): 1045-1051.
2.	Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol, 2015, 77(5): 753-759.
3.	张哲, 赵丹华, 刘靖, 等. 线粒体脑肌病伴乳酸血症和卒中样发作 190 例的临床特征分析. 中华神经科杂志, 2016, 49(3): 237-242.
4.	张晓, 王朝霞, 刘凤君, 等. 线粒体脑肌病伴高乳酸血症和卒中样发作的癫痫发作及脑电图特点分析. 中华神经科杂志, 2014, 47(5): 336-340.
5.	Whittaker RG, Devine HE, Gorman GS, et al. Epilepsy in adults with mitochondrial disease: a cohort study. Ann Neurol, 2015, 78(6): 949-957.
6.	Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol, 2010, 5: 297-348.
7.	Gábor Zsurka, Wolfram S Kunz. Mitochondrial dysfunction and seizures: the neuronal energy crisis. Lancet Neurol, 2015, 14(9): 956-966.
8.	Bindokas VP, Lee CC, Colmers WF, et al. Changes in mitochondrial function resulting from synaptic activity in the rat hippocampal slice. J Neurosci, 1998, 18(12): 4570-4587.
9.	Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration?. Trends Pharmacol Sci, 1998, 19(8): 328-334.
10.	Sesti F, Liu S, Cai SQ. Oxidation of potassium channels by ROS: a general mechanism of aging and neurodegeneration?. Trends Cell Biol, 2010, 20(1): 45-51.
11.	Kunz WS, Kudin AP, Vielhaber S, et al. Mitochondrial complex I deficiency in theepileptic focus of patients with temporal lobe epilepsy. Ann Neurol, 2000, 48(5): 766-773.
12.	Yamamoto H, Tang HW. Preventive effect of melatonin against cyanide-induced seizures and lipid peroxidation in mice. Neurosci Lett, 1996, 207(2): 89-92.
13.	Urbanska EM, Blaszczak P, Saran T, et al. Mitochondrial toxin 3-nitropropionic acid evokes seizures in mice. Eur J Pharmacol, 1998, 359(1): 55-58.
14.	Folbergrova J, Kunz WS. Mitochondrial dysfunction in epilepsy. Mitochondrion, 2012, 12(1): 35-40.
15.	Chuang YC, Chang AY, Lin JW, et al. Mitochondrial dysfunction and ultrastructural damage in the hippocampus during kainic acid-induced status epilepticus in the rat. Epilepsia, 2004, 45(10): 1202-1209.
16.	Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy. Epilepsia, 2012, 53 (Suppl 4): 92-97.
17.	Chevallier JA, Von Allmen GK, Koenig MK. Seizure semiology and EEG findings in mitochondrial diseases. Epilepsia, 2014, 55(5): 707-712.
18.	Nesbitt V, Pitceathly RD, Turnbull DM, et al. The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation--implications for diagnosis and management. J Neurol Neurosurg Psychiatry, 2013, 84(8): 936-938.
19.	Rahman S, Hanna MG. Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases. J Neurol Neurosurg Psychiatry, 2009, 80(9): 943-953.
20.	El-Hattab AW, Adesina AM, Jones J, et al. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab, 2015, 116(1-2): 4-12.
21.	Lee HN, Eom S, Kim SH, et al. Epilepsy characteristics and clinical outcome in patients with mitochondrial encephalomyopathy, lactic acidosis,and stroke-like episodes (MELAS). Pediatr Neurol, 2016, 64: 59-65.
22.	Chiyonobu T, Noda R, Yoshida M, et al.Intestinal pseudo-obstruction in a patient with mitochondrial myopathy, encephalopathy,lactic acidosis, and stroke-like episodes (MELAS) associated with phenytoin therapy. Brain Dev, 2008, 30(6): 430-433.
23.	Goodfellow JA, Dani K, Stewart W, et al. Mitochondrial myopathy,encephalopathy, lactic acidosis and stroke-like episodes: animportant cause of stroke in young people. Postgrad Med J, 2012, 88(1040): 326-334.
24.	Toribe Y, Tominaga K, Ogawa K, et al. Usefulness of L-arginine infusion for status epilepticus in mitochondrialmyopathy, encephalopathy, lactic acidosis, and stroke-like episodes. No To Hattatsu, 2007, 39(1): 38-43.
25.	Finsterer J, Kovacs GG. Psoriasis, hyperlipidemia, bulbar involvement,and diarrhoea in MERRF-syndrome due to the m.8344A>GtRNA(Lys) mutation. Iran J Neurol, 2017, 16(1): 45-49.
26.	Liu K, Zhao H, Ji K, et al. MERRF/MELAS overlap syndrome due to the m.3291T>Cmutation. Metab Brain Dis, 2014, 29(1): 139-144.
27.	Altmann J, Bu chner B, Nadaj-Pakleza A, et al. Expanded phenotypic spectrum of the m.8344A>G " MERRF” mutation: data from the german mitoNET registry. J Neurol, 2016, 263(5): 961-972.
28.	Finsterera J, Zarrouk-Mahjou S. Managementof epilepsy in MERRF syndrome. Seizure, 2017, 50: 166-170.
29.	Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy.Epilepsia, 2012, 53(Suppl.4): 92-97.
30.	Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the m.8344A>G mtDNA " MERRF” mutation. Neurology, 2013, 80(22): 2049-2054.
31.	Sitburana O, Witoonpanich R, Phudhichareonrat S,et al. Seizures in myoclonic epilepsy with ragged-red fibers detected by DNA analysis: a case report. J Med Assoc Thai, 2001, 84(7): 1051-1055.
32.	NIEHS-Mitochondrial DNA Replication Group. Human DNAPolymerase Gamma Mutation Database. http://tools.niehs.nih.gov/polg/. Accessed 01 Jul 2016.
33.	Hakonen AH, Davidzon G, Salemi R, et al. Abundance of the POLGdisease mutations in Europe, Australia, New Zealand, and the UnitedStates explained by single ancient European founders. Eur J Hum Genet, 2007, 15(7): 779-783.
34.	Neeve VC, Samuels DC, Bindoff LA, et al. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?. Brain, 2012, 135(Pt 12): 3614-3626.
35.	Anagnostou ME,Ng YS, Taylor RW, et al. Epilepsy due to mutations in the mitochondrial polymerasegamma (POLG) gene: A clinical and molecular genetic review. Epilepsia, 2016, 57(10):1531-1545.
36.	Engelsen BA, Tzoulis C, Karlsen B, et al. POLG1 mutations cause asyndromic epilepsy with occipital lobe predilection. Brain, 2008, 131(Pt 3): 818-828.
37.	Janssen W, Quaegebeur A, van Goethem G, et al.The spectrum of epilepsy caused by POLG mutations. Acta Neurol Belg, 2016, 116(1): 17-25.
38.	Darin N, Oldfors A, Moslemi AR, et al. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol, 2001, 49(3): 377-383.
39.	Saneto RP. Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team. J Multidiscip Healthc, 2016, 9: 323-333.
40.	Hunter MF, Peters H, Salemi R, et al. Alpers Syndrome With Mutations in POLG: Clinical and Investigative Features. Pediatric Neurology, 2011, 45(5): 311-318.
41.	Gerards M, Sallevelt SC, Smeets HJ, et al. Leigh syndmme: resolving the clinical and genetic heterogeneity paves the way for treatment opcions. Mol Genet Metab, 2016, 117(3): 300-312.
42.	Koene S, Rodenburg RJ, van der Knaap MS, et al. Natural disease course and genotype-phenotype correlations in complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis, 2012, 35(5): 737-747.
43.	Sofou K, de Coo IF. Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis, 2014, 9: 52.
44.	方方, 沈颖, 沈丹敏, 等. 儿童 Leigh 综合征临床及遗传特征分析. 中华儿科杂志, 2017, 55(3): 205-209.
45.	Agapitos E, Pavlopoulos PM, Patsouris E, et al. Subacute necrotizingencephalomyelopathy (Leigh’s disease):a clinicopathologic study of ten cases. Gen Diagn Pathol, 1997, 142(5-6): 335-341.
46.	Ortigoza-Escobar JD, Oyarzabal A, Montero R, et al. Ndufs4 related Leigh syndrome: A case report and review of the literature. Mitochondrion, 2016, 28: 73-78.

1. 袁云, 崔丽英, 赵重波, 等. 中国神经系统线粒体病的诊治指南. 中华神经科杂志, 2015, 48(12): 1045-1051.
2. Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol, 2015, 77(5): 753-759.
3. 张哲, 赵丹华, 刘靖, 等. 线粒体脑肌病伴乳酸血症和卒中样发作 190 例的临床特征分析. 中华神经科杂志, 2016, 49(3): 237-242.
4. 张晓, 王朝霞, 刘凤君, 等. 线粒体脑肌病伴高乳酸血症和卒中样发作的癫痫发作及脑电图特点分析. 中华神经科杂志, 2014, 47(5): 336-340.
5. Whittaker RG, Devine HE, Gorman GS, et al. Epilepsy in adults with mitochondrial disease: a cohort study. Ann Neurol, 2015, 78(6): 949-957.
6. Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol, 2010, 5: 297-348.
7. Gábor Zsurka, Wolfram S Kunz. Mitochondrial dysfunction and seizures: the neuronal energy crisis. Lancet Neurol, 2015, 14(9): 956-966.
8. Bindokas VP, Lee CC, Colmers WF, et al. Changes in mitochondrial function resulting from synaptic activity in the rat hippocampal slice. J Neurosci, 1998, 18(12): 4570-4587.
9. Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration?. Trends Pharmacol Sci, 1998, 19(8): 328-334.
10. Sesti F, Liu S, Cai SQ. Oxidation of potassium channels by ROS: a general mechanism of aging and neurodegeneration?. Trends Cell Biol, 2010, 20(1): 45-51.
11. Kunz WS, Kudin AP, Vielhaber S, et al. Mitochondrial complex I deficiency in theepileptic focus of patients with temporal lobe epilepsy. Ann Neurol, 2000, 48(5): 766-773.
12. Yamamoto H, Tang HW. Preventive effect of melatonin against cyanide-induced seizures and lipid peroxidation in mice. Neurosci Lett, 1996, 207(2): 89-92.
13. Urbanska EM, Blaszczak P, Saran T, et al. Mitochondrial toxin 3-nitropropionic acid evokes seizures in mice. Eur J Pharmacol, 1998, 359(1): 55-58.
14. Folbergrova J, Kunz WS. Mitochondrial dysfunction in epilepsy. Mitochondrion, 2012, 12(1): 35-40.
15. Chuang YC, Chang AY, Lin JW, et al. Mitochondrial dysfunction and ultrastructural damage in the hippocampus during kainic acid-induced status epilepticus in the rat. Epilepsia, 2004, 45(10): 1202-1209.
16. Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy. Epilepsia, 2012, 53 (Suppl 4): 92-97.
17. Chevallier JA, Von Allmen GK, Koenig MK. Seizure semiology and EEG findings in mitochondrial diseases. Epilepsia, 2014, 55(5): 707-712.
18. Nesbitt V, Pitceathly RD, Turnbull DM, et al. The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation--implications for diagnosis and management. J Neurol Neurosurg Psychiatry, 2013, 84(8): 936-938.
19. Rahman S, Hanna MG. Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases. J Neurol Neurosurg Psychiatry, 2009, 80(9): 943-953.
20. El-Hattab AW, Adesina AM, Jones J, et al. MELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab, 2015, 116(1-2): 4-12.
21. Lee HN, Eom S, Kim SH, et al. Epilepsy characteristics and clinical outcome in patients with mitochondrial encephalomyopathy, lactic acidosis,and stroke-like episodes (MELAS). Pediatr Neurol, 2016, 64: 59-65.
22. Chiyonobu T, Noda R, Yoshida M, et al.Intestinal pseudo-obstruction in a patient with mitochondrial myopathy, encephalopathy,lactic acidosis, and stroke-like episodes (MELAS) associated with phenytoin therapy. Brain Dev, 2008, 30(6): 430-433.
23. Goodfellow JA, Dani K, Stewart W, et al. Mitochondrial myopathy,encephalopathy, lactic acidosis and stroke-like episodes: animportant cause of stroke in young people. Postgrad Med J, 2012, 88(1040): 326-334.
24. Toribe Y, Tominaga K, Ogawa K, et al. Usefulness of L-arginine infusion for status epilepticus in mitochondrialmyopathy, encephalopathy, lactic acidosis, and stroke-like episodes. No To Hattatsu, 2007, 39(1): 38-43.
25. Finsterer J, Kovacs GG. Psoriasis, hyperlipidemia, bulbar involvement,and diarrhoea in MERRF-syndrome due to the m.8344A>GtRNA(Lys) mutation. Iran J Neurol, 2017, 16(1): 45-49.
26. Liu K, Zhao H, Ji K, et al. MERRF/MELAS overlap syndrome due to the m.3291T>Cmutation. Metab Brain Dis, 2014, 29(1): 139-144.
27. Altmann J, Bu chner B, Nadaj-Pakleza A, et al. Expanded phenotypic spectrum of the m.8344A>G " MERRF” mutation: data from the german mitoNET registry. J Neurol, 2016, 263(5): 961-972.
28. Finsterera J, Zarrouk-Mahjou S. Managementof epilepsy in MERRF syndrome. Seizure, 2017, 50: 166-170.
29. Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy.Epilepsia, 2012, 53(Suppl.4): 92-97.
30. Mancuso M, Orsucci D, Angelini C, et al. Phenotypic heterogeneity of the m.8344A>G mtDNA " MERRF” mutation. Neurology, 2013, 80(22): 2049-2054.
31. Sitburana O, Witoonpanich R, Phudhichareonrat S,et al. Seizures in myoclonic epilepsy with ragged-red fibers detected by DNA analysis: a case report. J Med Assoc Thai, 2001, 84(7): 1051-1055.
32. NIEHS-Mitochondrial DNA Replication Group. Human DNAPolymerase Gamma Mutation Database. http://tools.niehs.nih.gov/polg/. Accessed 01 Jul 2016.
33. Hakonen AH, Davidzon G, Salemi R, et al. Abundance of the POLGdisease mutations in Europe, Australia, New Zealand, and the UnitedStates explained by single ancient European founders. Eur J Hum Genet, 2007, 15(7): 779-783.
34. Neeve VC, Samuels DC, Bindoff LA, et al. What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?. Brain, 2012, 135(Pt 12): 3614-3626.
35. Anagnostou ME,Ng YS, Taylor RW, et al. Epilepsy due to mutations in the mitochondrial polymerasegamma (POLG) gene: A clinical and molecular genetic review. Epilepsia, 2016, 57(10):1531-1545.
36. Engelsen BA, Tzoulis C, Karlsen B, et al. POLG1 mutations cause asyndromic epilepsy with occipital lobe predilection. Brain, 2008, 131(Pt 3): 818-828.
37. Janssen W, Quaegebeur A, van Goethem G, et al.The spectrum of epilepsy caused by POLG mutations. Acta Neurol Belg, 2016, 116(1): 17-25.
38. Darin N, Oldfors A, Moslemi AR, et al. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol, 2001, 49(3): 377-383.
39. Saneto RP. Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team. J Multidiscip Healthc, 2016, 9: 323-333.
40. Hunter MF, Peters H, Salemi R, et al. Alpers Syndrome With Mutations in POLG: Clinical and Investigative Features. Pediatric Neurology, 2011, 45(5): 311-318.
41. Gerards M, Sallevelt SC, Smeets HJ, et al. Leigh syndmme: resolving the clinical and genetic heterogeneity paves the way for treatment opcions. Mol Genet Metab, 2016, 117(3): 300-312.
42. Koene S, Rodenburg RJ, van der Knaap MS, et al. Natural disease course and genotype-phenotype correlations in complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis, 2012, 35(5): 737-747.
43. Sofou K, de Coo IF. Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis, 2014, 9: 52.
44. 方方, 沈颖, 沈丹敏, 等. 儿童 Leigh 综合征临床及遗传特征分析. 中华儿科杂志, 2017, 55(3): 205-209.
45. Agapitos E, Pavlopoulos PM, Patsouris E, et al. Subacute necrotizingencephalomyelopathy (Leigh’s disease):a clinicopathologic study of ten cases. Gen Diagn Pathol, 1997, 142(5-6): 335-341.
46. Ortigoza-Escobar JD, Oyarzabal A, Montero R, et al. Ndufs4 related Leigh syndrome: A case report and review of the literature. Mitochondrion, 2016, 28: 73-78.

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