局灶性皮质发育不良的病理机制_Journal of Epilepsy

Authors：

IsaacMarin-Valencia , RenzoGuerrini ,  JosephG Gleeson , 迟潇洒 , 慕洁

Corresponding author：

JosephG Gleeson, Email: jogleeson@ucsd.edu

Keywords：

局灶性皮质发育不良; 巨细胞; 哺乳动物雷帕霉素靶蛋白; 巨颅-症状性癫痫综合征

DOI：

10.7507/2096-0247.20160095

Video：

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Abstract Full text Figures/Tables Video References Cited by

局灶性皮质发育不良(Focal cortical dysplasias, FCDs)是儿童难治性癫痫的常见病因,也是常需癫痫手术的原因。尽管近年来在细胞和分子生物上的进展,FCDs的病理机制仍不清楚。该研究旨在回顾FCDs的分子机制,系统地检索FCDs组织、分子和电生理方面的文献,以明确可能的治疗靶点。哺乳动物雷帕霉素靶蛋白信号通路(mammalian target of rapamycin,mTOR)是一些FCDs结构和电生理紊乱的重要机制。其他的假说包括病毒感染、早产、头部外伤和脑肿瘤。mTOR抑制剂(如:雷帕霉素)在动物和少量FCDs患者的队列癫痫控制中取得阳性结果。近期研究在发育不良组织细胞的分子和电生理机制方面取得了令人鼓舞的进展。尽管mTOR抑制剂有良好的治疗前景,但仍需大规模的随机对照研究评估其有效性和不良反应,并且需要基础研究发现新的分子水平诊断和治疗方式。

Citation： IsaacMarin-Valencia, RenzoGuerrini, JosephG Gleeson, 迟潇洒, 慕洁. 局灶性皮质发育不良的病理机制. Journal of Epilepsy, 2016, 2(6): 544-551. doi: 10.7507/2096-0247.20160095 Copy

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7.	Krsek P, Jahodova A, Maton B, et al. Low-grade focal cortical dysplasia is associated with prenatal and perinatal brain injury.Epilepsia, 2010, 51(8):2440-2448.
8.	Marin-Padilla M, Parisi JE, Armstrong DL, et al. Shaken infant syndrome:developmental neuropathology, progressive cortical dysplasia, and epilepsy. Acta Neuropathol, 2002, 103(5):321-332.
9.	Muhlebner A, Coras R, Kobow K, et al. Neuropathologic measurements in focal cortical dysplasias:validation of the ILAE 2011classification system and diagnostic implications for MRI. Acta Neuropathol, 2012, 123(5):259-272.
10.	Colombo N, Tassi L, Galli C, et al. Focal cortical dysplasias:MRimaging, histopathologic, and clinical correlations in surgically treated patients with epilepsy. AJNR Am J Neuroradiol, 2003, 24(2):724-733.
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1. Harvey AS, Cross JH, Shinnar S, et al. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia, 2008, 49(7):146-155.
2. Taylor DC, Falconer MA, Bruton CJ, et al. Focal dysplasia of the cerebral cortex in epilepsy. J Neurol Neurosurg Psychiatry, 1971, 34(9):369-387.
3. Mischel PS, Nguyen LP, Vinters HV. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for a grading system. J Neuropathol Exp Neurol, 1995, 54(10):137-153.
4. Palmini A, Najm I, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology, 2004, 62(Suppl 2):S2-S8.
5. Blumcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias:a consensus classification proposed by anad hoc task force of the ILAE Diagnostic methods commission.Epilepsia, 2011, 52(11):158-174.
6. Barkovich AJ, Guerrini R, Kuzniecky RI, et al. A developmental and genetic classification for malformations of cortical development:update 2012. Brain, 2012, 135(8):1348-1369.
7. Krsek P, Jahodova A, Maton B, et al. Low-grade focal cortical dysplasia is associated with prenatal and perinatal brain injury.Epilepsia, 2010, 51(8):2440-2448.
8. Marin-Padilla M, Parisi JE, Armstrong DL, et al. Shaken infant syndrome:developmental neuropathology, progressive cortical dysplasia, and epilepsy. Acta Neuropathol, 2002, 103(5):321-332.
9. Muhlebner A, Coras R, Kobow K, et al. Neuropathologic measurements in focal cortical dysplasias:validation of the ILAE 2011classification system and diagnostic implications for MRI. Acta Neuropathol, 2012, 123(5):259-272.
10. Colombo N, Tassi L, Galli C, et al. Focal cortical dysplasias:MRimaging, histopathologic, and clinical correlations in surgically treated patients with epilepsy. AJNR Am J Neuroradiol, 2003, 24(2):724-733.
11. Arai Y, Edwards V, Becker LE. A comparison of cell phenotypes in hemimegal encephaly and tuberous sclerosis. Acta Neuropathol, 1999, 98(11):407-413.
12. Widdess-Walsh P, Kellinghaus C, Jeha L, et al. Electro-clinical and imaging characteristics of focal cortical dysplasia:correlation with pathological subtypes. Epilepsy Res, 2005, 67(3):25-33.
13. Colombo N, Tassi L, Deleo F, et al. Focal cortical dysplasia type IIa and IIb:MRI aspects in 118 cases proven by histopathology. Neuroradiology, 2012, 54(7):1065-1077.
14. Wang DD, Deans AE, Barkovich AJ, et al. Transmantle sign in focal cortical dysplasia:a unique radiological entity with excellent prognosis for seizure control. J Neurosurg, 2013, 118(4):337-344.
15. Orlova KA, Tsai V, Baybis M, et al. Early progenitor cell marker expression distinguishes type II from type I focal cortical dysplasias.J Neuropathol Exp Neurol, 2010, 69(8):850-863.
16. Crino PB, Trojanowski JQ, Eberwine J. Internexin, MAP1B, and nestin in cortical dysplasia as markers of developmental maturity. Acta Neuropathol, 1997, 93(9):619-627.
17. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell, 2012, 149(5):274-293.
18. Hsu PP, Kang SA, Rameseder J, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science, 2011, 332(8):1317-1322.
19. Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibitedby Akt and suppresses mTOR signalling. Nat Cell Biol, 2002, 4(3):648-657.
20. Johannessen CM, Reczek EE, James MF, et al. The NF1 tumorsuppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA, 2005, 102(11):8573-8578.
21. Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene, 1999, 18(9):7034-7045.
22. Puffenberger EG, Strauss KA, Ramsey KE, et al. Polyhydramnios,megal encephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain, 2007, 130(12):1929-1941.
23. Tee AR, Fingar DC, Manning BD, et al. Tuberous sclerosis complex-1and -2 gene products function together to inhibit mammalian target ofrapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA,2002, 99(4):13571-13576.
24. Aronica E, Boer K, Baybis M, et al. Co-expression of cyclin D1 and phosphorylated ribosomal S6 proteins in hemimegal encephaly. ActaNeuropathol, 2007, 114(8):287-293.
25. Baybis M, Yu J, Lee A, et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol, 2004, 56(9):478-487.
26. Samadani U, Judkins AR, Akpalu A, et al. Differential cellular gene expression in ganglioglioma. Epilepsia, 2007, 48(11):646-653.
27. Boer K, Troost D, Spliet WG, et al. Cellular distribution of vascular endothelial growth factor A (VEGFA) and B (VEGFB) and VEGF receptors 1 and 2 in focal cortical dysplasia type IIB. Acta Neuropathol, 2008, 115(12):683-696.
28. Ma J, Meng Y, Kwiatkowski DJ, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J ClinInvest, 2010, 120(9):103-114.
29. Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci, 2009, 29(7):1773-1783.
30. Chen J, Tsai V, Parker WE, et al. Detection of human papillomavirusin human focal cortical dysplasia type IIB. Ann Neurol, 2012, 72(7):881-892.
31. Lu Z, Hu X, Li Y, et al. Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin.J Biol Chem,2004, 279(7):35664-35670.
32. Spangle JM, Munger K. The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesis. J Virol, 2010, 84(8):9398-9407.
33. Buchkovich NJ, Yu Y, Zampieri CA, et al. The TORrid affairs of viruses:effects of mammalian DNA viruses on the PI3K-Akt-mTOR signalling pathway. Nat Rev Microbiol, 2008, 6(4):266-275.
34. Liu S, Lu L, Cheng X, et al. Viral infection and focal cortical dysplasia. Ann Neurol, 2014, 75(7):614-616.
35. Schramm J, Kral T, Grunwald T, et al. Surgical treatment for neocortical temporal lobe epilepsy:clinical and surgical aspects and seizure outcome. J Neurosurg, 2001, 94(7):33-42.
36. Luyken C, Blumcke I, Fimmers R, et al. Supratentorialgangliogliomas:histopathologic grading and tumor recurrence in 184 patients with a median follow-up of 8 years. Cancer, 2004, 101(6):146-155.
37. Boer K, Troost D, Timmermans W, et al. Pi3K-mTOR signaling and AMOG expression in epilepsy-associated glioneuronal tumors. Brain Pathol, 2010, 20(5):234-244.
38. Chen B, Tardell C, Higgins B, et al. BRAFV600E negatively regulates the AKT pathway in melanoma cell lines. PLoSONE, 2012, 7(2):e42598.
39. Koelsche C, Sahm F, Paulus W, et al. BRAF V600E expression and distribution in desmoplastic infantile astrocytoma/ganglioglioma.Neuropathol Appl Neurobiol, 2014, 40(2):337-344.
40. Schindler G, Capper D, Meyer J, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma andextra-cerebellar pilocytic astrocytoma. Acta Neuropathol, 2011, 121(6):397-405.
41. Coffee EM, Faber AC, Roper J, et al. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E)colorectal cancer. Clin Cancer Res, 2013, 19(7):2688-2698.
42. Lee JH, Huynh M, Silhavy JL, et al. De novo somatic mutations incomponents of the PI3K-AKT3-mTOR pathway cause hemimegal encephaly. Nat Genet, 2012, 44(3):941-945.
43. Riviere JB, Mirzaa GM, O'Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause aspectrum of related megal encephaly syndromes. Nat Genet, 2012, 44(6):934-940.
44. Tsang HT, Connell JW, Brown SE, et al. A systematic analysis of human CHMP protein interactions:additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex. Genomics, 2006, 88(8):333-346.
45. McDonell LM, Mirzaa GM, Alcantara D, et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microc ephalycapillary malformation syndrome. Nat Genet, 2013, 45(4):556-562.
46. Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporallobe epilepsy. J Neurosci, 2009, 29(8):6964-6972.
47. Raffo E, Coppola A, Ono T, et al. A pulse rapamycin therapy for infantile spasms and associated cognitive decline. Neurobiol Dis, 2011, 43(8):322-329.
48. Cepeda C, Hurst RS, Flores-Hernandez J, et al. Morphological and electrophysiological characterization of abnormal cell types in pediatric cortical dysplasia. J NeurosciRes, 2003, 72(8):472-486.
49. Moddel G, Jacobson B, Ying Z, et al. The NMDA receptor NR2B subunit contributes to epileptogenesis in human cortical dysplasia.Brain Res, 2005, 1046(7):10-23.
50. Najm IM, Ying Z, Babb T, et al. Epileptogenicity correlated with increased N-methyl-D-aspartate receptor subunit NR2A/B in human focal cortical dysplasia. Epilepsia, 2000, 41(7):971-976.
51. Yamanouchi H. Activated remodeling and N-methyl-D-aspartate(NMDA) receptors in cortical dysplasia. J Child Neurol, 2005, 20(7):303-307.
52. Ying Z, Bingaman W, Najm IM. Increased numbers of coassembled PSD-95 to NMDA-receptor subunits NR2B and NR1 in human epileptic cortical dysplasia. Epilepsia, 2004, 45(7):314-321.
53. Andre VM, Flores-Hernandez J, Cepeda C, et al. NMDA receptor alterations in neurons from pediatric cortical dysplasia tissue. CerebCortex, 2004, 14(5):634-646.
54. Alonso-Nanclares L, Garbelli R, Sola RG, et al. Microanatomy of the dysplastic neocortex from epileptic patients. Brain, 2005, 128(6):158-173.
55. Duchowny M, Jayakar P, Levin B. Aberrant neural circuits in malformations of cortical development and focal epilepsy. Neurology, 2000, 55(7):423-428.
56. Perucca P, Dubeau F, Gotman J. Intracranial electroencephalographic seizure-onset patterns:effect of underlying pathology. Brain, 2014, 137(8):183-196.
57. Widdess-Walsh P, Jeha L, Nair D, et al. Subdural electrode analysis infocal cortical dysplasia:predictors of surgical outcome. Neurology, 2007, 69(6):660-667.
58. Ak H, Ay B, Tanriverdi T, et al. Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia. Seizure, 2007, 16(6):493-503.
59. Volk HA, Loscher W. Multidrug resistance in epilepsy:rats with drug resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. Brain, 2005, 128(7):1358-1368.
60. Wang Y, Greenwood JS, Calcagnotto ME, et al. Neocortical hyperexcitability in a human case of tuberous sclerosis complex and micelacking neuronal expression of TSC1. Ann Neurol, 2007, 61(6):139-152.
61. Talos DM, Kwiatkowski DJ, Cordero K, et al. Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann Neurol, 2008, 63(3):454-465.
62. Uhlmann EJ, Wong M, Baldwin RL, et al. Astrocyte-specific TSC1conditional knockout mice exhibit abnormal neuronal organization andseizures. Ann Neurol,2002, 52(8):285-296.
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