发育性和癫痫性脑病遗传学病因及诊疗的研究进展

金良，陈语婕，陈勇军

综 述

发育性和癫痫性脑病遗传学病因及诊疗的研究进展

金良，陈语婕，陈勇军

南华大学衡阳医学院附属南华医院神经内科，衡阳 421002

发育性和癫痫性脑病(developmental and epileptic encephalopathy, DEE)是一组临床和遗传异质的年龄依赖性神经系统疾病，其特征是在婴儿期或儿童早期出现难治性癫痫发作，且受影响的个体有精神运动发育迟缓或倒退。随着二代测序技术的发展，尤其是全外显子测序技术的应用，越来越多的基因被发现与DEE相关。这些发现将为临床工作中DEE致病基因的检测提供依据，同时将有助于加深对DEE发病机制的理解。本文主要对DEE的遗传学病因及诊疗的相关研究进展展开综述，以期帮助临床医生早期识别相关基因突变，从而加快疾病诊断并及时实施最佳治疗。

基因变异；发育性和癫痫性脑病；OMIM数据库；精准治疗

2001年，国际抗癫痫联盟(International League Against Epilepsy，ILAE)首次正式提出癫痫性脑病(epileptic encephalopathy)这一术语，其临床表现为频繁的癫痫发作、异常的脑电图和进行性下降的认知障碍[1]。这一临床表征在2010年被进一步阐释：癫痫活动本身可导致发育障碍，这表明后者可能是基于癫痫发作而获得的表型，并且这些表型可能随着时间的推移而恶化[2]。直到2017年，ILAE提出发育性和癫痫性脑病(developmental and epileptic encephalopathy，DEE)的新概念，并与“发育性脑病”和“癫痫性脑病”进行区分[3]：(1)“发育性脑病”即广义上表现为发育迟缓和智力残疾而无频繁的癫痫发作；(2)“癫痫性脑病”则表现为患者既有癫痫发作又有发育障碍，但发育问题是由癫痫活动导致的，二者具有一定的因果关系；(3) DEE表现出的“发育障碍”和“癫痫发作”两种临床表型可相互独立存在，发育障碍既可以出现在癫痫发作前，也可在其后。“发育障碍”和“癫痫发作”都有特定的遗传学病因而不是单纯的因果关系。这也更科学准确地对疾病本身进行解释，尤其对疾病的诊断和治疗有着重要的指导意义。

随着基因组学技术的进步，尤其是二代测序技术的发展，DEE越来越被认为与基因变异相关[4]。目前已有400多个基因被报道与DEE相关[5]，其中常染色体显性遗传(如、)多在家族中散发出现，近亲结婚可能会加剧常染色体隐性遗传(如、)变异的组合，X连锁遗传可在显性遗传(如、)和隐性遗传(如、)以及女性杂合或男性嵌合模式(如)中发生。截至2023年3月，在线人类孟德尔遗传(Online Mendelian Inheritance in Man，OMIM)数据库收录DEE致病基因已达110个，其中常染色体基因占比超过90%(图1A)。这些DEE基因编码蛋白涉及多种生物学功能，包括参与离子转运，膜运输调节，酶促分子代谢，细胞生长、增殖和细胞粘附等[6～8](图1B，表1)。这些单基因变体可导致患者出现从婴儿期或儿童期开始的顽固性癫痫发作和发育迟缓或退化[9]。此外，多基因相互作用，基因修饰以及表观遗传学因素也可以导致相关表型[10～12]。本文将对DEE致病基因的功能和致病机制、DEE综合征及潜在精准治疗方案的研究进展进行综述，以期为DEE的诊疗提供理论基础和应用参考价值。

1 DEE致病基因功能及其变异

1.1 离子通道

DEE致病基因编码蛋白涉及多种生物学功能，其中约25%的基因参与编码离子通道，包括电压门控离子通道(voltage-gated ion channels，VGICs)和配体门控离子通道(ligand-gated ion channels，LGICs)等(图2)。这些离子通道在调节细胞内外离子浓度，突触传递和神经元兴奋性中具有重要作用。下面将进行详细介绍。

1.1.1 钠离子通道

电压门控钠离子通道通常是由1个α亚基和1个或多个β亚基组成的蛋白复合体，其可以通过改变门控通道开闭的状态来控制钠离子的进出。α亚基存在9种不同的同工型(Nav1.1～Nav1.9)。基因编码Nav1.1[13]，其主要在抑制性中间神经元表达，大部分位于神经元的胞体部位，负责建立动作电位产生和传播的阈值。基因突变导致抑制性神经递质减少，从而使中枢神经系统处于异常兴奋状态而引起癫痫发作。突变可导致以发热为主要特点的癫痫发作，约60%患儿第一次发作与热相关，大多数患者被诊断为Dravet综合征(Dravet syndrome，DS)，发病率约为1/15,500[14]。DS表现为出生后的第一年开始出现长时间的全身性癫痫发作，表现为高热惊厥[15]。经历第一年的发热性癫痫发作后，患者在第二年出现频繁的肌阵挛、全身性强直阵挛、反复交替的单侧肢体阵挛以及局灶性意识受损等[16,17]。DS临床可表现为DEE，其出现的发育障碍是独立而明显的，往往在癫痫发作之后，频繁的癫痫持续状态可造成神经功能缺陷和认知恶化，以及死亡风险的增加[18]。突变多以新生突变为主，大多数患者为错义突变，部分患者携带剪切位点突变、截短突变、移码突变以及拷贝数异常等[19,20]，新生突变患者较家系遗传变异的患者具有更为严重的临床表型。截短突变为功能丧失型(loss of function，LOF)，蛋白翻译被提前终止而产生没有功能或功能活性极低的截短蛋白，可发生单倍剂量不足(haploinsufficiency)或显性负效应(dominant negative，DN)。错义突变多为LOF，也可表现为功能获得(gain of function，GOF)，这可能与突变位置相关，位于不同功能区D I～IV、“孔区”、“电压感受区”或“连接区”的点突变导致了不同的功能改变，也影响了不同严重程度的癫痫表型[21]。

图1 DEE基因的遗传模式及功能

A：不同遗传方式的DEE基因占比；B：不同功能的DEE基因占比。

表1 DEE基因功能

图2 离子通道相关DEE基因在神经元的功能定位

分别编码电压门控钠通道Nav1.2和Nav1.6的基因和基因变异同样会导致严重的DEE[22,23]。或基因变异均为常染色体显性遗传。家族遗传性变异患者可能表现为轻度的癫痫表型，如良性家族性新生儿-婴儿癫痫(benign familial neonatal-infantile seizures，BFNIS)[24]，而新生突变的患者可发展为严重的发育迟缓和癫痫发作，表现为DEE，如大田原综合征(Ohtahara syndrome，OS)、Lennox-Gastaut综合征(Lennox-Gastaut syndrome，LGS)、肌阵挛-无张力癫痫等[25]。这些患者临床可表现为多种癫痫发作类型，包括婴儿痉挛、全身性强直-阵挛、肌阵挛、失神发作等[26,27]。然而有趣的是，有研究表明婴儿早期(＜3个月)的变异通常是GOF，癫痫晚发的患者(＞3个月)可能是与该基因LOF有关[28]，而大多数变异则表现为钠通道GOF[29,30]，根据这些现象可在基因诊断的基础上指导临床用药[28,31]。

1.1.2 钾离子通道

钾离子通道是一种位于细胞膜的四聚体跨膜蛋白，其可通过调节细胞内外的离子浓度和电位，在神经元正常的信号传导、调节和稳态中发挥重要的作用。钾离子通道包括电压门控钾通道(voltage- gated potassium channels，Kv)、钙离子激活钾通道(Ca2+activated K+channel，KCa)、钠离子激活钾通道(Na+activated K+channel，KNa)、内向整流钾通道(inwardly-rectifying potassium channels，Kir)、转运调控钾通道(transport-regulated potassium channels，KUP)、双孔钾通道(two-pore-domain potassium channel，K2P)、K2C型两性离子通道(two-pore domain K+channel of the KCNK family，K2C)等。其中、编码KVα亚基，编码KVβ亚基，而、编码KNa。和是两种较为常见的DEE致病基因。基因编码Kv7.2，其变异表型谱从轻度的良性家族性新生儿惊厥1(benign familial neonatal seizures 1，BFNS1)到重度的新生儿DEE。重度患者表现为新生儿开始的发育迟缓和难治性癫痫发作，其中以强直发作为主，伴有局灶性和阵挛性癫痫发作以及自主神经功能障碍。研究表明KCNQ2蛋白可与KCNQ3蛋白相互作用[32]，它们在人类皮质和海马体的锥体和多态性神经元上以躯体发育模式共定位，二者的共聚合可在体外表达时形成M通道[33]，这是一种缓慢激活和失活的钾电导，可在神经元的阈下电兴奋性以及突触输入的反应性中起关键作用[34]。当 M通道介导的M电流被抑制时，KCNQ通道功能下调，可使神经元静息电位更接近于阈值，使得神经元兴奋性增加，从而导致癫痫的发生。基因编码KNa1.1，在突变的患者中，抑制性中间神经元中增强的钾电流导致超极化延长，引起神经元兴奋-抑制失衡，从而引发癫痫发作[35]。散发性的突变主要与婴儿癫痫伴游走性局灶性发作(epilepsy of infancy with migrating focal seizures，EIMFS)相关[36]，患者表现为出生后6个月内连续的多灶性和迁移性癫痫发作，逐渐发展为耐药性癫痫，并伴有获得性小头畸形，发育倒退和严重的智力障碍，甚至死亡。家族遗传性突变主要导致睡眠相关过度运动性癫痫(sleep-related hypermotor epilepsy，SHE)，伴有过度运动行为和(或)张力障碍性姿势[37]。

1.1.3 钙离子通道

钙离子通道是一种能够调节细胞内外钙离子浓度差以及各种生物学功能的跨膜蛋白通道。根据调节方式的不同，可分为电压门控钙通道(voltage- gated calcium channels，VGCC)和配体门控钙通道(ligand-gated calcium channels，LGCC)。VGCC是去极化诱导钙离子进入神经元的主要媒介，其由α1、α2δ、β1-4和γ亚基构成。VGCC主要分为L型、P/Q型、N型、R型和T型钙通道。电压门控钙通道可触发钙依赖过程，包括调节基因转录，神经递质释放、神经元生长及钙依赖酶的激活[38]。基因编码P/Q型钙通道的跨膜成孔亚基[39]，其突变可导致DEE42型(MIM #617106)，来自Epi4K的数据表明，DEE42型患者通常在出生后的几个小时或几天内发生各种类型的难治性癫痫发作，并有全面发育迟缓、智力障碍、伴或不伴轴性张力减退、反射亢进、震颤和共济失调等[40]。此外基因变异患者临床也可表现为发作性共济失调(episodic ataxia 2，EA)，脊髓小脑性共济失调(spino­cere­bellar ataxia，SCA)，家族性偏瘫偏头痛(familial hemiplegic migraine，FHM)等[41]。在变异家族中，癫痫发作、偏瘫、偏头痛或共济失调等多种表型可相互重叠或独立存在[42,43]。研究表明，基因突变无论是LOF还是GOF都可以导致严重的DEE[44]，尽管传统上认为LOF的变异导致癫痫和EA[45]，而GOF变异导致FHM[46]。

1.1.4 配体门控通道GABA受体

γ-氨基丁酸(GABA)是哺乳动物中枢神经系统主要的抑制性神经递质，它作用于GABAA和GABAB两种不同的配体门控受体亚型。GABAA受体是多亚基氯离子通道，介导中枢神经系统中的抑制性突触传递，其可由α、β、γ、δ和ρ等同源亚基类别的蛋白质组成。GABAA受体的遗传性缺陷可导致DEE。编码GABAA型受体亚单位α1，其突变可导致婴儿期开始出现的癫痫发作，主要为强直性阵挛和肌阵挛性癫痫发作。大多数患者为新生突变，少数患者为家系遗传。Carvill 等[47]在一名患有DEE19型(MIM #615744)的2岁女童身上，发现了基因的新生杂合错义突变(p.Gly251Ser)，通过对该变体的体外功能研究表明癫痫发作是由于大脑中GABA抑制功能受损，而大脑兴奋性异常增加所致。GABAB受体是一种G蛋白偶联受体，主要分布于突触前末梢上，激活后可抑制Ca2+内流，在突触前抑制中起重要的作用，GABAB受体是由和编码蛋白组成的异二聚体复合物，其中基因突变可导致DEE59型(MIM #617904)，为常染色体显性遗传。Hamdan等[48]在一名DEE59型的14岁男孩的基因中，发现的新生杂合错义突变(p.Gly693Trp)，并指出可能参与了突触抑制。目前暂未被收录相关表型，该基因变体偶尔在自闭症谱系障碍中有报道[49]，基因型-表型相关性仍不明确。

1.1.5 配体门控通道谷氨酸受体

谷氨酸是中枢神经系统一种主要的兴奋性递质，在兴奋性突触的传递中具有重要的作用。离子型谷氨酸受体包括NMDA(N-甲基-D-天冬氨酸)受体、AMPA(α-氨基-3-羟基-5-甲基-4-异恶丙酸)受体和Kainate受体，它们是配体门控的离子通道，通过结合谷氨酸从而调控通道的开闭状态。编码NMDA受体中的亚基，作为谷氨酸的激动剂结合位点，参与长时程增强作用，并在记忆和学习中具有重要作用。基因突变可导致DEE27型(MIM #616139)，为常染色体显性遗传。有研究表明GOF突变会导致West综合征(West syndrome，WS)、儿童局灶性癫痫伴智力障碍，表型严重程度可能与通道功能受损的程度相关[50]。

1.1.6 HCN通道

HCN通道由4个亚单位组成，每个亚单位包含6个跨膜结构域(S1～S6)和一个贯穿膜区域的核心结构(P区)，其中P区是离子通道的重要部分。HCN通道在调控神经元兴奋性和抑制性平衡、调节神经元活动等方面具有重要的作用。当HCN通道功能下降或丧失时，可使得神经元兴奋性增加，从而引发癫痫发作[51]。HCN通道由HCN (hyperpolarization- activated cyclic nucleotide-gated)基因家族()编码。其中HCN1亚型分布最广，Marini 等[52]在8例DEE24型(MIM #615871)患者中，发现了新生杂合错义突变，且严重表型的突变往往倾向于聚集在跨膜结构域内或靠近跨膜结构域，作者由此推测突变可能导致GOF或DN，从而引起神经元过度兴奋。

1.2 非离子通道功能

除编码离子通道基因可导致DEE表型外，编码非离子通道基因也与DEE相关。这些基因参与膜运输调节，酶促分子代谢，细胞生长、增殖、分化，细胞粘附和蛋白转运等。尽管一部分基因功能定位明确，但并未在DEE致病机制中进行深入研究，下面将介绍主要的一些功能(表1)。

1.2.1 膜运输调节

神经元突触是信号传递的重要结构。突触前膜的活性区可聚集大量包裹神经递质的突触囊泡，当动作电位到达突触前膜时，聚集于活性区的突触囊泡将与细胞质膜融合，随后神经递质通过突触间隙到达突触后膜受体，进而实现信号的传递。基因编码突触融合蛋白结合蛋白1，参与突触囊泡和突触前膜的对接及融合，在突触前膜对神经递质释放中起重要作用[53]。可与突触体相关蛋白25(SNAP25)和突触素2(Syb2)组合成可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合物[54]，进而促进突触小泡的对接，引发和融合。根据人类基因突变数据库(Human Gene Mutation Database，HGMD)收录的数据，目前已报道超过340个变异，主要为错义突变，少数为无义突变、移码突变、剪接位点突变和框内缺失等。单倍体剂量不足被认为是在体内外动物模型中研究突变导致DEE的重要病理机制[55]。变异可涉及多种癫痫综合征，包括DS、OS、WS、LGS等[56]。

1.2.2 酶促分子代谢

脑内代谢酶的异常也与癫痫的发生和发展有关。某些代谢酶可将蛋白质/氨基酸、核酸、能量等进行转化代谢，在酶活性降低或缺乏这种酶的条件下，大脑内进入代谢的大分子物质会异常累积或正常代谢产物异常减少[57,58]，从而引起脑发育异常和癫痫发作。基因位于X染色体上，编码一个具有蛋白激酶活性的磷酸化蛋白，该蛋白是丝氨酸/苏氨酸蛋白激酶家族成员。突变会导致激酶活性的丧失[59]，而激酶活性的维持对大脑的正常发育至关重要。2004年，Kalscheuer等[60]报道了2例发育性和癫痫性脑病的女孩，并诊断为婴儿痉挛症。2006年，Archer等[61]在一组73名参与分析的患者中筛查突变，其中有49名患者在出生后6个月内就发生了癫痫发作，Archer等由此提出突变是女性患者婴儿痉挛和早期癫痫发作的重要原因，并且容易进展为难治性癫痫发作。

1.2.3 转运蛋白

转运蛋白是一种功能性蛋白质，可以促进细胞或细胞器内外物质的转运，从而参与维持细胞稳态，调节细胞代谢等重要的生理功能。DEE基因编码蛋白涉及多种转运功能，其中包括蛋白质/氨基酸转运蛋白，阴/阳离子转运蛋白，核苷酸-糖转运蛋白等。基因编码一种钙结合线粒体载体蛋白，可将天冬氨酸从线粒体转运到细胞质以交换谷氨酸。Falk等[62]在进行体外功能学研究发现，突变蛋白大约有15%的剩余活性，并指出由于谷氨酸-天冬氨酸穿梭细胞产生的细胞还原等量物缺乏会导致能量不足，从而引发神经元损伤，最终导致脑发育异常。H+-ATP酶(V-ATPase)是一种ATP 依赖性蛋白泵，参与溶酶体和其他细胞器的酸化以及氢离子(H+)的转运。V-ATPase由V1结构域和V0跨膜结构域组成，V1结构域由A、B、C、D、E、F、G、H八种亚基组成，V0结构域由a、b、c、d、e五种亚基组成，其中DEE致病基因编码V1结构域A亚基，编码V0结构域的a亚基。V-ATPase在溶酶体系统稳态维持、神经递质贮存释放以及神经元兴奋性调控中具有重要作用。Fassio等[63]在4例无关的DEE93型(MIM #618012)患者中鉴定了新生杂合错义突变(Asp100Try和Asp349Asn)。通过体外功能表达研究表明，Asp100Try变体可导致LOF，使得蛋白产物表达降低，而Asp349Asn突变则导致GOF，使得质子泵送增加。这两种突变都可导致神经突伸长缺陷和突触形成受损，这一现象表明溶酶体稳态和神经元连接异常会影响神经发育并最终导致DEE。基因编码一种UDP-半乳糖转运蛋白(UGT)，可将UDP-半乳糖从细胞质转运到高尔基体作为糖基供体生成聚糖，基因突变可导致先天性糖基化障碍和DEE，其中先天性糖基化障碍可由体细胞嵌合突变导致，而DEE主要由新生突变导致[64,65]。Kodera等[65]报告了3名携带基因突变且被诊断为DEE的患者，这些患者在6天至3个月大之间出现了顽固性癫痫发作，并有严重精神运动及语言发育迟缓。

1.2.4 细胞代谢和信号转导

细胞正常生长和增殖对维持神经系统形态与功能至关重要。神经元和非神经元细胞异常的生命历程(生长、分化、增殖和迁移等)可导致脑发育异常和癫痫发作。基因位于X染色体，其编码ARX蛋白在胚胎时期对生长发育和神经元分化及迁移非常重要。根据HGMD收录的数据，截止目前已报道变异位点150余个，其中大多数为错义突变，少数变异为截短突变、移码突变和剪切位点突变等。突变表型谱包括DEE1型(MIM #308350)、积水性无脑畸形伴生殖器异常、智力障碍、Partington综合征、Proud综合征等[66～69]。其中DEE1型为X连锁隐性遗传，患者通常表现为婴儿期开始的频繁的强直性癫痫发作或痉挛，并伴有抑制-爆发模式的脑电图表现[70]，男性患者较女性患者有着相对更为严重的临床表型。有研究表明，该基因破坏性突变的患者通常表现为脑畸形综合征，而聚丙氨酸扩张突变的患者可能只导致DEE[71]。基因编码SZT2蛋白亚基，与KPTN、ITFG2、KICS2组成KICSTOR复合体，与神经发育相关。其可通过调节mTORC1信号通路而导致癫痫发作。基因变异可导致DEE18型(MIM #615476)，为常染色体隐性遗传模式。其破坏性变体携带者可表现为特殊的MRI模式，严重的DEE患者可观察到胼胝体增厚及透明室腔隔形成，临床表现为顽固性癫痫发作，药物控制差，并有严重的发育迟缓、智力障碍及运动障碍。目前已报道30多个变异位点，其中错义和无义突变最为常见[72]。

1.2.5 细胞粘附

细胞粘附即细胞表面一系列分子之间的相互作用，这种相互作用可以通过细胞表面分子上的配体与另一分子上的受体结合来实现。不稳定的细胞粘附会导致神经元和神经胶质细胞之间的紊乱，尤其是在突触传递过程中，这种紊乱将导致神经元放电的不稳定性[73]，从而诱发癫痫发作。细胞粘附分子通常分为四大家族，包括免疫球蛋白超家族、整合素家族、选择素家族和钙粘蛋白家族[74]。基因位于X染色体，编码一种在脑中(尤其是皮质和海马)高度表达的钙依赖性细胞粘附蛋白，该蛋白属于钙粘蛋白超家族的δ-2原钙粘蛋白亚类的成员[75]。变异具有特殊的X连锁遗传模式，杂合子女性表现为癫痫与智力障碍(epilepsy and mental retardation，EFMR)(DEE9 #300088)，半合子男性无症状[75]。然而，有研究表明嵌合体的男性可以表现为完全或不完全外显状态[76,77]，因此携带嵌合突变的男性可产生疾病表型。这种特殊的机制被称为细胞干扰[75,78]，受影响的女性是突变细胞群和野生型细胞的“共存体”(杂合状态)，而嵌合体的男性患者同样携带这两种细胞群，并且这种嵌合状态可能会干扰细胞间通讯。2008年，基因突变首次由Dibbens等[75]在导致女性DEE的7个家系中报道。2009年，Depienne等[78]在28个具有类似EFMR表型的男性患者中发现1名携带了基因缺失的体细胞嵌合体。

2 DEE相关综合征

DEE是一种很广泛的概念，临床上大多数癫痫综合征都可表现为DEE，并且这些综合征都有潜在的遗传病因，可由单基因或多基因突变导致。如前文提到的基因突变导致DS，基因突变导致EIMFS。了解这些DEE相关的临床特点(如起病年龄、癫痫发作及发育特征)和基因变异特点，对加快疾病诊断、及时实施干预有着重要意义。

DEE相关综合征包括早期肌阵挛性脑病(early myoclonic encephalopathy，EME)、OS、WS、婴儿期癫痫伴有迁移性局灶性癫痫发作(epilepsy of infancy with migrating focal seizures，EIMFS)、非进展性疾病中的肌阵挛性脑病(myoclonic encephalo­pathy in non-progressive disorders，MENPD)、LGS、癫痫性脑病伴睡眠期间持续性棘波(epileptic ence­phalopathy with continuous spike-and-wave during sleep，CSWS)和Landau Kleffner 综合征(Landau Kleffner syndrome，LKS)等(表2)。这些DEE综合征表现为特殊的临床表型，且具有以下特点：(1)发育落后可发生在癫痫发作之前(或之后)；(2)减轻癫痫发作，严重的发育障碍仍可长期存在，并可能持续恶化。这些DEE综合征均可由基因突变导致，临床医生在对DEE患者进行诊疗时，应注意遗传缺陷带来的影响。

值得注意的是，除了大多数癫痫综合征表现为DEE以外，在其他遗传性疾病中也可观察到DEE表型(https://www.omim.org/entry/308350)，如甘氨酸脑病(MIM #605899)、GLUT1缺乏综合征(MIM #606777)、艾卡迪-古蒂埃斯综合征(MIM #225750)和突变(MIM #300673)的男性患者等。

3 基于DEE基因变异的治疗

基因测序给疾病诊断带来便利的同时，针对单基因变异所采取的独特分子遗传学“精准治疗”措施往往更加受到临床工作者的关注。目前，针对一些基因的特定致病机制所采取的靶向干预获得了较好临床治疗预期。其中包括离子通道调节剂、饮食、维生素、基因治疗、信号转导调节剂等。

表2 DEE相关的癫痫综合征

对于钠离子通道基因突变来说，如基因LOF往往导致钠通道被阻断，应避免使用钠离子通道阻滞剂[79]，如卡马西平、奥卡西平和拉莫三嗪等，以免加重癫痫发作。而GOF患者可考虑使用钠离子通道阻滞剂[80]；对于钾离子通道基因突变来说，有研究表明，针对编码电压门控钾离子通道基因LOF突变可以考虑使用瑞替加滨和加巴喷丁[81,82]，但由于瑞替加滨不良反应多，已经开始逐渐退出临床使用。此外，钠离子通道阻滞剂虽然并不是针对钾通道的靶向治疗药物，但是也可以表现出一定的疗效[83]。对于GOF的基因变异可以考虑使用钾离子通道阻滞剂如4-氨基吡啶等[84]。对于编码钾通道的基因的GOF突变，奎尼丁可能有效[85]，但这是一种抗心律失常药，其抗癫痫效果可能大打折扣。临床研究表明，在奎尼丁药物治疗下，只有20%的变异患者的癫痫发作减少了50%[86]。

对于编码非离子通道基因变异来说，饮食、激素、基因治疗等方法则更为常见。Koch等[58]在4名患有癫痫性脑病、全面发育迟缓的儿童中发现了双等位基因变异，这是一种编码吡啶核苷酸的从头生物合成基因，口服尿苷补充剂(嘧啶再循环)可改善发育落后。对于基因变异，人工合成的加纳索酮或辅助使用己烯戊醇可能有效[87,88]。此外变异患者可考虑使用生酮饮食[89]，变异患者可考虑使用丙戊酸[90]，变异导致的DEE可考虑采用AAV介导的基因治疗、芬氟拉明、GSK3B-HDAC双抑制剂、GABA受体拮抗剂等多种治疗方案[91-94]。应注意的是，一部分疗法只在体外研究中证实有效，实际临床价值仍待考究。

4 结语与展望

DNA测序技术的出现，使人类对疾病的发生和发展有了更为深刻的认识。然而，“一个基因——一种表型”范式越来越具有挑战性。目前明确导致DEE表型的基因中，有44个(44/110，40%)基因具有多个表型，其中还包括中枢神经系统外的疾病，如阵发性睡眠性血红蛋白尿(MIM #300818)、先天性糖基化障碍(MIM #300896)、食道鳞状细胞癌(MIM #133239)等。这些基因变异可能导致多个表型重叠或替代，临床医生需要综合分析，准确做出判断。但值得肯定的是，改善病人严重的癫痫发作和发育落后，无论对于患者本人还是其家庭看护者，都是至关重要的。

随着新的研究和发现，DEE致病基因的数量在不断更新，DEE致病基因的功能与致病机制也将不断扩展。不得否认的是，新基因的发现对推动疾病的诊疗具有十分重大的意义。广州医科大学附属第二医院廖卫平教授牵头中国抗癫痫协会1.0项目(http://caae.org.cn/)，发现了一系列新的癫痫致病基因，如、、、和等[95～99]，这大大扩充了癫痫的致病基因谱。基因测序技术，尤其是全外显子测序在DEE的诊断上具有重要作用，建议对不能明确病因的特发性癫痫患者，尤其是具有DEE表型特征的患者，采用三人组(先证者+父母)的全外显子测序，早期诊断和干预是十分必要的。

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Advances in genetic etiology, diagnosis and treatment of developmental and epileptic encephalopathy

Liang Jin, Yujie Chen, Yongjun Chen

Developmental and epileptic encephalopathy (DEE) is a clinically and genetically heterogeneous group of age-dependent neurological disorders characterized by onset of refractory seizures in infancy or early childhood and affected individuals with delayed or regressive psychomotor development. With the development of next-generation sequencing technology, especially the application of whole-exome sequencing technology, more and more genes have been found to be associated with DEE.These discoveriesprovide a basis for the detection of pathogenic genes for DEE in clinical work, andalso help to deepen our understanding of the pathogenesis of DEE. In this review, we provide a comprehensive review of the genetic etiology, diagnosis and treatment of DEE, in order to assist clinicians in early identification of relevant gene mutations, thereby expediting disease diagnosis and timely implementation of optimal treatment.

genetic variation; DEE; OMIM database; precise treatment

2023-04-19;

2023-05-21;

2023-05-31

湖南省卫生健康委重点指导课题(编号：20201910)和南华大学临床医学研究“4310”计划项目(编号：20224310NHYCG11)资助[Support by the Key Project of Hunan Provincial Health and Health Commission (No. 20201910), and the “4310” Program of Clinical Medical Research of the University of South China (No. 20224310NHYCG11)]

金良，在读硕士研究生，专业方向：神经遗传性疾病。E-mail: Jliang811@163.com

陈勇军，博士，主任医师，研究方向：神经遗传性疾病。E-mail: chenyj-usc@foxmail.com

10.16288/j.yczz.23-105

(责任编委: 阳小飞)