金良，陳語(yǔ)婕，陳勇軍

綜 述

發(fā)育性和癲癇性腦病遺傳學(xué)病因及診療的研究進(jìn)展

金良，陳語(yǔ)婕，陳勇軍

南華大學(xué)衡陽(yáng)醫(yī)學(xué)院附屬南華醫(yī)院神經(jīng)內(nèi)科，衡陽(yáng) 421002

發(fā)育性和癲癇性腦病(developmental and epileptic encephalopathy, DEE)是一組臨床和遺傳異質(zhì)的年齡依賴性神經(jīng)系統(tǒng)疾病，其特征是在嬰兒期或兒童早期出現(xiàn)難治性癲癇發(fā)作，且受影響的個(gè)體有精神運(yùn)動(dòng)發(fā)育遲緩或倒退。隨著二代測(cè)序技術(shù)的發(fā)展，尤其是全外顯子測(cè)序技術(shù)的應(yīng)用，越來(lái)越多的基因被發(fā)現(xiàn)與DEE相關(guān)。這些發(fā)現(xiàn)將為臨床工作中DEE致病基因的檢測(cè)提供依據(jù)，同時(shí)將有助于加深對(duì)DEE發(fā)病機(jī)制的理解。本文主要對(duì)DEE的遺傳學(xué)病因及診療的相關(guān)研究進(jìn)展展開(kāi)綜述，以期幫助臨床醫(yī)生早期識(shí)別相關(guān)基因突變，從而加快疾病診斷并及時(shí)實(shí)施最佳治療。

基因變異；發(fā)育性和癲癇性腦病；OMIM數(shù)據(jù)庫(kù)；精準(zhǔn)治療

2001年，國(guó)際抗癲癇聯(lián)盟(International League Against Epilepsy，ILAE)首次正式提出癲癇性腦病(epileptic encephalopathy)這一術(shù)語(yǔ)，其臨床表現(xiàn)為頻繁的癲癇發(fā)作、異常的腦電圖和進(jìn)行性下降的認(rèn)知障礙[1]。這一臨床表征在2010年被進(jìn)一步闡釋：癲癇活動(dòng)本身可導(dǎo)致發(fā)育障礙，這表明后者可能是基于癲癇發(fā)作而獲得的表型，并且這些表型可能隨著時(shí)間的推移而惡化[2]。直到2017年，ILAE提出發(fā)育性和癲癇性腦病(developmental and epileptic encephalopathy，DEE)的新概念，并與“發(fā)育性腦病”和“癲癇性腦病”進(jìn)行區(qū)分[3]：(1)“發(fā)育性腦病”即廣義上表現(xiàn)為發(fā)育遲緩和智力殘疾而無(wú)頻繁的癲癇發(fā)作；(2)“癲癇性腦病”則表現(xiàn)為患者既有癲癇發(fā)作又有發(fā)育障礙，但發(fā)育問(wèn)題是由癲癇活動(dòng)導(dǎo)致的，二者具有一定的因果關(guān)系；(3) DEE表現(xiàn)出的“發(fā)育障礙”和“癲癇發(fā)作”兩種臨床表型可相互獨(dú)立存在，發(fā)育障礙既可以出現(xiàn)在癲癇發(fā)作前，也可在其后?！鞍l(fā)育障礙”和“癲癇發(fā)作”都有特定的遺傳學(xué)病因而不是單純的因果關(guān)系。這也更科學(xué)準(zhǔn)確地對(duì)疾病本身進(jìn)行解釋，尤其對(duì)疾病的診斷和治療有著重要的指導(dǎo)意義。

隨著基因組學(xué)技術(shù)的進(jìn)步，尤其是二代測(cè)序技術(shù)的發(fā)展，DEE越來(lái)越被認(rèn)為與基因變異相關(guān)[4]。目前已有400多個(gè)基因被報(bào)道與DEE相關(guān)[5]，其中常染色體顯性遺傳(如、)多在家族中散發(fā)出現(xiàn)，近親結(jié)婚可能會(huì)加劇常染色體隱性遺傳(如、)變異的組合，X連鎖遺傳可在顯性遺傳(如、)和隱性遺傳(如、)以及女性雜合或男性嵌合模式(如)中發(fā)生。截至2023年3月，在線人類孟德?tīng)栠z傳(Online Mendelian Inheritance in Man，OMIM)數(shù)據(jù)庫(kù)收錄DEE致病基因已達(dá)110個(gè)，其中常染色體基因占比超過(guò)90%(圖1A)。這些DEE基因編碼蛋白涉及多種生物學(xué)功能，包括參與離子轉(zhuǎn)運(yùn)，膜運(yùn)輸調(diào)節(jié)，酶促分子代謝，細(xì)胞生長(zhǎng)、增殖和細(xì)胞粘附等[6～8](圖1B，表1)。這些單基因變體可導(dǎo)致患者出現(xiàn)從嬰兒期或兒童期開(kāi)始的頑固性癲癇發(fā)作和發(fā)育遲緩或退化[9]。此外，多基因相互作用，基因修飾以及表觀遺傳學(xué)因素也可以導(dǎo)致相關(guān)表型[10～12]。本文將對(duì)DEE致病基因的功能和致病機(jī)制、DEE綜合征及潛在精準(zhǔn)治療方案的研究進(jìn)展進(jìn)行綜述，以期為DEE的診療提供理論基礎(chǔ)和應(yīng)用參考價(jià)值。

1 DEE致病基因功能及其變異

1.1 離子通道

DEE致病基因編碼蛋白涉及多種生物學(xué)功能，其中約25%的基因參與編碼離子通道，包括電壓門控離子通道(voltage-gated ion channels，VGICs)和配體門控離子通道(ligand-gated ion channels，LGICs)等(圖2)。這些離子通道在調(diào)節(jié)細(xì)胞內(nèi)外離子濃度，突觸傳遞和神經(jīng)元興奮性中具有重要作用。下面將進(jìn)行詳細(xì)介紹。

1.1.1 鈉離子通道

電壓門控鈉離子通道通常是由1個(gè)α亞基和1個(gè)或多個(gè)β亞基組成的蛋白復(fù)合體，其可以通過(guò)改變門控通道開(kāi)閉的狀態(tài)來(lái)控制鈉離子的進(jìn)出。α亞基存在9種不同的同工型(Nav1.1～Nav1.9)?；蚓幋aNav1.1[13]，其主要在抑制性中間神經(jīng)元表達(dá)，大部分位于神經(jīng)元的胞體部位，負(fù)責(zé)建立動(dòng)作電位產(chǎn)生和傳播的閾值?；蛲蛔儗?dǎo)致抑制性神經(jīng)遞質(zhì)減少，從而使中樞神經(jīng)系統(tǒng)處于異常興奮狀態(tài)而引起癲癇發(fā)作。突變可導(dǎo)致以發(fā)熱為主要特點(diǎn)的癲癇發(fā)作，約60%患兒第一次發(fā)作與熱相關(guān)，大多數(shù)患者被診斷為Dravet綜合征(Dravet syndrome，DS)，發(fā)病率約為1/15,500[14]。DS表現(xiàn)為出生后的第一年開(kāi)始出現(xiàn)長(zhǎng)時(shí)間的全身性癲癇發(fā)作，表現(xiàn)為高熱驚厥[15]。經(jīng)歷第一年的發(fā)熱性癲癇發(fā)作后，患者在第二年出現(xiàn)頻繁的肌陣攣、全身性強(qiáng)直陣攣、反復(fù)交替的單側(cè)肢體陣攣以及局灶性意識(shí)受損等[16,17]。DS臨床可表現(xiàn)為DEE，其出現(xiàn)的發(fā)育障礙是獨(dú)立而明顯的，往往在癲癇發(fā)作之后，頻繁的癲癇持續(xù)狀態(tài)可造成神經(jīng)功能缺陷和認(rèn)知惡化，以及死亡風(fēng)險(xiǎn)的增加[18]。突變多以新生突變?yōu)橹?，大多?shù)患者為錯(cuò)義突變，部分患者攜帶剪切位點(diǎn)突變、截短突變、移碼突變以及拷貝數(shù)異常等[19,20]，新生突變患者較家系遺傳變異的患者具有更為嚴(yán)重的臨床表型。截短突變?yōu)楣δ軉适?loss of function，LOF)，蛋白翻譯被提前終止而產(chǎn)生沒(méi)有功能或功能活性極低的截短蛋白，可發(fā)生單倍劑量不足(haploinsufficiency)或顯性負(fù)效應(yīng)(dominant negative，DN)。錯(cuò)義突變多為L(zhǎng)OF，也可表現(xiàn)為功能獲得(gain of function，GOF)，這可能與突變位置相關(guān)，位于不同功能區(qū)D I～I(xiàn)V、“孔區(qū)”、“電壓感受區(qū)”或“連接區(qū)”的點(diǎn)突變導(dǎo)致了不同的功能改變，也影響了不同嚴(yán)重程度的癲癇表型[21]。

圖1 DEE基因的遺傳模式及功能

A：不同遺傳方式的DEE基因占比；B：不同功能的DEE基因占比。

表1 DEE基因功能

圖2 離子通道相關(guān)DEE基因在神經(jīng)元的功能定位

分別編碼電壓門控鈉通道Nav1.2和Nav1.6的基因和基因變異同樣會(huì)導(dǎo)致嚴(yán)重的DEE[22,23]?；蚧蜃儺惥鶠槌Ｈ旧w顯性遺傳。家族遺傳性變異患者可能表現(xiàn)為輕度的癲癇表型，如良性家族性新生兒-嬰兒癲癇(benign familial neonatal-infantile seizures，BFNIS)[24]，而新生突變的患者可發(fā)展為嚴(yán)重的發(fā)育遲緩和癲癇發(fā)作，表現(xiàn)為DEE，如大田原綜合征(Ohtahara syndrome，OS)、Lennox-Gastaut綜合征(Lennox-Gastaut syndrome，LGS)、肌陣攣-無(wú)張力癲癇等[25]。這些患者臨床可表現(xiàn)為多種癲癇發(fā)作類型，包括嬰兒痙攣、全身性強(qiáng)直-陣攣、肌陣攣、失神發(fā)作等[26,27]。然而有趣的是，有研究表明嬰兒早期(＜3個(gè)月)的變異通常是GOF，癲癇晚發(fā)的患者(＞3個(gè)月)可能是與該基因LOF有關(guān)[28]，而大多數(shù)變異則表現(xiàn)為鈉通道GOF[29,30]，根據(jù)這些現(xiàn)象可在基因診斷的基礎(chǔ)上指導(dǎo)臨床用藥[28,31]。

1.1.2 鉀離子通道

鉀離子通道是一種位于細(xì)胞膜的四聚體跨膜蛋白，其可通過(guò)調(diào)節(jié)細(xì)胞內(nèi)外的離子濃度和電位，在神經(jīng)元正常的信號(hào)傳導(dǎo)、調(diào)節(jié)和穩(wěn)態(tài)中發(fā)揮重要的作用。鉀離子通道包括電壓門控鉀通道(voltage- gated potassium channels，Kv)、鈣離子激活鉀通道(Ca2+activated K+channel，KCa)、鈉離子激活鉀通道(Na+activated K+channel，KNa)、內(nèi)向整流鉀通道(inwardly-rectifying potassium channels，Kir)、轉(zhuǎn)運(yùn)調(diào)控鉀通道(transport-regulated potassium channels，KUP)、雙孔鉀通道(two-pore-domain potassium channel，K2P)、K2C型兩性離子通道(two-pore domain K+channel of the KCNK family，K2C)等。其中、編碼KVα亞基，編碼KVβ亞基，而、編碼KNa。和是兩種較為常見(jiàn)的DEE致病基因?；蚓幋aKv7.2，其變異表型譜從輕度的良性家族性新生兒驚厥1(benign familial neonatal seizures 1，BFNS1)到重度的新生兒DEE。重度患者表現(xiàn)為新生兒開(kāi)始的發(fā)育遲緩和難治性癲癇發(fā)作，其中以強(qiáng)直發(fā)作為主，伴有局灶性和陣攣性癲癇發(fā)作以及自主神經(jīng)功能障礙。研究表明KCNQ2蛋白可與KCNQ3蛋白相互作用[32]，它們?cè)谌祟惼べ|(zhì)和海馬體的錐體和多態(tài)性神經(jīng)元上以軀體發(fā)育模式共定位，二者的共聚合可在體外表達(dá)時(shí)形成M通道[33]，這是一種緩慢激活和失活的鉀電導(dǎo)，可在神經(jīng)元的閾下電興奮性以及突觸輸入的反應(yīng)性中起關(guān)鍵作用[34]。當(dāng) M通道介導(dǎo)的M電流被抑制時(shí)，KCNQ通道功能下調(diào)，可使神經(jīng)元靜息電位更接近于閾值，使得神經(jīng)元興奮性增加，從而導(dǎo)致癲癇的發(fā)生?；蚓幋aKNa1.1，在突變的患者中，抑制性中間神經(jīng)元中增強(qiáng)的鉀電流導(dǎo)致超極化延長(zhǎng)，引起神經(jīng)元興奮-抑制失衡，從而引發(fā)癲癇發(fā)作[35]。散發(fā)性的突變主要與嬰兒癲癇伴游走性局灶性發(fā)作(epilepsy of infancy with migrating focal seizures，EIMFS)相關(guān)[36]，患者表現(xiàn)為出生后6個(gè)月內(nèi)連續(xù)的多灶性和遷移性癲癇發(fā)作，逐漸發(fā)展為耐藥性癲癇，并伴有獲得性小頭畸形，發(fā)育倒退和嚴(yán)重的智力障礙，甚至死亡。家族遺傳性突變主要導(dǎo)致睡眠相關(guān)過(guò)度運(yùn)動(dòng)性癲癇(sleep-related hypermotor epilepsy，SHE)，伴有過(guò)度運(yùn)動(dòng)行為和(或)張力障礙性姿勢(shì)[37]。

1.1.3 鈣離子通道

鈣離子通道是一種能夠調(diào)節(jié)細(xì)胞內(nèi)外鈣離子濃度差以及各種生物學(xué)功能的跨膜蛋白通道。根據(jù)調(diào)節(jié)方式的不同，可分為電壓門控鈣通道(voltage- gated calcium channels，VGCC)和配體門控鈣通道(ligand-gated calcium channels，LGCC)。VGCC是去極化誘導(dǎo)鈣離子進(jìn)入神經(jīng)元的主要媒介，其由α1、α2δ、β1-4和γ亞基構(gòu)成。VGCC主要分為L(zhǎng)型、P/Q型、N型、R型和T型鈣通道。電壓門控鈣通道可觸發(fā)鈣依賴過(guò)程，包括調(diào)節(jié)基因轉(zhuǎn)錄，神經(jīng)遞質(zhì)釋放、神經(jīng)元生長(zhǎng)及鈣依賴酶的激活[38]?；蚓幋aP/Q型鈣通道的跨膜成孔亞基[39]，其突變可導(dǎo)致DEE42型(MIM #617106)，來(lái)自Epi4K的數(shù)據(jù)表明，DEE42型患者通常在出生后的幾個(gè)小時(shí)或幾天內(nèi)發(fā)生各種類型的難治性癲癇發(fā)作，并有全面發(fā)育遲緩、智力障礙、伴或不伴軸性張力減退、反射亢進(jìn)、震顫和共濟(jì)失調(diào)等[40]。此外基因變異患者臨床也可表現(xiàn)為發(fā)作性共濟(jì)失調(diào)(episodic ataxia 2，EA)，脊髓小腦性共濟(jì)失調(diào)(spino-cere-bellar ataxia，SCA)，家族性偏癱偏頭痛(familial hemiplegic migraine，F(xiàn)HM)等[41]。在變異家族中，癲癇發(fā)作、偏癱、偏頭痛或共濟(jì)失調(diào)等多種表型可相互重疊或獨(dú)立存在[42,43]。研究表明，基因突變無(wú)論是LOF還是GOF都可以導(dǎo)致嚴(yán)重的DEE[44]，盡管傳統(tǒng)上認(rèn)為L(zhǎng)OF的變異導(dǎo)致癲癇和EA[45]，而GOF變異導(dǎo)致FHM[46]。

1.1.4 配體門控通道GABA受體

γ-氨基丁酸(GABA)是哺乳動(dòng)物中樞神經(jīng)系統(tǒng)主要的抑制性神經(jīng)遞質(zhì)，它作用于GABAA和GABAB兩種不同的配體門控受體亞型。GABAA受體是多亞基氯離子通道，介導(dǎo)中樞神經(jīng)系統(tǒng)中的抑制性突觸傳遞，其可由α、β、γ、δ和ρ等同源亞基類別的蛋白質(zhì)組成。GABAA受體的遺傳性缺陷可導(dǎo)致DEE。編碼GABAA型受體亞單位α1，其突變可導(dǎo)致嬰兒期開(kāi)始出現(xiàn)的癲癇發(fā)作，主要為強(qiáng)直性陣攣和肌陣攣性癲癇發(fā)作。大多數(shù)患者為新生突變，少數(shù)患者為家系遺傳。Carvill 等[47]在一名患有DEE19型(MIM #615744)的2歲女童身上，發(fā)現(xiàn)了基因的新生雜合錯(cuò)義突變(p.Gly251Ser)，通過(guò)對(duì)該變體的體外功能研究表明癲癇發(fā)作是由于大腦中GABA抑制功能受損，而大腦興奮性異常增加所致。GABAB受體是一種G蛋白偶聯(lián)受體，主要分布于突觸前末梢上，激活后可抑制Ca2+內(nèi)流，在突觸前抑制中起重要的作用，GABAB受體是由和編碼蛋白組成的異二聚體復(fù)合物，其中基因突變可導(dǎo)致DEE59型(MIM #617904)，為常染色體顯性遺傳。Hamdan等[48]在一名DEE59型的14歲男孩的基因中，發(fā)現(xiàn)的新生雜合錯(cuò)義突變(p.Gly693Trp)，并指出可能參與了突觸抑制。目前暫未被收錄相關(guān)表型，該基因變體偶爾在自閉癥譜系障礙中有報(bào)道[49]，基因型-表型相關(guān)性仍不明確。

1.1.5 配體門控通道谷氨酸受體

谷氨酸是中樞神經(jīng)系統(tǒng)一種主要的興奮性遞質(zhì)，在興奮性突觸的傳遞中具有重要的作用。離子型谷氨酸受體包括NMDA(N-甲基-D-天冬氨酸)受體、AMPA(α-氨基-3-羥基-5-甲基-4-異惡丙酸)受體和Kainate受體，它們是配體門控的離子通道，通過(guò)結(jié)合谷氨酸從而調(diào)控通道的開(kāi)閉狀態(tài)。編碼NMDA受體中的亞基，作為谷氨酸的激動(dòng)劑結(jié)合位點(diǎn)，參與長(zhǎng)時(shí)程增強(qiáng)作用，并在記憶和學(xué)習(xí)中具有重要作用?；蛲蛔兛蓪?dǎo)致DEE27型(MIM #616139)，為常染色體顯性遺傳。有研究表明GOF突變會(huì)導(dǎo)致West綜合征(West syndrome，WS)、兒童局灶性癲癇伴智力障礙，表型嚴(yán)重程度可能與通道功能受損的程度相關(guān)[50]。

1.1.6 HCN通道

HCN通道由4個(gè)亞單位組成，每個(gè)亞單位包含6個(gè)跨膜結(jié)構(gòu)域(S1～S6)和一個(gè)貫穿膜區(qū)域的核心結(jié)構(gòu)(P區(qū))，其中P區(qū)是離子通道的重要部分。HCN通道在調(diào)控神經(jīng)元興奮性和抑制性平衡、調(diào)節(jié)神經(jīng)元活動(dòng)等方面具有重要的作用。當(dāng)HCN通道功能下降或喪失時(shí)，可使得神經(jīng)元興奮性增加，從而引發(fā)癲癇發(fā)作[51]。HCN通道由HCN (hyperpolarization- activated cyclic nucleotide-gated)基因家族()編碼。其中HCN1亞型分布最廣，Marini 等[52]在8例DEE24型(MIM #615871)患者中，發(fā)現(xiàn)了新生雜合錯(cuò)義突變，且嚴(yán)重表型的突變往往傾向于聚集在跨膜結(jié)構(gòu)域內(nèi)或靠近跨膜結(jié)構(gòu)域，作者由此推測(cè)突變可能導(dǎo)致GOF或DN，從而引起神經(jīng)元過(guò)度興奮。

1.2 非離子通道功能

除編碼離子通道基因可導(dǎo)致DEE表型外，編碼非離子通道基因也與DEE相關(guān)。這些基因參與膜運(yùn)輸調(diào)節(jié)，酶促分子代謝，細(xì)胞生長(zhǎng)、增殖、分化，細(xì)胞粘附和蛋白轉(zhuǎn)運(yùn)等。盡管一部分基因功能定位明確，但并未在DEE致病機(jī)制中進(jìn)行深入研究，下面將介紹主要的一些功能(表1)。

1.2.1 膜運(yùn)輸調(diào)節(jié)

神經(jīng)元突觸是信號(hào)傳遞的重要結(jié)構(gòu)。突觸前膜的活性區(qū)可聚集大量包裹神經(jīng)遞質(zhì)的突觸囊泡，當(dāng)動(dòng)作電位到達(dá)突觸前膜時(shí)，聚集于活性區(qū)的突觸囊泡將與細(xì)胞質(zhì)膜融合，隨后神經(jīng)遞質(zhì)通過(guò)突觸間隙到達(dá)突觸后膜受體，進(jìn)而實(shí)現(xiàn)信號(hào)的傳遞?；蚓幋a突觸融合蛋白結(jié)合蛋白1，參與突觸囊泡和突觸前膜的對(duì)接及融合，在突觸前膜對(duì)神經(jīng)遞質(zhì)釋放中起重要作用[53]。可與突觸體相關(guān)蛋白25(SNAP25)和突觸素2(Syb2)組合成可溶性N-乙基馬來(lái)酰亞胺敏感因子附著蛋白受體(SNARE)復(fù)合物[54]，進(jìn)而促進(jìn)突觸小泡的對(duì)接，引發(fā)和融合。根據(jù)人類基因突變數(shù)據(jù)庫(kù)(Human Gene Mutation Database，HGMD)收錄的數(shù)據(jù)，目前已報(bào)道超過(guò)340個(gè)變異，主要為錯(cuò)義突變，少數(shù)為無(wú)義突變、移碼突變、剪接位點(diǎn)突變和框內(nèi)缺失等。單倍體劑量不足被認(rèn)為是在體內(nèi)外動(dòng)物模型中研究突變導(dǎo)致DEE的重要病理機(jī)制[55]。變異可涉及多種癲癇綜合征，包括DS、OS、WS、LGS等[56]。

1.2.2 酶促分子代謝

腦內(nèi)代謝酶的異常也與癲癇的發(fā)生和發(fā)展有關(guān)。某些代謝酶可將蛋白質(zhì)/氨基酸、核酸、能量等進(jìn)行轉(zhuǎn)化代謝，在酶活性降低或缺乏這種酶的條件下，大腦內(nèi)進(jìn)入代謝的大分子物質(zhì)會(huì)異常累積或正常代謝產(chǎn)物異常減少[57,58]，從而引起腦發(fā)育異常和癲癇發(fā)作?；蛭挥赬染色體上，編碼一個(gè)具有蛋白激酶活性的磷酸化蛋白，該蛋白是絲氨酸/蘇氨酸蛋白激酶家族成員。突變會(huì)導(dǎo)致激酶活性的喪失[59]，而激酶活性的維持對(duì)大腦的正常發(fā)育至關(guān)重要。2004年，Kalscheuer等[60]報(bào)道了2例發(fā)育性和癲癇性腦病的女孩，并診斷為嬰兒痙攣癥。2006年，Archer等[61]在一組73名參與分析的患者中篩查突變，其中有49名患者在出生后6個(gè)月內(nèi)就發(fā)生了癲癇發(fā)作，Archer等由此提出突變是女性患者嬰兒痙攣和早期癲癇發(fā)作的重要原因，并且容易進(jìn)展為難治性癲癇發(fā)作。

1.2.3 轉(zhuǎn)運(yùn)蛋白

轉(zhuǎn)運(yùn)蛋白是一種功能性蛋白質(zhì)，可以促進(jìn)細(xì)胞或細(xì)胞器內(nèi)外物質(zhì)的轉(zhuǎn)運(yùn)，從而參與維持細(xì)胞穩(wěn)態(tài)，調(diào)節(jié)細(xì)胞代謝等重要的生理功能。DEE基因編碼蛋白涉及多種轉(zhuǎn)運(yùn)功能，其中包括蛋白質(zhì)/氨基酸轉(zhuǎn)運(yùn)蛋白，陰/陽(yáng)離子轉(zhuǎn)運(yùn)蛋白，核苷酸-糖轉(zhuǎn)運(yùn)蛋白等。基因編碼一種鈣結(jié)合線粒體載體蛋白，可將天冬氨酸從線粒體轉(zhuǎn)運(yùn)到細(xì)胞質(zhì)以交換谷氨酸。Falk等[62]在進(jìn)行體外功能學(xué)研究發(fā)現(xiàn)，突變蛋白大約有15%的剩余活性，并指出由于谷氨酸-天冬氨酸穿梭細(xì)胞產(chǎn)生的細(xì)胞還原等量物缺乏會(huì)導(dǎo)致能量不足，從而引發(fā)神經(jīng)元損傷，最終導(dǎo)致腦發(fā)育異常。H+-ATP酶(V-ATPase)是一種ATP 依賴性蛋白泵，參與溶酶體和其他細(xì)胞器的酸化以及氫離子(H+)的轉(zhuǎn)運(yùn)。V-ATPase由V1結(jié)構(gòu)域和V0跨膜結(jié)構(gòu)域組成，V1結(jié)構(gòu)域由A、B、C、D、E、F、G、H八種亞基組成，V0結(jié)構(gòu)域由a、b、c、d、e五種亞基組成，其中DEE致病基因編碼V1結(jié)構(gòu)域A亞基，編碼V0結(jié)構(gòu)域的a亞基。V-ATPase在溶酶體系統(tǒng)穩(wěn)態(tài)維持、神經(jīng)遞質(zhì)貯存釋放以及神經(jīng)元興奮性調(diào)控中具有重要作用。Fassio等[63]在4例無(wú)關(guān)的DEE93型(MIM #618012)患者中鑒定了新生雜合錯(cuò)義突變(Asp100Try和Asp349Asn)。通過(guò)體外功能表達(dá)研究表明，Asp100Try變體可導(dǎo)致LOF，使得蛋白產(chǎn)物表達(dá)降低，而Asp349Asn突變則導(dǎo)致GOF，使得質(zhì)子泵送增加。這兩種突變都可導(dǎo)致神經(jīng)突伸長(zhǎng)缺陷和突觸形成受損，這一現(xiàn)象表明溶酶體穩(wěn)態(tài)和神經(jīng)元連接異常會(huì)影響神經(jīng)發(fā)育并最終導(dǎo)致DEE?；蚓幋a一種UDP-半乳糖轉(zhuǎn)運(yùn)蛋白(UGT)，可將UDP-半乳糖從細(xì)胞質(zhì)轉(zhuǎn)運(yùn)到高爾基體作為糖基供體生成聚糖，基因突變可導(dǎo)致先天性糖基化障礙和DEE，其中先天性糖基化障礙可由體細(xì)胞嵌合突變導(dǎo)致，而DEE主要由新生突變導(dǎo)致[64,65]。Kodera等[65]報(bào)告了3名攜帶基因突變且被診斷為DEE的患者，這些患者在6天至3個(gè)月大之間出現(xiàn)了頑固性癲癇發(fā)作，并有嚴(yán)重精神運(yùn)動(dòng)及語(yǔ)言發(fā)育遲緩。

1.2.4 細(xì)胞代謝和信號(hào)轉(zhuǎn)導(dǎo)

細(xì)胞正常生長(zhǎng)和增殖對(duì)維持神經(jīng)系統(tǒng)形態(tài)與功能至關(guān)重要。神經(jīng)元和非神經(jīng)元細(xì)胞異常的生命歷程(生長(zhǎng)、分化、增殖和遷移等)可導(dǎo)致腦發(fā)育異常和癲癇發(fā)作。基因位于X染色體，其編碼ARX蛋白在胚胎時(shí)期對(duì)生長(zhǎng)發(fā)育和神經(jīng)元分化及遷移非常重要。根據(jù)HGMD收錄的數(shù)據(jù)，截止目前已報(bào)道變異位點(diǎn)150余個(gè)，其中大多數(shù)為錯(cuò)義突變，少數(shù)變異為截短突變、移碼突變和剪切位點(diǎn)突變等。突變表型譜包括DEE1型(MIM #308350)、積水性無(wú)腦畸形伴生殖器異常、智力障礙、Partington綜合征、Proud綜合征等[66～69]。其中DEE1型為X連鎖隱性遺傳，患者通常表現(xiàn)為嬰兒期開(kāi)始的頻繁的強(qiáng)直性癲癇發(fā)作或痙攣，并伴有抑制-爆發(fā)模式的腦電圖表現(xiàn)[70]，男性患者較女性患者有著相對(duì)更為嚴(yán)重的臨床表型。有研究表明，該基因破壞性突變的患者通常表現(xiàn)為腦畸形綜合征，而聚丙氨酸擴(kuò)張突變的患者可能只導(dǎo)致DEE[71]?；蚓幋aSZT2蛋白亞基，與KPTN、ITFG2、KICS2組成KICSTOR復(fù)合體，與神經(jīng)發(fā)育相關(guān)。其可通過(guò)調(diào)節(jié)mTORC1信號(hào)通路而導(dǎo)致癲癇發(fā)作?；蜃儺惪蓪?dǎo)致DEE18型(MIM #615476)，為常染色體隱性遺傳模式。其破壞性變體攜帶者可表現(xiàn)為特殊的MRI模式，嚴(yán)重的DEE患者可觀察到胼胝體增厚及透明室腔隔形成，臨床表現(xiàn)為頑固性癲癇發(fā)作，藥物控制差，并有嚴(yán)重的發(fā)育遲緩、智力障礙及運(yùn)動(dòng)障礙。目前已報(bào)道30多個(gè)變異位點(diǎn)，其中錯(cuò)義和無(wú)義突變最為常見(jiàn)[72]。

1.2.5 細(xì)胞粘附

細(xì)胞粘附即細(xì)胞表面一系列分子之間的相互作用，這種相互作用可以通過(guò)細(xì)胞表面分子上的配體與另一分子上的受體結(jié)合來(lái)實(shí)現(xiàn)。不穩(wěn)定的細(xì)胞粘附會(huì)導(dǎo)致神經(jīng)元和神經(jīng)膠質(zhì)細(xì)胞之間的紊亂，尤其是在突觸傳遞過(guò)程中，這種紊亂將導(dǎo)致神經(jīng)元放電的不穩(wěn)定性[73]，從而誘發(fā)癲癇發(fā)作。細(xì)胞粘附分子通常分為四大家族，包括免疫球蛋白超家族、整合素家族、選擇素家族和鈣粘蛋白家族[74]?；蛭挥赬染色體，編碼一種在腦中(尤其是皮質(zhì)和海馬)高度表達(dá)的鈣依賴性細(xì)胞粘附蛋白，該蛋白屬于鈣粘蛋白超家族的δ-2原鈣粘蛋白亞類的成員[75]。變異具有特殊的X連鎖遺傳模式，雜合子女性表現(xiàn)為癲癇與智力障礙(epilepsy and mental retardation，EFMR)(DEE9 #300088)，半合子男性無(wú)癥狀[75]。然而，有研究表明嵌合體的男性可以表現(xiàn)為完全或不完全外顯狀態(tài)[76,77]，因此攜帶嵌合突變的男性可產(chǎn)生疾病表型。這種特殊的機(jī)制被稱為細(xì)胞干擾[75,78]，受影響的女性是突變細(xì)胞群和野生型細(xì)胞的“共存體”(雜合狀態(tài))，而嵌合體的男性患者同樣攜帶這兩種細(xì)胞群，并且這種嵌合狀態(tài)可能會(huì)干擾細(xì)胞間通訊。2008年，基因突變首次由Dibbens等[75]在導(dǎo)致女性DEE的7個(gè)家系中報(bào)道。2009年，Depienne等[78]在28個(gè)具有類似EFMR表型的男性患者中發(fā)現(xiàn)1名攜帶了基因缺失的體細(xì)胞嵌合體。

2 DEE相關(guān)綜合征

DEE是一種很廣泛的概念，臨床上大多數(shù)癲癇綜合征都可表現(xiàn)為DEE，并且這些綜合征都有潛在的遺傳病因，可由單基因或多基因突變導(dǎo)致。如前文提到的基因突變導(dǎo)致DS，基因突變導(dǎo)致EIMFS。了解這些DEE相關(guān)的臨床特點(diǎn)(如起病年齡、癲癇發(fā)作及發(fā)育特征)和基因變異特點(diǎn)，對(duì)加快疾病診斷、及時(shí)實(shí)施干預(yù)有著重要意義。

DEE相關(guān)綜合征包括早期肌陣攣性腦病(early myoclonic encephalopathy，EME)、OS、WS、嬰兒期癲癇伴有遷移性局灶性癲癇發(fā)作(epilepsy of infancy with migrating focal seizures，EIMFS)、非進(jìn)展性疾病中的肌陣攣性腦病(myoclonic encephalo-pathy in non-progressive disorders，MENPD)、LGS、癲癇性腦病伴睡眠期間持續(xù)性棘波(epileptic ence-phalopathy with continuous spike-and-wave during sleep，CSWS)和Landau Kleffner 綜合征(Landau Kleffner syndrome，LKS)等(表2)。這些DEE綜合征表現(xiàn)為特殊的臨床表型，且具有以下特點(diǎn)：(1)發(fā)育落后可發(fā)生在癲癇發(fā)作之前(或之后)；(2)減輕癲癇發(fā)作，嚴(yán)重的發(fā)育障礙仍可長(zhǎng)期存在，并可能持續(xù)惡化。這些DEE綜合征均可由基因突變導(dǎo)致，臨床醫(yī)生在對(duì)DEE患者進(jìn)行診療時(shí)，應(yīng)注意遺傳缺陷帶來(lái)的影響。

值得注意的是，除了大多數(shù)癲癇綜合征表現(xiàn)為DEE以外，在其他遺傳性疾病中也可觀察到DEE表型(https://www.omim.org/entry/308350)，如甘氨酸腦病(MIM #605899)、GLUT1缺乏綜合征(MIM #606777)、艾卡迪-古蒂埃斯綜合征(MIM #225750)和突變(MIM #300673)的男性患者等。

3 基于DEE基因變異的治療

基因測(cè)序給疾病診斷帶來(lái)便利的同時(shí)，針對(duì)單基因變異所采取的獨(dú)特分子遺傳學(xué)“精準(zhǔn)治療”措施往往更加受到臨床工作者的關(guān)注。目前，針對(duì)一些基因的特定致病機(jī)制所采取的靶向干預(yù)獲得了較好臨床治療預(yù)期。其中包括離子通道調(diào)節(jié)劑、飲食、維生素、基因治療、信號(hào)轉(zhuǎn)導(dǎo)調(diào)節(jié)劑等。

表2 DEE相關(guān)的癲癇綜合征

對(duì)于鈉離子通道基因突變來(lái)說(shuō)，如基因LOF往往導(dǎo)致鈉通道被阻斷，應(yīng)避免使用鈉離子通道阻滯劑[79]，如卡馬西平、奧卡西平和拉莫三嗪等，以免加重癲癇發(fā)作。而GOF患者可考慮使用鈉離子通道阻滯劑[80]；對(duì)于鉀離子通道基因突變來(lái)說(shuō)，有研究表明，針對(duì)編碼電壓門控鉀離子通道基因LOF突變可以考慮使用瑞替加濱和加巴噴丁[81,82]，但由于瑞替加濱不良反應(yīng)多，已經(jīng)開(kāi)始逐漸退出臨床使用。此外，鈉離子通道阻滯劑雖然并不是針對(duì)鉀通道的靶向治療藥物，但是也可以表現(xiàn)出一定的療效[83]。對(duì)于GOF的基因變異可以考慮使用鉀離子通道阻滯劑如4-氨基吡啶等[84]。對(duì)于編碼鉀通道的基因的GOF突變，奎尼丁可能有效[85]，但這是一種抗心律失常藥，其抗癲癇效果可能大打折扣。臨床研究表明，在奎尼丁藥物治療下，只有20%的變異患者的癲癇發(fā)作減少了50%[86]。

對(duì)于編碼非離子通道基因變異來(lái)說(shuō)，飲食、激素、基因治療等方法則更為常見(jiàn)。Koch等[58]在4名患有癲癇性腦病、全面發(fā)育遲緩的兒童中發(fā)現(xiàn)了雙等位基因變異，這是一種編碼吡啶核苷酸的從頭生物合成基因，口服尿苷補(bǔ)充劑(嘧啶再循環(huán))可改善發(fā)育落后。對(duì)于基因變異，人工合成的加納索酮或輔助使用己烯戊醇可能有效[87,88]。此外變異患者可考慮使用生酮飲食[89]，變異患者可考慮使用丙戊酸[90]，變異導(dǎo)致的DEE可考慮采用AAV介導(dǎo)的基因治療、芬氟拉明、GSK3B-HDAC雙抑制劑、GABA受體拮抗劑等多種治療方案[91-94]。應(yīng)注意的是，一部分療法只在體外研究中證實(shí)有效，實(shí)際臨床價(jià)值仍待考究。

4 結(jié)語(yǔ)與展望

DNA測(cè)序技術(shù)的出現(xiàn)，使人類對(duì)疾病的發(fā)生和發(fā)展有了更為深刻的認(rèn)識(shí)。然而，“一個(gè)基因——一種表型”范式越來(lái)越具有挑戰(zhàn)性。目前明確導(dǎo)致DEE表型的基因中，有44個(gè)(44/110，40%)基因具有多個(gè)表型，其中還包括中樞神經(jīng)系統(tǒng)外的疾病，如陣發(fā)性睡眠性血紅蛋白尿(MIM #300818)、先天性糖基化障礙(MIM #300896)、食道鱗狀細(xì)胞癌(MIM #133239)等。這些基因變異可能導(dǎo)致多個(gè)表型重疊或替代，臨床醫(yī)生需要綜合分析，準(zhǔn)確做出判斷。但值得肯定的是，改善病人嚴(yán)重的癲癇發(fā)作和發(fā)育落后，無(wú)論對(duì)于患者本人還是其家庭看護(hù)者，都是至關(guān)重要的。

隨著新的研究和發(fā)現(xiàn)，DEE致病基因的數(shù)量在不斷更新，DEE致病基因的功能與致病機(jī)制也將不斷擴(kuò)展。不得否認(rèn)的是，新基因的發(fā)現(xiàn)對(duì)推動(dòng)疾病的診療具有十分重大的意義。廣州醫(yī)科大學(xué)附屬第二醫(yī)院廖衛(wèi)平教授牽頭中國(guó)抗癲癇協(xié)會(huì)1.0項(xiàng)目(http://caae.org.cn/)，發(fā)現(xiàn)了一系列新的癲癇致病基因，如、、、和等[95～99]，這大大擴(kuò)充了癲癇的致病基因譜。基因測(cè)序技術(shù)，尤其是全外顯子測(cè)序在DEE的診斷上具有重要作用，建議對(duì)不能明確病因的特發(fā)性癲癇患者，尤其是具有DEE表型特征的患者，采用三人組(先證者+父母)的全外顯子測(cè)序，早期診斷和干預(yù)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

湖南省衛(wèi)生健康委重點(diǎn)指導(dǎo)課題(編號(hào)：20201910)和南華大學(xué)臨床醫(yī)學(xué)研究“4310”計(jì)劃項(xiàng)目(編號(hào)：20224310NHYCG11)資助[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，在讀碩士研究生，專業(yè)方向：神經(jīng)遺傳性疾病。E-mail: Jliang811@163.com

陳勇軍，博士，主任醫(yī)師，研究方向：神經(jīng)遺傳性疾病。E-mail: chenyj-usc@foxmail.com

10.16288/j.yczz.23-105

(責(zé)任編委: 陽(yáng)小飛)