临床特征.

Leigh综合征（或亚急性坏死性脑病） 以疾病发作间期机体出现失代偿（常伴血液和/或脑脊液中乳酸水平升高）为特征，通常与精神运动迟缓或退化有关，患者发病后常可出现一过性或长期稳定状态， 甚至可出现症状好转，但最终患者常不可避免出现进行性神经系统衰退，且常在逐渐减少药量期间出现。该病的神经系统表现包括肌张力降低、痉挛、运动障碍（包 括舞 蹈病）、小脑共济失调和周围神经病。

非神经系统表现可包括肥厚型心肌病、多毛症、贫血、肾小管病变、肝脏受累、 上睑下垂及肌无力。患者发病年龄通常介于12个月至3岁之间，约有50%患者在三岁时死亡，最常见诱因为呼吸衰竭或心力衰竭。偶尔存在晚期发病（包括成年期发病）及长期生存者。

诊断/检测.

核基因缺 陷性Leigh综合征诊断的建立需要结合患者特征性的临床表现、颅脑核磁检查结果（基底神经节和/或脑干出现双侧对称性T2加权高信号）、 血液和/或脑脊液（Cerebrospinal fluid，CSF）变化（乳酸水平升高），以及遗传学病变（确认存在某具体核基因致病突变或排除mtDNA突变）进行综合考虑。

备注：术语“Leigh样综合征”常用于描述临床和其它特征明显提示为Leigh综合征，但由于神经影像学检查结果非典型或正常、正常的血液及CSF乳酸水平、 非典型性神经病理学特征和/或不完全的疾病评估，而不满足严格的Leigh综合征诊断标准的疾病。

遗传咨询.

核基因缺陷性Leigh综合征和Leigh样综合征以常染色体隐性或X连锁的方式遗传。

疾病管理.

症状治疗：特殊治疗方法可用于这三类核基因缺陷性Leigh样综合征的治疗：生物素-硫胺素反应性基底节病变 （Biotin-thiamine-responsive basal ganglia disease，BTBGD）、生物素酶缺乏症及由PDSS2突变所引起的辅酶Q10缺乏症。同时，针对所有核基因缺陷性Leigh综合征的支持性治疗包括酸中毒治疗、癫痫发作、肌张力障碍和心肌病的治疗，关注营养状态，并为患者的看护人员提供心理支持。

原发疾病表征预防：BTBGD、生物素酶缺乏症和由PDSS2突变所引起的辅酶Q10缺乏症的疾病表征可被预防。参见症状治疗。

继发性并发症预防：由于麻醉可加重患者的呼吸系统症状而引发呼吸衰竭，因而此类患者接受麻醉时应谨慎，且在麻醉开始前、麻醉过程中及麻醉操作结束后都应对病情进行密切监测。

病情监测：定期对患病个体进行随访（通常每半年至一年随访一次），以监测其疾病进展及有无新的表征出现。建议对患者进行神经系统、眼科、听力和心脏评估。

避免用药/情况：患者应避免使用丙戊酸钠、巴比妥类药物及二氯乙酸盐类药物。

核基因缺陷性Leigh综合征的临床表征

Leigh综合征（或亚急性坏死性脑病）以疾病发作间期机体出现失代偿（常伴血液和/或脑脊液中乳酸水平升高）为特征，通常与精神运动迟缓或退化有关，患者发病后常可出现一过性或长期稳定状态，甚至可出现症状好转，但最终常不可避免出现进行性神经系统衰退，且常在逐渐减少药量期间出现。

神经系统表现包括肌张力降低、痉挛、运动障碍（包括舞蹈病）、小脑共济失调和周围神经病。

非神经系统表现可包括肥厚型心肌病、多毛症、贫血、肾小管病变、肝脏受累、 上睑下垂及肌无力。

患者发病年龄常介于12个月至3岁之间，约有50%患者在三岁时死亡，最常见诱因为呼吸衰竭或心力衰竭。

偶尔存在晚期发病（包括成年期发病）及长期生存者。

患者的预期寿命似乎与非神经系统表现有关，至少在一定程度上与其潜在遗传缺陷有关[Wedatilake et al 2013]。

建立核基因缺陷性Leigh综合征诊断

建立核基因缺陷性Leigh综合征的诊断需要满足以下条件[Rahman et al 1996, Lake et al 2015]：

• 特征性临床表征（见定义）
• 脑部核磁检查显示基底神经节和/或脑干出现双侧对称性T2加权高密度信号
• 血液和/或脑脊液（CSF）中乳酸升高
• 检出特定核基因致病突变或排除mtDNA突变
  备注：如果对患者进行验尸检查，可发现该病的特征性神经病理学变化包括：位于基底神经节、丘脑、脑干、齿状核和视神经的多灶性对称性坏死病变。从组织学角度而言，病变呈海绵状外观，伴脱髓鞘、胶质细胞增生和血管增生。患者可出现神经元丢失，但相对较少。

Leigh样综合征.术 语“Leigh样综合征”常用于描述临床和其它特征明显提示为Leigh综合征，但由于神经影像检查结果非典型或正常、正常血液及CSF乳酸水平、 非典型性神经病理学特征（病变部位或特征出现差异或伴随其他异常特征，例如广泛的皮质损伤）和/或不完全的疾病评估，而不满足严格的Leigh综合征诊断标准的疾病。

核基因缺陷性Leigh综合征的患病率

核基因缺陷性Leigh综合征的患病率约为1:40,000 [Rahman et al 1996]。

常染色体隐性遗传性Leigh综合征和Leigh样综合征

常染色体隐性核基因缺陷性Leigh综合征的诱因 (表1)包括：编码OXPHOS酶及其组装因子的基因突变，mtDNA维持、基因表达和蛋白合成缺陷，辅因子的生物合成（硫辛酸和辅酶Q10)缺陷，线粒体膜脂质重塑缺陷， 丙酮酸脱氢酶缺陷，生物素酶缺陷，维生素转运蛋白缺陷以及有机酸血症伴随代谢产物累积继发的OXPHOS功能障碍。

尽管某个特定基因突变可引起“经典” Leigh综合征或Leigh样综合征，但某些基因突变通常可导致经典Leigh综合征(表1)，而其他基因突变常可引起Leigh样综合征或其他临床表现，且极少与经典Leigh综合征有关 (表2)。

X连锁遗传性Leigh综合征和Leigh样综合征

以X连锁方式遗传的核基因缺陷性Leigh综合征和Leigh样综合征总结见表3。

核基因缺陷性Leigh综合征的鉴别诊断

核基因缺陷性Leigh综合征的鉴别诊断包括线粒体DNA相关的Leigh综合征、非线粒体遗传引起的双侧纹状体坏死（例如由ADAR1基因、NUP62基因或RANBP2基因突变所引起）以及获得性非遗传性诱因，例如病毒性脑病。

线粒体DNA相关的Leigh综合征（也称为母系遗传性Leigh综合征，MILS）的特征总结见表4。另见mtDNA相关性Leigh综合征和NARP及线粒体疾病概述。

检测

血液和/或脑脊液乳酸水平升高可以：

• 提示Leigh综合征及其他具有类似临床表现的疾病；
• 当乳酸/丙酮酸比值偏低或正常时，提示为可引起PDH缺陷症的基因突变 [Debray et al 2007]。

酶活性评估. 酶类，例如通常会在体外培养的皮肤成纤维细胞中进行PDH评估（fbs见表1、表2及表3），而呼吸链酶通常在骨骼肌中进行评估（mb见表1、表2及表3）。尽管明确酶缺陷可帮助确定分子遗传学检测的优先级，但该方法仍可造成大量待测基因（例如呼吸链酶复合物I-缺陷性Leigh 综合征至今已被证明可由至少15种常染色体基因（表1）、1种X连锁基因（表3）和6种线粒体基因（表4）的致病突变引起）。

• 串联单基因检测 可在于下列情况下考虑使用，如果(1) 某种特定基因突变是该疾病的主要诱因或者 (2)临床发现、实验室检查结果和/或家族数据（表1、表2及表3)提示某种特定基因突变最有可能是是该疾病的主要诱因。通常会先对可疑基因进行序列分析，只有当发现某个常染色体隐性疾病的致病突变或未发现常染色体隐性或X连锁疾病的致病突变时，才会进行后续的基因靶向缺失/复制分析。
• 多基因组检测包括对所有这些基因中的多个基因或全部基因进行检测（参见鉴别诊断），对其他相关基因也可考虑进行检测。 备注：多基因检测所包括的基因检测范围和其灵敏度因检测实验室和时间而异。
  更多关于多基因检测的信息，请点击这里。
• 更为全面的基因组学检测（如果可用）包括外显子测序、基因组测序以及线粒体测序。如果串联单基因检测（和/或使用多基因组检测）不能为存在核基因缺陷性Leigh综合征的患者明确其诊断，则可考虑使用更为全面的基因组学检测。更多关于全面基因组测序的信息，请点击这里。

可治疗性疾病.可治疗性核基因缺陷性Leigh样综合征（参见症状治疗）的诱因包括：

• 生物素-硫胺素-反应性基底神经节疾病（BTBGD）（也称为硫胺素转运蛋白2缺陷症）（SLC19A3基因突变）
• 生物素酶缺陷症（BTD）
• 辅酶Q10生物合成缺陷 （PDSS2）

怀 疑这些疾病时应根据疾病指征尽快进行生化或遗传学检测，或者如果无法进行这些检测，那么一旦怀疑患者为该疾病则应尽快开始尝试使用相关维生素/辅因子治 疗。理想情况下，治疗应该持续下去，直至生化和/或遗传学检测结果排除这些疾病诊断，而且如果证实为该诊断也应继续治疗以维持生命。

遗传模式

核基因缺陷性Leigh综合征和Leigh样综合征以常染色体隐性或X连锁的方式遗传。

先症者父母

• 患者的父母是必然杂合子（即某种致病突变的携带者）。
• 杂合子（携带者）无症状且无发病风险。 

先症者同胞

• 怀孕时，患者的所有同胞都具有25%的患病风险、50%的无症状携带者风险以及25% 的不受影响亦不是携带者的几率。
• 杂合子（携带者）无症状，也不具有发病风险。

其他家族成员. 先症者父母的所有同胞成为某个致病突变的携带者的风险都为50%。

携带者（杂合子）检测 . 高危风险亲属进行携带者检测时，需要事先明确其家族中的致病突变类型。

家族成员风险— X连锁遗传性Leigh综合征

由PDHA1基因、NDUFA1基因和AIFM1基因突变所引起的核基因缺陷性Leigh综合征的遗传方式为X连锁遗传。

目前已被报道的PDHA1基因相关的Leigh综合征患者中男性和女性的数量几乎相等[Lissens et al 2000, Imbard et al 2011]。尽管已被报道的NDUFA1基因相关的LS和AIFM1基因相关的LS患者的例数相对较少，但预期所有这三种疾病的性别比例类似。

先症者父母

• 患病儿童的父亲不会出现X连锁性Leigh综合征，也不会是PDHA1基因、NDUFA1基因或AIFM1基因致病突变的半合子，因此，患儿父亲无需接受进一步评估/检测。
• 患病儿童的母亲可能是某个致病突变的杂合子；参见杂合子（携带者）检测。PDHA1基因致病突变患儿的母亲中约有25%经检测为PDHA1基因突变的杂合子[Lissens et al 2000, Imbard et al 2011]。
• 如果一名家族成员患病（即一个单发案例），其母亲可能为杂合子或者患病儿童可能存在新的或体细胞PDHA1基因、NDUFA1基因或AIFM1基因致病突变（在这种情况下，母亲就不是杂合子）。
  • Lissens et al [2000]和Imbard et al [2011]所报道的数据表明高达75%的患者可存在某种新型致病突变。
  • 在至少七名患病个体中，体细胞嵌合突变已被证明可出现在胚胎形成早期或中期[Imbard et al 2011]。
• 如果家族中患者数量超过一人时，则患儿的母亲为必然杂合子。备注：如果一名女性生育多名患病儿童，且家族中无其他患病亲属，但在她的白细胞DNA中检测不出致病突变，则说明她的体内存在生殖系嵌合体。
• 备注：如果母亲是首先出现致病突变的个体，她的体内可能存在体细胞突变和生殖系嵌合体，可受到轻度/微小影响。

先症者同胞

• 先症者同胞的患病风险取决于母亲的遗传状态。
• 如果先症者母亲存在PDHA1基因、NDUFA1基因或AIFM1基因的致病突变，则每次母亲通过妊娠将该突变遗传给子女的几率为50%。遗传该致病突变的男性个体将会成为患病个体；而遗传该致病突变的女性个体也很可能会患病，除非她们存在有利的X染色体失活偏倚。
• 如果先症者是某个单发案例（即家族中仅出现一个案例），并且在母亲的白细胞DNA中检测不出PDHA1基因、NDUFA1基因或AIFM1基因的致病突变，那么同胞的患病风险较低。但是由于可能存在母系生殖系嵌合体，其风险仍高于一般人群。

先症者后代. 患者未曾生育过后代。

其他家族成员. 先症者的姨母可能是高危杂合子，而这个姨母的儿子具有遗传致病突变及患病的风险。

杂合子(携带者)检测

如果已在先症者体内检出致病突变，则针对高危女性亲属进行分子遗传学检测以明确其遗传状态的说服力最强。

存在PDHA1基因、NDUFA1基因或AIFM1基因致病突变的杂合子女性很可能患病，除非她们存在有利的X染色体失活偏倚。预计X染色体失活模式，尤其是在脑部的模式，可在很大程度上决定患者的临床状态。

备注：据说由Imbard et al [2011]报道的11名杂合子母亲未出现疾病症状。然而，根据作者的临床经验，杂合子个体常可出现一些学习障碍或其他特征。

遗传咨询相关问题

DNA库可用于储存DNA（ 常提取自白细胞）以供将来使用。因为未来很有可能会出现更好的检测方法，而且我们对于基因、等位基因突变和疾病的认识会也有所提高，所以应考虑储存患病个体的DNA。

产前检测和胚胎着床前遗传学诊断

一旦某个患病家族成员被检测出致病突变，可针对核基因缺陷性Leigh综合征进行高危妊娠产前检测及胚胎着床前遗传诊断。

备注：对于存在X连锁性Leigh综合征的家族，分子遗传学产前检测结果无法用于预测携带家族性致病突变的女性胚胎出现疾病结局的风险。

症状治疗

特殊治疗方法可用于下述三类核基因缺陷性Leigh样综合征的治疗：

• 生物素-硫胺素-反应性基底神经节疾病（BTBGD） (也称为硫胺素转运蛋白2缺陷症）（SLC19A3基因突变）。生物素（5-10 mg/kg/day）及硫胺素（给药剂量范围：300-900 mg）应尽量在疾病早期开始口服给药，并终生持续用药。症状常可在数日内缓解。
• 生物素酶缺乏症 （BTD）.复杂生物素酶缺乏症患儿可每天使用5-10mg口服生物素治疗以改善症状。所有复杂生物素酶缺乏症患者都应终生持续使用生物素治疗。
• 辅酶Q10生物合成缺陷症 （PDSS2）.口服辅酶Q10补充剂（儿童给药剂量：10-30 mg/kg/day in children，成人给药剂量：1200-3000 mg/day ）应尽量在疾病早期开始给药，并终生持续用药 [Rahman et al 2012]。

支持性治疗可针对核基因缺陷性Leigh综合征的诱因进行治疗，包括以下内容：

• 酸中毒. 碳酸氢钠或枸橼酸钠可用于治疗急性酸中毒加重。
• 癫痫发作. 在神经科医师的指导下根据患者癫痫的类型选择适宜的抗癫痫药物进行治疗。由于丙戊酸钠和巴比妥类药物对线粒体呼吸链酶具有抑制作用，治疗时应避免使用这些药物[Melegh & Trombitas 1997, Anderson et al 2002]。
• 肌张力障碍
  • 苯海索、巴氯芬、丁苯喹嗪和加巴喷丁单独给药或联合用药可治疗肌张力障碍；治疗应从低剂量给药开始，并逐渐增加给药剂量至控制症状或患者出现了不能耐受的副作用。
  • 肉毒杆菌毒素注射剂也可用于Leigh综合征及患有严重难治性肌张力障碍的患者。
• 心肌病.患者可能需要采用药物治疗，应在心脏科医师的监督下用药。
• 营养状况. 须对患者每日热量摄入及饮食结构是否合理进行定期评估，包括微营养元素和喂养管理。
• 心理支持对患者及其家属而言十分必要。

原发症状预防

关于以下疾病的治疗方案，参见症状治疗：

• 硫胺素转运蛋白缺陷症（SLC19A3基因突变）
• 生物素缺乏症（BTD）
• 辅酶Q10生物合成缺陷（PDSS2）

继发性并发症预防

麻醉可加重患者的呼吸症状并引发患者出现呼吸衰竭，因而，患者接受麻醉时应谨慎，且在麻醉操作前、操作过程中及操作完成之后对患者进行密切监测[Shear & Tobias 2004, Niezgoda & Morgan 2013]。

疾病监测

定期 (通常为每6-12个月)对患者进行随访以监测其疾病进展及有无出现新的表征。另外，建议对患者进行神经系统、眼科、听力及心脏学评估。

避免用药/环境

丙戊酸钠和巴比妥类药物应避免使用，因为它们对线粒体呼吸链酶具有抑制作用[Melegh & Trombitas 1997, Anderson et al 2002]。

二氯乙酸盐（Dichloroacetate ，DCA）可通过激活PDH复合物降而低血液乳酸水平。

• 一项DCA应用于另一种线粒体疾病MELAS的双盲安慰剂对照试验未发现该药物对治疗该疾病有任何益处，却发现DCA对周围神经具有毒副作用[Kaufmann et al 2006]。
•  一项后续报道描述了36名先天性乳酸酸中毒患儿长期接受DCA给药的结局(开放性随机对照试验）[Stacpoole et al 2008]。 该研究总结称年幼先天性乳酸酸中毒患儿对口服DCA耐受良好，无法判定长期DCA给药相关的周围神经病是否应归因于药物作用或归因于潜在的疾病过程。鉴于 在这些情况下存在疾病本身可诱发周围神经病的潜在风险，因此，核编码基因缺陷性LS患者应避免使用DCA。

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Author Notes

Professor Rahman’s Web page

Professor Thorburn’s Web page

Professor Rahman’s research interests include identification of novel nuclear genes causing mitochondrial disease, using a combination of approaches including homozygosity mapping and 外显子组 and genome next-generation sequencing. Her group has identified a number of nuclear genes causing childhood-onset mitochondrial disorders, including genes involved in mitochondrial DNA maintenance and expression, complex I and complex IV function and biosynthesis of coenzyme Q10. Other research interests aim to identify biomarkers and novel therapies for childhood mitochondrial disorders.

David Thorburn's research focuses on improving diagnosis, prevention and treatment of mitochondrial energy generation disorders. This has included translating knowledge of mitochondrial DNA genetics into reproductive options for families, defining diagnostic criteria and epidemiology and discovery of new “disease” genes through Next Generation DNA sequencing. His group also uses cellular and mouse models to understand pathogenic mechanisms and trial new treatment approaches.

Revision History

• 1 October 2015 (me) Review posted live
• 17 February 2015 (sr) Original submission