Nafisinia Michael, Guo Yiran, Dang Xiao, Li Jiankang, Chen Yulan, Zhang Jianguo, Lake Nicole J, Gold Wendy A, Riley Lisa G, Thorburn David R, Keating Brendan, Xu Xun, Hakonarson Hakon, Christodoulou John
Genetic Metabolic Disorders Research Unit, Western Sydney Genetics Program, The Children's Hospital at Westmead, Locked Bag 4001, Sydney, NSW, 2145, Australia.
Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
JIMD Rep. 2017;32:117-124. doi: 10.1007/8904_2016_541. Epub 2016 Jun 26.
Leigh syndrome is a subacute necrotising encephalomyopathy proven by post-mortem analysis of brain tissue showing spongiform lesions with vacuolation of the neuropil followed by demyelination, gliosis and capillary proliferation caused by mutations in one of over 75 different genes, including nuclear- and mitochondrial-encoded genes, most of which are associated with mitochondrial respiratory chain function. In this study, we report a patient with suspected Leigh syndrome presenting with seizures, ptosis, scoliosis, dystonia, symmetrical putaminal abnormalities and a lactate peak on brain MRS, but showing normal MRC enzymology in muscle and liver, thereby complicating the diagnosis. Whole exome sequencing uncovered compound heterozygous mutations in NADH dehydrogenase (ubiquinone) flavoprotein 1 gene (NDUFV1), c.1162+4A>C (NM_007103.3), resulting in skipping of exon 8, and c.640G>A, causing the amino acid substitution p.Glu214Lys, both of which have previously been reported in a patient with complex I deficiency. Patient fibroblasts showed a significant reduction in NDUFV1 protein expression, decreased complex CI and complex IV assembly and consequential reductions in the enzymatic activities of both complexes by 38% and 67%, respectively. The pathogenic effect of these variations was further confirmed by immunoblot analysis of subunits for MRC enzyme complexes in patient muscle, liver and fibroblast where we observed 90%, 60% and 95% reduction in complex CI, respectively. Together these studies highlight the importance of a comprehensive, multipronged approach to the laboratory evaluation of patients with suspected Leigh syndrome.
Leigh综合征是一种亚急性坏死性脑脊髓病，通过对脑组织进行尸检分析得以证实。脑组织显示出海绵状病变，神经纤维网有空泡形成，随后出现脱髓鞘、胶质细胞增生和毛细血管增殖，这是由75种以上不同基因中的一种发生突变引起的，这些基因包括核编码基因和线粒体编码基因，其中大多数与线粒体呼吸链功能相关。在本研究中，我们报告了一名疑似Leigh综合征的患者，该患者表现为癫痫发作、上睑下垂、脊柱侧弯、肌张力障碍、双侧壳核异常以及脑部磁共振波谱（MRS）显示乳酸峰，但肌肉和肝脏中的线粒体呼吸链（MRC）酶学检查结果正常，从而使诊断变得复杂。全外显子组测序发现烟酰胺腺嘌呤二核苷酸脱氢酶（泛醌）黄素蛋白1基因（NDUFV1）存在复合杂合突变，即c.1162 + 4A>C（NM_007103.3），导致外显子8跳跃，以及c.640G>A，导致氨基酸替换p.Glu214Lys，这两种突变此前在一名患有复合体I缺乏症的患者中已有报道。患者成纤维细胞显示NDUFV1蛋白表达显著降低，复合体CI和复合体IV组装减少，两种复合体的酶活性分别相应降低38%和67%。通过对患者肌肉、肝脏和成纤维细胞中线粒体呼吸链酶复合物亚基的免疫印迹分析进一步证实了这些变异的致病作用，我们观察到复合体CI分别减少了90%、60%和95%。这些研究共同强调了采用全面、多管齐下的方法对疑似Leigh综合征患者进行实验室评估的重要性。
