Department of Biotechnology, Centre for Emerging Diseases, Jaypee Institute of Information Technology, Noida 201301, India; Centre for Cellular and Molecular Biology, Hyderabad 500007, India.
Government Institute of Child Health, Niloufer Hospital for Women and Children, Red Hills, Hyderabad, India.
J Neurol Sci. 2019 Sep 15;404:91-100. doi: 10.1016/j.jns.2019.07.007. Epub 2019 Jul 10.
In our previously published study, we cared for 165 thiamine deficient Leigh syndrome (LS) patients who presented in acute life threatening conditions with severe neurological abnormalities. However the molecular basis for this atypical phenotype was not explored. This study is an effort to undermine the possible molecular defects in mitochondria of those patients and put-forth an explanation towards this clinical presentation. Protein coding genes of mitochondrial (mt) DNA were sequenced in total 165 LS patients and 94 age matched controls. To understand their pathogenic significance, nucleotide variations were also studied using various in-silico tools. Histochemical and electron microscopic analysis was also done in tissue samples obtained from 23 patients. We observed a very high level of genetic heterogeneity across the mt DNA of all these patients. In the concordance of published literature we also observed a large number of variations in ND5 gene (hot spot for LS). We also observed a total 13 nucleotide variations across COX genes, which is otherwise not common in LS. As per in-silico analysis, many of these variations were suggested to be pathogenic. Histochemical and electron microscopic studies also suggested the defects in the mitochondria of these patients. As these patients were thiamine deficient, hence we propose that genetic defects and thiamine deficiency may together severely affect the ATP levelof these patients, leading to acute and life threatening clinical presentation. Present study has opened up many avenues for further research towards understanding the genetic basis and possible role of thiamine deficiency in LS patients.
在我们之前发表的研究中，我们照顾了 165 名患有硫胺素缺乏性 Leigh 综合征 (LS) 的患者，这些患者在急性危及生命的情况下出现严重的神经异常。然而，这种非典型表型的分子基础尚未得到探索。本研究旨在探讨这些患者线粒体中可能存在的分子缺陷，并对这种临床表现提出解释。对 165 名 LS 患者和 94 名年龄匹配的对照者的线粒体 (mt) DNA 编码蛋白基因进行了测序。为了了解它们的致病意义，还使用各种计算机工具研究了核苷酸变异。对从 23 名患者获得的组织样本进行了组织化学和电子显微镜分析。我们观察到所有这些患者的 mtDNA 存在非常高水平的遗传异质性。在与已发表文献的一致性中，我们还观察到 ND5 基因（LS 的热点）中有大量变异。我们还观察到 COX 基因中有 13 个核苷酸的变异，这在 LS 中并不常见。根据计算机分析，许多这些变异被认为是致病的。组织化学和电子显微镜研究也表明这些患者的线粒体存在缺陷。由于这些患者缺乏硫胺素，因此我们认为遗传缺陷和硫胺素缺乏可能共同严重影响这些患者的 ATP 水平，导致急性和危及生命的临床表现。本研究为进一步研究 LS 患者的遗传基础和可能的硫胺素缺乏作用开辟了许多途径。
