Shivani Sharma, Anita Mahadevan, Gayathri Narayanappa, Monojit Debnath, Periyasamy Govindaraj, Sumanth Shivaram, Doniparthi V Seshagiri, Ramesh Siram, Akhilesh Shroti, Parayil S Bindu, Yasha T Chickabasaviah, Arun B Taly, Madhu Nagappa
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Patients (<i>n</i> = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (<i>n</i> = 14), auditory (<i>n</i> = 12) and visual + auditory pathways (<i>n</i> = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (<i>n</i> = 45) identified a homoplasmic variant (<i>MT-ND6)</i> and a heteroplasmic variant (<i>MT-COI</i>) in one patient each. CES (<i>n</i> = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (<i>n</i> = 27), deafness (<i>n</i> = 7), ataxia (<i>n</i> = 4), and mitochondrial phenotypes (<i>n</i> = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. 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引用次数: 0
摘要
热带共济失调性神经病(TAN)的特征是共济失调性多神经病、后柱和锥体束变性、视神经萎缩和感音神经性听力损失。该病被归因于营养/毒性病因,但相关证据并不明确。TAN 与遗传性神经病和线粒体疾病具有共同的临床特征,因此可以假设遗传异常可能是 TAN 病理生理学的基础。本研究旨在通过综合生化和多管齐下的遗传分析,确定线粒体功能障碍的证据。患有慢性进行性共济失调性神经病并累及视觉和/或听觉通路的患者(n = 65)接受了深度表型分析和遗传学研究,包括线粒体 DNA(mtDNA)缺失分析、mtDNA 和临床外显子组测序(CES)以及呼吸链复合物(RCC)检测。表型特征包括视觉(14 例)、听觉(12 例)和视觉+听觉通路(29 例)功能障碍。13 名患者的 RCC 活性降低。5 名患者的线粒体 DNA 存在缺失。mtDNA 测序(n = 45)在一名患者中分别发现了同质变异体(MT-ND6)和异质变异体(MT-COI)。CES(n = 45)揭示了核基因中的 55 个变体,这些变体与 36 名患者的神经病变(n = 27)、耳聋(n = 7)、共济失调(n = 4)和线粒体表型(n = 5)有关。这项研究提供了初步证据,证明 TAN 与一系列基因异常有关,包括与线粒体功能障碍有关的基因异常。对这些遗传变异的功能相关性进行分析,可提高对 TAN 发病机制的认识。
Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy.
Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.
期刊介绍:
The Journal is appropriate for papers on behavioral, biochemical, or cellular aspects of neural function, plasticity, aging or disease. In addition to analyses in the traditional genetic-model organisms, C. elegans, Drosophila, mouse and the zebrafish, the Journal encourages submission of neurogenetic investigations performed in organisms not easily amenable to experimental genetics. Such investigations might, for instance, describe behavioral differences deriving from genetic variation within a species, or report human disease studies that provide exceptional insights into biological mechanisms