A novel MT-CO2 variant causing cerebellar ataxia and neuropathy: The role of muscle biopsy in diagnosis and defining pathogenicity.
A novel MT-CO2 variant causing cerebellar ataxia and neuropathy: The role of muscle biopsy in diagnosis and defining pathogenicity.
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DOI：
10.1016/j.nmd.2021.05.014
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Ng YS
中科院分区：
文献类型：
--
作者：
Baty K;Farrugia ME;Hopton S;Falkous G;Schaefer AM;Stewart W;Willison HJ;Reilly MM;Blakely EL;Taylor RW;Ng YS
线粒体DNA相关成人疾病的非综合征表现在诊断上具有挑战性。获取患者及其临床未受影响的母亲的诊断肌肉活检对于确定通过线粒体DNA测序确定的两种异质性MT-CO2变异中的哪一种是重要的。在下一代测序时代，肌肉活检仍然是一项重要的诊断研究。线粒体DNA(MtDNA)的致病变异与临床上常见的神经肌肉受累的异质性有关。线粒体DNA病的非综合征性表现继续对诊断构成挑战，在许多情况下，基因组检测仍然需要肌肉活检。在这里，我们描述了一名成年患者，他表现为进行性共济失调、神经病变和运动不耐受，许多孟德尔基因板的应用未能做出基因诊断。肌肉活检发现了特征性的线粒体病理(细胞色素c氧化酶缺乏，粗糙的红色纤维)，促使对线粒体基因组进行彻底的研究。两个异质性MT-CO2基因变异(NC_012920.1：m.7887G>；A和m.8250G>；A)被鉴定出来，需要进行单纤维分离和家族性研究--包括患者临床未受影响的母亲的活检--以证明新的m.7887G>；A p.(Gly101Asp)变异的致病性，并确定这是线粒体生化缺陷和临床表现的原因。在高通量整个外显子组和基因组测序的时代，肌肉活检仍然是诊断无综合征表现的成人起病线粒体疾病患者的关键研究，并充分确定新的mtDNA变异的致病性。
Non-syndromic presentations of mtDNA-related adult disease are diagnostically challenging. Access to diagnostic muscle biopsies from the patient and his clinically-unaffected mother were essential in defining which of two heteroplasmic MT-CO2 variants identified through mitochondrial DNA sequencing were causal. Muscle biopsy remains a vital diagnostic investigation in the era of next generation sequencing. Pathogenic variants in mitochondrial DNA (mtDNA) are associated with significant clinical heterogeneity with neuromuscular involvement commonly reported. Non-syndromic presentations of mtDNA disease continue to pose a diagnostic challenge and with genomic testing still necessitating a muscle biopsy in many cases. Here we describe an adult patient who presented with progressive ataxia, neuropathy and exercise intolerance in whom the application of numerous Mendelian gene panels had failed to make a genetic diagnosis. Muscle biopsy revealed characteristic mitochondrial pathology (cytochrome c oxidase deficient, ragged-red fibers) prompting a thorough investigation of the mitochondrial genome. Two heteroplasmic MT-CO2 gene variants (NC_012920.1: m.7887G>A and m.8250G>A) were identified, necessitating single fiber segregation and familial studies – including the biopsy of the patient's clinically-unaffected mother - to demonstrate pathogenicity of the novel m.7887G>A p.(Gly101Asp) variant and establishing this as the cause of the mitochondrial biochemical defects and clinical presentation. In the era of high throughput whole exome and genome sequencing, muscle biopsy remains a key investigation in the diagnosis of patients with non-syndromic presentations of adult-onset mitochondrial disease and fully defining the pathogenicity of novel mtDNA variants.
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与成年线粒体疾病有关的核和线粒体DNA突变的患病率。
影响因子：
11.2
作者：
Gorman GS;Schaefer AM;Ng Y;Gomez N;Blakely EL;Alston CL;Feeney C;Horvath R;Yu-Wai-Man P;Chinnery PF;Taylor RW;Turnbull DM;McFarland R
通讯作者：
McFarland R
影响因子：
4.2
作者：
Thompson, Kyle;Collier, Jack J.;Taylor, Robert W.
通讯作者：
Taylor, Robert W.
影响因子：
4
作者：
Rodriguez-Lopez, Claudia;Garcia-Cardaba, Luis M.;Dominguez-Gonzalez, Cristina
通讯作者：
Dominguez-Gonzalez, Cristina
影响因子：
--
作者：
Bargiela D;Shanmugarajah P;Lo C;Blakely EL;Taylor RW;Horvath R;Wharton S;Chinnery PF;Hadjivassiliou M
通讯作者：
Hadjivassiliou M
DOI：
10.1016/j.nmd.2017.11.006
发表时间：
2018-04
期刊：
Neuromuscular disorders : NMD
影响因子：
--
作者：
Bacalhau M;Simões M;Rocha MC;Hardy SA;Vincent AE;Durães J;Macário MC;Santos MJ;Rebelo O;Lopes C;Pratas J;Mendes C;Zuzarte M;Rego AC;Girão H;Wong LC;Taylor RW;Grazina M
通讯作者：
Grazina M