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.

线粒体 DNA (mtDNA) 的致病变异与显着的临床异质性相关，通常报道神经肌肉受累。线粒体DNA疾病的非综合征表现继续构成诊断挑战，并且在许多情况下基因组测试仍然需要肌肉活检。在这里，我们描述了一名患有进行性共济失调、神经病变和运动不耐受的成年患者，应用大量孟德尔基因组未能对其进行基因诊断。肌肉活检揭示了特征性线粒体病理学（细胞色素 C 氧化酶缺陷、参差不齐的红色纤维），促使对线粒体基因组进行彻底研究。鉴定出两种异质性MT-CO2基因变异（NC_012920.1：m.7887G>A 和 m.8250G>A），需要进行单纤维分离和家族研究（包括对患者临床上未受影响的母亲进行活检）以证明其致病性新的 m.7887G>A p.(Gly101Asp) 变体并将其确定为线粒体生化缺陷和临床表现的原因。在高通量全外显子组和基因组测序时代，肌肉活检仍然是诊断非综合征性成人发病线粒体疾病患者和全面确定新 mtDNA 变异致病性的关键研究。