Genetic defects in mitochondrial DNA encoded tRNA genes impair mitochondrial translation with resultant defects in the mitochondrial respiratory chain and oxidative phosphorylation system. The phenotypic spectrum of disease seen in mitochondrial tRNA defects is variable and proving pathogenicity of new variants is challenging. Only three pathogenic variants have been described previously in the mitochondrial tRNA^Tyr gene MT-TY, with the reported phenotypes consisting largely of adult onset myopathy and ptosis. We report a patient with a novel MT-TY acceptor stem variant m.5889A>G at high heteroplasmy in muscle, low in blood, and absent in the mother's blood. The phenotype consisted of a childhood-onset severe multi-system disorder characterized by a neurodegenerative course including ataxia and seizures, failure-to-thrive, combined myopathy and neuropathy, and hearing and vision loss. Brain imaging showed progressive atrophy and basal ganglia calcifications. Mitochondrial biomarkers lactate and GDF15 were increased. Functional studies showed a deficient activity of the respiratory chain enzyme complexes containing mtDNA-encoded subunits I, III and IV. There were decreased steady state levels of these mitochondrial complex proteins, and presence of incompletely assembled complex V forms in muscle. These changes are typical of a mitochondrial translational defect. These data support the pathogenicity of this novel variant. Careful review of variants in MT-TY additionally identified two other pathogenic variants, one likely pathogenic variant, nine variants of unknown significance, five likely benign and four benign variants.

线粒体 DNA 编码的 tRNA 基因中的遗传缺陷会损害线粒体翻译，从而导致线粒体呼吸链和氧化磷酸化系统的缺陷。在线粒体 tRNA 缺陷中观察到的疾病表型谱是可变的，证明新变异的致病性具有挑战性。先前在线粒体 tRNA ^Tyr基因MT-TY 中仅描述了三种致病变异，报告的表型主要包括成人发病的肌病和上睑下垂。我们报告了一名患有新型MT-TY的患者受体干变体 m.5889A>G 在肌肉中异质性高​​，血液中低，并且在母亲的血液中不存在。该表型包括儿童期发病的严重多系统疾病，其特征是神经退行性疾病，包括共济失调和癫痫发作、发育迟缓、肌病和神经病合并，以及听力和视力丧失。脑成像显示进行性萎缩和基底神经节钙化。线粒体生物标志物乳酸和 GDF15 增加。功能研究表明，含有 mtDNA 编码的亚基 I、III 和 IV 的呼吸链酶复合物活性不足。这些线粒体复合体蛋白的稳态水平降低，肌肉中存在未完全组装的复合体 V 型。这些变化是典型的线粒体翻译缺陷。这些数据支持这种新型变异的致病性。仔细审查中的变体MT-TY还鉴定了另外两种致病变异，一种可能的致病变异，九种意义不明的变异，五种可能的良性变异和四种良性变异。