PDF(Pubmed)
Abstract：
Biallelic variants in the mitochondrial form of the tryptophanyl-tRNA synthetases (WARS2) can cause a neurodevelopmental disorder with movement disorders including early-onset tremor-parkinsonism syndrome. Here, we describe four new patients, who all presented at a young age with a tremor-parkinsonism syndrome and responded well to levodopa. All patients carry the same recurrent, hypomorphic missense variant (NM_015836.4: c.37T>G; p.Trp13Gly) either together with a previously described truncating variant (NM_015836.4: c.797Cdel; p.Pro266ArgfsTer10), a novel truncating variant (NM_015836.4: c.346C>T; p.Gln116Ter), a novel canonical splice site variant (NM_015836.4: c.349-1G>A), or a novel missense variant (NM_015836.4: c.475A>C, p.Thr159Pro). We investigated the mitochondrial function in patients and found increased levels of mitochondrially encoded cytochrome C Oxidase II as part of the mitochondrial respiratory chain as well as decreased mitochondrial integrity and branching. Finally, we conducted a literature review and here summarize the broad phenotypical spectrum of reported WARS2-related disorders. In conclusion, WARS2-related disorders are diagnostically challenging diseases due to the broad phenotypic spectrum and the disease relevance of a relatively common missense change that is often filtered out in a diagnostic setting since it occurs in ~0.5% of the general European population.
摘要：
色氨酸-tRNA合成酶（WARS2）线粒体形式的双等位基因变体可引起神经发育障碍，包括运动障碍，包括早发性震颤-帕金森病综合征。这里,我们描述了四个新病人，他们都在年轻时出现震颤-帕金森病综合征，对左旋多巴反应良好。所有患者都携带相同的复发性疾病，双态错义变体（NM_015836.4：c.37T>G;p.Trp13Gly）与先前描述的截断变体（NM_015836.4：c.797Cdel;p.Pro266ArgfsTer10）一起，一个新的截短变体(NM_015836.4:c.346C>T;p.Gln116Ter)，一种新的典型剪接位点变体（NM_015836.4：c.349-1G>A），或一个新颖的错义变体(NM_015836.4:c.475A>C，p.Thr159Pro)。我们调查了患者的线粒体功能，发现线粒体编码的细胞色素C氧化酶II作为线粒体呼吸链的一部分的水平升高，线粒体完整性和分支降低。最后,我们进行了文献综述,并在此总结了已报道的WARS2相关疾病的广泛表型谱.总之,由于广泛的表型谱和相对常见的错义变化的疾病相关性，WARS2相关疾病在诊断上具有挑战性，通常在诊断环境中被过滤掉，因为它发生在约0.5％的普通欧洲人群中。
