VU University Medical Centre, De Boelelaan 1117, Amsterdam, The Netherlands.
Brain. 2012 May;135(Pt 5):1387-94. doi: 10.1093/brain/aws070. Epub 2012 Apr 4.
In the large group of genetically undetermined infantile-onset mitochondrial encephalopathies, multiple defects of mitochondrial DNA-related respiratory-chain complexes constitute a frequent biochemical signature. In order to identify responsible genes, we used exome-next-generation sequencing in a selected cohort of patients with this biochemical signature. In an isolated patient, we found two mutant alleles for EARS2, the gene encoding mitochondrial glutamyl-tRNA synthetase. The brain magnetic resonance imaging of this patient was hallmarked by extensive symmetrical cerebral white matter abnormalities sparing the periventricular rim and symmetrical signal abnormalities of the thalami, midbrain, pons, medulla oblongata and cerebellar white matter. Proton magnetic resonance spectroscopy showed increased lactate. We matched this magnetic resonance imaging pattern with that of a cohort of 11 previously selected unrelated cases. We found mutations in the EARS2 gene in all. Subsequent detailed clinical and magnetic resonance imaging based phenotyping revealed two distinct groups: mild and severe. All 12 patients shared an infantile onset and rapidly progressive disease with severe magnetic resonance imaging abnormalities and increased lactate in body fluids and proton magnetic resonance spectroscopy. Patients in the 'mild' group partially recovered and regained milestones in the following years with striking magnetic resonance imaging improvement and declining lactate levels, whereas those of the 'severe' group were characterized by clinical stagnation, brain atrophy on magnetic resonance imaging and persistent lactate increases. This new neurological disease, early-onset leukoencephalopathy with thalamus and brainstem involvement and high lactate, is hallmarked by unique magnetic resonance imaging features, defined by a peculiar biphasic clinical course and caused by mutations in a single gene, EARS2, expanding the list of medically relevant defects of mitochondrial DNA translation.
在一大组遗传未确定的婴儿期起病的线粒体脑肌病中，线粒体 DNA 相关呼吸链复合物的多种缺陷构成了常见的生化特征。为了确定相关基因，我们在具有这种生化特征的选定患者队列中使用了外显子组下一代测序。在一个孤立的患者中，我们发现编码线粒体谷氨酰-tRNA 合成酶的 EARS2 基因有两个突变等位基因。该患者的脑磁共振成像以广泛的对称性大脑白质异常为特征，脑室周围边缘保留，丘脑、中脑、脑桥、延髓和小脑白质信号异常对称。质子磁共振波谱显示乳酸增加。我们将这种磁共振成像模式与之前选择的 11 例无关病例的队列进行了匹配。我们发现 EARS2 基因在所有病例中均存在突变。随后基于详细临床和磁共振成像的表型分析发现存在两个不同的组：轻度和重度。所有 12 名患者均具有婴儿期起病和进行性加重的疾病，伴有严重的磁共振成像异常和体液中乳酸增加以及质子磁共振波谱异常。“轻度”组的所有患者在接下来的几年中部分恢复并重新获得里程碑，磁共振成像明显改善，乳酸水平下降，而“重度”组的患者以临床停滞、磁共振成像上的脑萎缩和持续的乳酸增加为特征。这种新的神经疾病，早发性脑白质病伴丘脑和脑干受累和高乳酸血症，以独特的磁共振成像特征为特征，由独特的双相临床病程定义，并由单个基因 EARS2 的突变引起，扩大了线粒体 DNA 翻译的医学相关缺陷的列表。
