Paediatric Neurology Research Group, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Pediatrics, Granollers General Hospital, Granollers, Spain.
Dev Med Child Neurol. 2022 Jun;64(6):743-752. doi: 10.1111/dmcn.15125. Epub 2022 Jan 5.
To correlate clinical, radiological, and biochemical features with genetic findings in children with bilateral basal ganglia lesions of unknown aetiology, and propose a diagnostic algorithm for early recognition.
Children with basal ganglia disease were recruited in a 2-year prospective multicentre study for clinical, biomarker, and genetic studies. Radiological pattern recognition was examined by hierarchical clustering analysis.
We identified 22 genetic conditions in 30 out of 62 paediatric patients (37 males, 25 females; mean age at onset 2y, SD 3; range 0-10y; mean age at assessment 11y, range 1-25y) through gene panels (n=11), whole-exome sequencing (n=13), and mitochondrial DNA (mtDNA) sequencing (n=6). Genetic aetiologies included mitochondrial diseases (57%), Aicardi-Goutières syndrome (20%), and monogenic causes of dystonia and/or epilepsy (17%) mimicking Leigh syndrome. Radiological abnormalities included T2-hyperintense lesions (n=26) and lesions caused by calcium or manganese mineralization (n=9). Three clusters were identified: the pallidal, neostriatal, and striatal, plus the last including mtDNA defects in the oxidative phosphorylation system with prominent brain atrophy. Mitochondrial biomarkers showed poor sensitivity and specificity in children with mitochondrial disease, whereas interferon signature was observed in all patients with patients with Aicardi-Goutières syndrome.
Combined whole-exome and mtDNA sequencing allowed the identification of several genetic conditions affecting basal ganglia metabolism. We propose a diagnostic algorithm which prioritizes early use of next-generation sequencing on the basis of three clusters of basal ganglia lesions.
将临床表现、影像学和生化特征与病因不明的双侧基底节病变患儿的基因发现相关联，并提出早期识别的诊断算法。
在一项为期 2 年的前瞻性多中心研究中，招募了基底节疾病患儿，进行临床、生物标志物和遗传研究。通过层次聚类分析检查放射影像学模式识别。
通过基因面板（n=11）、全外显子组测序（n=13）和线粒体 DNA（mtDNA）测序（n=6），我们在 62 名儿科患者中的 30 名（37 名男性，25 名女性；发病年龄平均 2 岁，标准差 3；范围 0-10 岁；评估时平均年龄 11 岁，范围 1-25 岁）中确定了 22 种遗传疾病。遗传病因包括线粒体疾病（57%）、Aicardi-Goutières 综合征（20%）和模仿 Leigh 综合征的单基因病因引起的肌张力障碍和/或癫痫（17%）。放射学异常包括 T2 高信号病变（n=26）和钙或锰矿化引起的病变（n=9）。确定了三个聚类：苍白球、新纹状体和纹状体，最后一个包括氧化磷酸化系统中线粒体 DNA 缺陷，伴有明显的脑萎缩。在患有线粒体疾病的儿童中，线粒体生物标志物的敏感性和特异性较差，而干扰素特征在所有患有 Aicardi-Goutières 综合征的患者中均观察到。
全外显子组和 mtDNA 测序的联合使用可鉴定出几种影响基底节代谢的遗传疾病。我们提出了一种诊断算法，根据基底节病变的三个聚类，优先早期使用下一代测序。
