Skorvanek Matej, Rektorova Irena, Mandemakers Wim, Wagner Matias, Steinfeld Robert, Orec Laura, Han Vladimir, Pavelekova Petra, Lackova Alexandra, Kulcsarova Kristina, Ostrozovicova Miriam, Gdovinova Zuzana, Plecko Barbara, Brunet Theresa, Berutti Riccardo, Kuipers Demy J S, Boumeester Valerie, Havrankova Petra, Tijssen M A J, Kaiyrzhanov Rauan, Rizig Mie, Houlden Henry, Winkelmann Juliane, Bonifati Vincenzo, Zech Michael, Jech Robert
Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic.
First Department of Neurology, Faculty of Medicine, St. Anne's University Hospital, and CEITEC, Masaryk University, Brno, Czech Republic.
Parkinsonism Relat Disord. 2022 Jan;94:54-61. doi: 10.1016/j.parkreldis.2021.11.030. Epub 2021 Dec 2.
Sixteen subjects with biallelic WARS2 variants encoding the tryptophanyl mitochondrial aminoacyl-tRNA synthetase, presenting with a neonatal- or infantile-onset mitochondrial disease, have been reported to date. Here we present six novel cases with WARS2-related diseases and expand the spectrum to later onset phenotypes including dopa-responsive early-onset parkinsonism and progressive myoclonus-ataxia.
Six individuals from four families underwent whole-exome sequencing within research and diagnostic settings. Following the identification of a genetic defect, in-depth phenotyping and protein expression studies were performed.
A relatively common (gnomAD MAF = 0.0033) pathogenic p.(Trp13Gly) missense variant in WARS2 was detected in trans in all six affected individuals in combination with different pathogenic alleles (exon 2 deletion in family 1; p.(Leu100del) in family 2; p.(Gly50Asp) in family 3; and p.(Glu208*) in family 4). Two subjects presented with action tremor around age 10-12 years and developed tremor-dominant parkinsonism with prominent neuropsychiatric features later in their 20s. Two subjects presented with a progressive myoclonus-ataxia dominant phenotype. One subject presented with spasticity, choreo-dystonia, myoclonus, and speech problems. One subject presented with speech problems, ataxia, and tremor. Western blotting analyses in patient-derived fibroblasts showed a markedly decreased expression of the full-length WARS2 protein in both subjects carrying p.(Trp13Gly) and an exon-2 deletion in compound heterozygosity.
This study expands the spectrum of the disease to later onset phenotypes of early-onset tremor-dominant parkinsonism and progressive myoclonus-ataxia phenotypes.
迄今为止，已报道了16名携带编码色氨酰线粒体氨酰 - tRNA合成酶的双等位基因WARS2变异体的受试者，他们患有新生儿或婴儿期起病的线粒体疾病。在此，我们报告6例与WARS2相关疾病的新病例，并将疾病谱扩展至较晚起病的表型，包括多巴反应性早发性帕金森病和进行性肌阵挛性共济失调。
来自四个家庭的6名个体在研究和诊断环境中接受了全外显子组测序。在确定遗传缺陷后，进行了深入的表型分析和蛋白质表达研究。
在所有6名受影响个体中均检测到WARS2基因中一个相对常见的（gnomAD MAF = 0.0033）致病性p.(Trp13Gly)错义变异体，其与不同的致病等位基因呈反式组合（家族1中的外显子2缺失；家族2中的p.(Leu100del)；家族3中的p.(Gly50Asp)；家族4中的p.(Glu208*)）。两名受试者在10 - 12岁左右出现动作性震颤，并在20多岁后期发展为以震颤为主的帕金森病，伴有明显的神经精神特征。两名受试者表现为以进行性肌阵挛性共济失调为主的表型。一名受试者表现为痉挛、舞蹈样肌张力障碍、肌阵挛和言语问题。一名受试者表现为言语问题、共济失调和震颤。对患者来源的成纤维细胞进行的蛋白质免疫印迹分析显示，在携带p.(Trp13Gly)和外显子2缺失的复合杂合子的两名受试者中，全长WARS2蛋白的表达均明显降低。
本研究将该疾病谱扩展至早发性震颤为主的帕金森病和进行性肌阵挛性共济失调表型的较晚起病形式。
