背景:ADP-核糖丝氨酸水解酶的基因变异,也称为ADP-核糖水解酶样2(ADPRS或ADPRLH2;OMIM:610624),可导致应激诱导的儿童期发作的神经变性,伴有不同的共济失调和癫痫发作(CONDSIAS,OMIM:618170),一种超罕见的神经退行性常染色体隐性疾病。ADPRS编码ADP-核糖水解酶3,可去除聚(ADP-核糖)聚合物,其翻译后添加发生在压力条件下。病例介绍:呼吸道感染后,一名30个月大的男性患者,步态不稳定,没有外部帮助就无法行走。神经系统检查显示急性小脑共济失调,脑电图结果异常,脑磁共振成像显示小脑沟轻度增宽。实验室检查显示促甲状腺激素水平下降,血浆乳酸和血清心肌酶水平升高。脑脊液葡萄糖试验阳性。发病四个月后,病人死于突然抽搐。使用全外显子组测序,我们鉴定了两个新的复合杂合ADPRS变体:NM_017825.3:c.580C>T(p。Gln194Ter)和NM_017825.3:c.803-1G>A.RNA测序表明前一种突变可能导致无义介导的mRNA衰减。发现c.803-1G>A变体是导致内含子5转录保留的剪接位点突变。根据美国医学遗传学和基因组学学院的指导方针,这两种变异被归类为致病性。结论:我们首次报道了ADPRS的两个复合杂合变体的存在,这导致了CONDSIAS。
Background: Gene variants of ADP-ribosylserine hydrosylase, also known as ADP-ribosylhydrolase-like 2 (ADPRS or ADPRLH2; OMIM: 610624), can cause stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS, OMIM: 618170), an ultra-rare neurodegenerative autosomal recessive disorder. ADPRS encodes ADP-ribosylhydrolase 3, which removes poly(ADP-ribose) polymers, whose posttranslational addition occurs under stressful conditions.
Case Presentation: After a respiratory tract infection, a 30-month-old male patient presented with unsteady gait that rendered walking impossible without external help. Neurological examination revealed acute cerebellar ataxia, electroencephalogram results were abnormal, and brain magnetic resonance imaging revealed slightly widened cerebellar sulci. Laboratory tests showed decreased levels of thyroid-stimulating hormone, and increased levels of plasma lactic acid and serum cardiac enzymes. The cerebrospinal fluid glucose test was positive. Four months after onset, the patient died of sudden convulsions. Using whole exome sequencing, we identified two novel compound heterozygous ADPRS variants: NM_017825.3:c.580C>T (p.Gln194Ter) and NM_017825.3:c.803-1G>A. RNA sequencing indicated that the former mutation might cause nonsense-mediated mRNA decay. The c.803-1G>A variant was found to be a splice-site mutation that leads to the transcriptional retention of intron 5. According to the guidelines of the American College of Medical Genetics and Genomics, the two variants were classified as pathogenic. Conclusion: We present the first report of the existence of two compound heterozygous variants of ADPRS, which leads to CONDSIAS.