Abstract:
Thrombotic microangiopathy (TMA) in association with RNA exosome encoding mutations has only recently been recognized. Here, we present an infant (female) with an EXOSC5 mutation (c.230_232del p.Glu77del) associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA. At the age of four months, she presented with signs of septic illness, after which she developed TMA. A stool culture showed rotavirus as a potential trigger. The patient received eculizumab once, alongside supportive treatment, while awaiting diagnostic analysis of TMA, including genetic complement analysis, all of which were negative. Eculizumab was withdrawn and the patient\'s TMA recovered quickly. A review of the literature identified an additional four patients (age < 1 year) who developed TMA after a viral trigger in the presence of mutations in EXOSC3. The recurrence of TMA in one of these patients with an EXOSC3 mutation while on eculizumab treatment underscores the apparent lack of responsiveness to C5 inhibition. In conclusion, mutations in genes influencing the RNA exosome, like EXOSC3 and EXOSC5, characterized by neurodevelopment and neurodegenerative disorders could potentially lead to TMA in the absence of complement dysregulation. Hence, these patients were likely non-responsive to eculizumab.
摘要:
最近才认识到与RNA外泌体编码突变相关的血栓性微血管病(TMA)。这里,我们提出了一个婴儿(女性)与EXOSC5突变(c.230_232delp.Glu77del)相关的临床表型称为CABAC综合征(小脑共济失调,大脑异常,和心脏传导缺陷),包括小脑桥发育不全,得了肾TMA.在四个月大的时候,她有败血症的迹象,之后她患上了TMA.粪便培养物显示轮状病毒是潜在的触发因素。患者接受过一次eculizumab,除了支持性治疗,在等待TMA的诊断分析时,包括遗传补体分析,所有这些都是负面的。Eculizumab停药,患者的TMA迅速恢复。对文献的回顾确定了另外四名患者(年龄<1岁)在EXOSC3中存在突变的病毒触发后发展为TMA。在这些具有EXOSC3突变的患者之一中,在进行依库珠单抗治疗时,TMA的复发强调了对C5抑制的反应性明显缺乏。总之,影响RNA外泌体的基因突变,如EXOSC3和EXOSC5,以神经发育和神经退行性疾病为特征,在没有补体失调的情况下可能导致TMA。因此,这些患者可能对依库珠单抗无反应.