Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy

• Published in: International journal of molecular sciences 2024-07, Vol.25 (14), p.7604
• Main Authors: Wijnsma, Kioa L, Schijvens, Anne M, Bouwmeester, Romy N, Aarts, Lonneke A M, van den Heuvel, Lambertus Bert P, Haaxma, Charlotte A, van de Kar, Nicole C A J
• Format: Article
• Language: English
• Subjects: Anemia; Ataxia; Cell cycle; Children; Convulsions & seizures; Genes; Genetic aspects; Genomes; Health aspects; hemolytic uremic syndrome; Levetiracetam; Mutation; Nervous system diseases; Ribonucleic acid; RNA; RNA exosome; Rotavirus; Sepsis; Streptococcus infections; thrombotic microangiopathy; Viruses
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25147604

Thrombotic microangiopathy (TMA) in association with RNA exosome encoding mutations has only recently been recognized. Here, we present an infant (female) with an 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 Eculizumab was withdrawn and the patient's TMA recovered quickly.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 . The recurrence of TMA in one of these patients with an mutation while on eculizumab treatment underscores the apparent lack of responsiveness to C5 inhibition. In conclusion, mutations in genes influencing the RNA exosome, like and , 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.