{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:47:10Z","timestamp":1790192830186,"version":"4.1.0"},"reference-count":14,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 Eculizumab was withdrawn and the patient\u2019s TMA recovered quickly. A review of the literature identified an additional four patients (age &lt; 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.<\/jats:p>","DOI":"10.3390\/ijms25147604","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T08:47:41Z","timestamp":1720774061000},"page":"7604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0019-109X","authenticated-orcid":false,"given":"Kioa L.","family":"Wijnsma","sequence":"first","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Schijvens","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy N.","family":"Bouwmeester","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lonneke A. M.","family":"Aarts","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lambertus (Bert) P.","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0682-345X","authenticated-orcid":false,"given":"Charlotte A.","family":"Haaxma","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1990-1189","authenticated-orcid":false,"given":"Nicole C. A. J.","family":"van de Kar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Amalia Children\u2019s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S0140-6736(17)30062-4","article-title":"Haemolytic uraemic syndrome","volume":"390","author":"Fakhouri","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1182\/blood.2022018833","article-title":"Atypical haemolytic uraemic syndrome in the era of terminal complement inhibition\u2014An observational cohort study","volume":"142","author":"Brocklebank","year":"2023","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1007\/s00467-022-05566-6","article-title":"Atypical hemolytic uremic syndrome induced by SARS-CoV2 infection in infants with EXOSC3 mutation","volume":"37","author":"Latta","year":"2022","journal-title":"Pediatr. 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Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1261\/rna.064626.117","article-title":"The RNA exosome and RNA exosome-linked disease","volume":"24","author":"Morton","year":"2018","journal-title":"RNA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/cge.14105","article-title":"A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome","volume":"101","author":"Canpolat","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1002\/ajmg.a.62352","article-title":"Risk of sudden cardiac death in EXOSC5-related disease","volume":"185","author":"Calame","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1182\/blood-2017-10-804096","article-title":"How I treat disseminated intravascular coagulation","volume":"131","author":"Levi","year":"2018","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/ajmg.a.10863","article-title":"Extended phenotype of pontocerebellar hypoplasia with infantile spinal muscular atrophy","volume":"117A","author":"Sztriha","year":"2003","journal-title":"Am. J. Med. Genet. 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