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Teenagers generally present mild to no symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present report, we present the case of a 14-year-old boy with Angelman syndrome (AS) who presented with severe COVID-19 symptoms. He spent 20 days in the ICU with elevated inflammatory biomarkers (C-reactive protein and D-dimer) and increased peaks of neutrophil-to-lymphocyte ratio, which is uncommon for teenagers diagnosed with COVID-19. Although he showed physiological instability, he was able to produce neutralizing antibodies, suggesting a functional immune response. The literature concerning the immune response to infections in patients with AS is still poor, and to our knowledge, this was the first report of a patient with AS diagnosed with COVID-19. As such, the present study may alert other patients with AS or other rare diseases that they lack a competent immune response and could suffer severe consequences of SARS-CoV-2 infection., Competing Interests: MA and DO report grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). RM reports fellowship from FAPESP. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lopes, Celestino, Barros, Fevereiro, Gejer, Oliveira, Brasil, Bossolan, Pinto, Santos, Divan, Alves, Oliveira, Machado, Thomazelli, Hiyane, Brelaz-Abreu, Bragança-Jardim, Heinen, Barrientos, Mau, Camara, Bueno and Amano.)