De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: expanding the phenotypic spectrum

Thea Giacomini, Marcello Scala, Giulia Nobile, Mariasavina Severino, Domenico Tortora, Lino Nobili, Andrea Accogli, Annalaura Torella, Valeria Capra, Maria Margherita Mancardi, Vincenzo Nigro, Annalaura Torella, Gerarda Cappuccio, Francesco Musacchia, Margherita Mutarelli, Diego Carrella, Giuseppina Vitiello, Giancarlo Parenti, Valeria Capra, Vincenzo LeuzziAngelo Selicorni, Silvia Maitz, Nicola Brunetti Pierri, Sandro Banfi, Marcella Zollino, Martino Montomoli, Donatella Milani, Corrado Romano, Albina Tummolo, Daniele De Brasi, Antonietta Coppola, Claudia Santoro

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Background: Heterozygous POLR2A variants have been recently reported in patients with a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia. POLR2A encodes the highly conserved RBP1 protein, an essential subunit of the DNA-dependent RNA polymerase II. Case presentation: We investigated a 12-year-old girl presenting with an early-onset encephalopathy characterized by psychomotor delay, facial dysmorphism, refractory epilepsy with variable seizure types, behavioural abnormalities, and sleep disorder. Brain MRI showed a slowly progressive cerebellar atrophy. Trio-exome sequencing (Trio-ES) revealed the de novo germline variant NM_000937.5:c.1370T>C; p.(Ile457Thr) in POLR2A. This variant was previously reported in a subject with profound generalized hypotonia and muscular atrophy by Haijes et al. Our patient displayed instead a severe epileptic phenotype with refractory hypotonic seizures with impaired consciousness, myoclonic jerks, and drop attacks. Conclusion: This case expands the clinical spectrum of POLR2A-related syndrome, highlighting its phenotypic variability and supporting the relevance of epilepsy as a core feature of this emerging condition.
Lingua originaleEnglish
pagine (da-a)480-485
Numero di pagine6
RivistaBRAIN & DEVELOPMENT
Volume44
DOI
Stato di pubblicazionePubblicato - 2022

Keywords

  • Cerebellar atrophy
  • Epileptic encephalopathy
  • Sleep disorder
  • POLR2A
  • Neurodevelopmental disorder

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