TY - JOUR
T1 - De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: expanding the phenotypic spectrum
AU - Giacomini, Thea
AU - Scala, Marcello
AU - Nobile, Giulia
AU - Severino, Mariasavina
AU - Tortora, Domenico
AU - Nobili, Lino
AU - Accogli, Andrea
AU - Torella, Annalaura
AU - Capra, Valeria
AU - Mancardi, Maria Margherita
AU - Nigro, Vincenzo
AU - Torella, Annalaura
AU - Cappuccio, Gerarda
AU - Musacchia, Francesco
AU - Mutarelli, Margherita
AU - Carrella, Diego
AU - Vitiello, Giuseppina
AU - Parenti, Giancarlo
AU - Capra, Valeria
AU - Leuzzi, Vincenzo
AU - Selicorni, Angelo
AU - Maitz, Silvia
AU - Pierri, Nicola Brunetti
AU - Banfi, Sandro
AU - Zollino, Marcella
AU - Montomoli, Martino
AU - Milani, Donatella
AU - Romano, Corrado
AU - Tummolo, Albina
AU - De Brasi, Daniele
AU - Coppola, Antonietta
AU - Santoro, Claudia
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Cerebellar atrophy
KW - Epileptic encephalopathy
KW - Sleep disorder
KW - POLR2A
KW - Neurodevelopmental disorder
KW - Cerebellar atrophy
KW - Epileptic encephalopathy
KW - Sleep disorder
KW - POLR2A
KW - Neurodevelopmental disorder
UR - http://hdl.handle.net/10807/298402
U2 - 10.1016/j.braindev.2022.04.002
DO - 10.1016/j.braindev.2022.04.002
M3 - Article
SN - 0387-7604
VL - 44
SP - 480
EP - 485
JO - BRAIN & DEVELOPMENT
JF - BRAIN & DEVELOPMENT
ER -