GABRB1‐related early onset developmental and epileptic encephalopathy: Clinical trajectory and novel de novo mutation

Abstract Developmental and epileptic encephalopathy 45 (DEE45) is a neurogenetic disorder caused by heterozygous pathogenic variants of GABRB1 , encoding the beta1 subunit of the GABA type A receptor. Only three infants with DEE45 have been reported so far, and a detailed description of the disease history of these patients is still lacking. We describe the clinical and genetic findings of a 21‐year‐old woman with DEE45 carrying a novel de novo GABRB1 mutation (c.841A>G, p.T281A). The patient presented at birth with hypotonia and focal apneic seizures evolving in a phenotype of epilepsy of infancy with migrating focal seizures that were refractory to antiseizure medications. Epileptic spasms partially responsive to steroid therapy appeared in the second year of life. Acquired microcephaly, profound mental retardation, and tetraparesis became evident with development. During childhood and adolescence, the epileptic phenotype evolved toward a Lennox–Gastaut Syndrome. Atypical absence status and clusters of tonic seizures occurred, often triggered by respiratory infections. The main strengths of this work are the identification of a novel pathogenic GABRB1 variant localized in the same transmembrane domain of a previously described mutation and the detailed description of the clinical trajectory of GABRB1‐related encephalopathy along 21 years of disease history.