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.

Identification of novel and <i>de novo GABRB1</i> mutation in Chinese patient with developmental and epileptic encephalopathy 45

“…Monfrini et al (2023) described the clinical and genetic findings of a 21-year-old woman with DEE45 carrying a novel de novo GABRB1 variation (c.841A>G, p.T281A) which was the fourth report of a DEE45 patient (18). This 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 anti-seizure medications.…”

Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine

“…With regard to IESS development, previous studies have shown alterations in neurosteroid sensitivity and decreased expression of GABA A receptors in IESS models and from a management perspective, one effective treatment of spasms is the GABA transaminase inhibitor, vigabatrin [ 36 , 46 , 47 ]. Interestingly, pathogenic variants in a number of GABA-related epilepsy genes have been implicated in the development of IESS, such as pathogenic variants in GABRB1 , GABRA1 and GABRB3 , highlighting the importance of GABA-related transmission in the development of IESS [ 48 , 49 , 50 , 51 ].…”

“…Examples of other genes associated with IESS, which are mechanistically involved in GABAergic transmission, include GABRB1 , GABRB3 and GABRA1 , amongst others [ 48 , 49 , 50 , 51 ]. Specifically, the aforementioned genes encode subunits of GABA receptors.…”