PP01.10 – 3014: GABRA1 neonatal encephalopathy: a clinical, genetic and pathological study

Abstract

Objectives To describe a novel phenotype of neonatal encephalopathy and infantile refractory epilepsy and their genetic and pathological underpinnings. Methods After unremarkable gestation and delivery, a male newborn presented with profound lethargy immediately after birth. Initial physical exam was otherwise normal with no microcephaly or dysmorphic features. He remained in a state of continuous behavioural sleep – arguably a coma state starting at birth – in the ensuing weeks. EEG was initially normal. Brain MRI, metabolic screen and array CGH were normal. By age 2 months, developmental arrest, hypotonic tetraparesis and head growth deceleration were evident and remained unchanged thereafter. Around that age, seizures were first noticed and included daily focal clonic, myoclonic and tonic seizures that proved resistant to multiple AEDs. EEG revealed multifocal epileptiform discharges and diffuse slowing of background activity. Ictal recordings suggested a migrating pattern of the seizures. Throughout patient's life, eye opening was only noted at the time of tonic seizures. He died at age 16 months from respiratory complications. Results Brain pathology showed diffuse hypomyelination and mild gliotic changes. The mamillary bodies were conspicuously absent. Microscopically, there were no cytoarchitectural abnormalities but the neocortex showed abundance of type II Alzheimer astrocytes. Whole exome sequencing revealed a heterozygous c.1303C> G missense mutation in the GABRA1A gene, producing a p.L267V substitution. This de novo variant was confirmed by PCR and Sanger sequencing and is predicted to alter the assembly and functional properties of the GABA receptor. Conclusions Mutations in GABRA1, encoding the GABA-A receptor alpha-1 subunit, have been associated with generalized epilepsies and more recently childhood epileptic encephalopathies. The present observation expands the spectrum of GABRA1-linked phenotypes to include a severe neonatal-onset encephalopathy featuring a continuous sleep state, infantile refractory epilepsy and distinctive neuropathological abnormalities.