Abstracts

Rationale: GABA-transaminase (GABA-T) deficiency has been reported previously in only three patients from two families, with the first two children (siblings) having had neonatal onset epileptic encephalopathy, macrosomia, and early mortality. We describe the only three known living patients including a novel therapeutic approach.Methods: Two new patients, identified by whole exome sequencing, are reported, with 5-year follow-up provided on the only other reported surviving case. Clinical features, MRI, EEG, genotype, and CSF GABA are reported, followed by a trial of benzodiazepine-receptor antagonist intervention in the newest diagnosed patient.Results: Patient ages are 21 months and 7 years; clinical features are developmental impairment, GTCS, choreoathetosis, and myoclonus. WES revealed ABAT compound heterozygosity (case 1): c.454C>T (p.P152S), c.1393G>C (p.G465R), and homozygous c.1129C>T (p.R377W) mutations (case 2). In case 1, CSF [GABA] was elevated: free 0.25 µmol/L (ref range 0.02-0.07) and total 33.4 µmol/L (4.2-13.4). Metabolites showed increased plasma 2-pyrrolidinone, a GABA ketone reported in the first published family. EEG showed high-voltage polymorphic delta and multifocal and generalized spike-wave. Treatment (case 1) was implemented with flumazenil infusion 0.5 mg/kg/hr with clinical and EEG improvement. The infusion has been maintained for three months with clinical stability; the nighttime infusion rate was halved because of sleep impairment. The other surviving case, reported at 28 months of age and now 7 years 10 months, has profound developmental impairment without mobility or language.Conclusions: GABA-transaminase deficiency is likely to be detected in more individuals with increased clinical use of advanced generation sequencing. Of five patients now reported, three have survived infancy and intervention with flumazenil appears to be associated with improved short-term outcome. While initially considered to be a neonatal onset epileptic encephalopathy with early fatality, this report demonstrates survival past infancy and potential therapeutic intervention.