Abstracts

Rationale: GABA-transaminase (GABA-T; ABAT) deficiency is a rare disorder of GABA degradation. Previously reported in three patients from two families, we report six additional patients and an enlarging phenotypic spectrum to this condition previously described as a neonatal onset epileptic encephalopathy with macrosomia and early mortality. Methods: Newly reported patients were seen clinically to obtain medical history. We contacted the authors of previously reported cases to obtain follow-up information. Results: There are four surviving patients (3 M, 1 F), ages 3 months ?" 8 years. Clinical manifestations include developmental impairment, hypotonia, generalized tonic-clonic seizures, choreoathetosis, and subcortical myoclonus. Whole exome sequencing in the two previously unpublished cases revealed ABAT compound heterozygosity (case 1) and homozygous mutations (case 2)-see table. Case 1 had significant choreoathetosis and was unresponsive to auditory and visual stimuli at 20 months of age (Video 1). At 21 months, he initiated treatment with flumazenil infusion and is maintained on a regimen of 1.7 mg/kg/day with clinical improvement (Video 2 - 30 months). EEG recordings post-flumazenil show improved background. Clinically, case 1 is able to communicate with several words and follow simple commands. Case 8 was initiated on a two-month trial of oral flumazenil; however, it was discontinued without improvement. The two remaining patients are treated with the ketogenic diet and a combination of AEDs without clear benefit (see table).With the exception of case 1, all patients remain without mobility or language. Conclusions: GABA-transaminase deficiency is characterized by early onset epileptic encephalopathy and an extrapyramidal syndrome of choreoathetosis and myoclonus. While diagnosis previously relied on CSF GABA quantification or MR spectroscopy utilizing special editing for the detection of intraparenchymal GABA, this disorder is likely to be detected more frequently with increased use of advanced generation sequencing. The effect of long-term treatment with the benzodiazepine receptor antagonist flumazenil is unclear, but warrants further investigation. This series demonstrates a wider phenotypic spectrum in GABA-transaminase deficiency, without early mortality and, in the case of patient 1, less neurodevelopmental impairment than previously described. We describe three previously unreported patients and a series of nine patients in whom the phenotype is known, including three who have survived infancy contrary to earlier descriptions of the disorder. Funding: Internal Funding