Phenotyping GABA transaminase deficiency: a case description and literature review

Abstract

Gamma-aminobutyric acid transaminase (GABA-T) deficiency is an autosomal recessive disorder reported in only three unrelated families. It is caused by mutations in the ABAT gene, which encodes 4-aminobutyrate transaminase, an enzyme of GABA catabolism and mitochondrial nucleoside salvage. We report the case of a boy, deceased at 12 months of age, with early-onset epileptic encephalopathy, severe psychomotor retardation, hypotonia, lower-limb hyporeflexia, central hypoventilation, and rapid increase in weight and, to a lesser rate, length and head circumference. He presented signs of premature pubarche, thermal instability, and water-electrolyte imbalance. Serum total testosterone was elevated (43.3 ng/dl; normal range <16), as well as serum growth hormone (7.7 ng/ml; normal range <1). Brain magnetic resonance imaging (MRI) showed decreased myelination and generalized brain atrophy, later confirmed by post-mortem examination.

Phenotype of GABA-transaminase deficiency

“…6 Patient 10 was published as a postmortem diagnosis using whole exome sequencing with fatality at 12 months of age. 8 …”

“…Since the first report of GABA-T deficiency in 1984, 6 7 additional cases have been reported. [7][8][9][10][11] The syndrome was previously characterized as early-onset epileptic encephalopathy with mortality within the first 2 years of life. We present a case series of 10 patients, including a previously unreported case and 2 with follow-up subsequent to initial publication, with an expanded phenotype and a novel therapeutic intervention.…”

Neuroimaging Spectrum of Inherited Neurotransmitter Disorders

“…The diagnosis of GABA-transaminase deficiency requires a high index of suspicion and detecting elevated amino acids in the CSF, specifically GABA and β-alanine. 42 Imaging findings described in these case reports include severe enlargement of CSF-containing spaces, [45][46][47][48] decreased myelination, [45][46][47][48] generalized brain atrophy, 48 and restricted diffusion involving the subcortical and periventricular white matter, globus pallidi, and the internal and external capsules. [45][46][47][48]…”

“…GABA-transaminase deficiency has only been confirmed in four unrelated individuals. [45][46][47][48] GABA-transaminase deficien-cy is associated with severe neonatal-infantile epileptic encephalopathy and cranial growth acceleration, the latter possibly due to the relationship between GABA metabolism and the mTOR pathway. 42 The more severe clinical phenotype associated with GABA-transaminase deficiency may be correlated with the higher intracerebral accumulation of GABA.…”

High methylation of the 4-aminobutyrate aminotransferase gene predicts a poor prognosis in patients with myelodysplastic syndrome

“…Mutations in IDH1 and IDH2 genes, which serve an important role in the TCA cycle, have been reported to participate in the pathogenesis and progression of MDS (27); therefore, it was hypothesized that mutations in the ABAT gene may be involved in the pathogenesis of MDS, due to its relation to the TCA cycle. However, the frequency of ABAT mutations is very low; the mutation sites include 631C>T, 275G>A, 1433T>C, 659G>A, 454C>T and 888G>T (8,15,28). ABAT mutations can lead to inactivation of ABAT and elevated GABA concentrations.…”