A new case of GABA transaminase deficiency facilitated by proton MR spectroscopy

Abstract

BackgroundDeficiency of 4-aminobutyrate aminotransferase (GABA-T) is a rare disorder of GABA catabolism, with only a single sibship reported. We report on a third case, a Japanese female infant with severe psychomotor retardation and recurrent episodic lethargy with intractable seizures, with the diagnosis facilitated by proton magnetic resonance (MR) spectroscopy (1H-MRS).MethodsNeuroimaging was performed at the first episode of lethargy. For 1H-MRS, locations were placed in the semioval center and the basal ganglia. Quantification of metabolite concentrations were derived using the LCModel. We confirmed the diagnosis subsequently by enzyme and molecular studies, which involved direct DNA sequence analysis and the development of a novel multiplex ligation-dependent probe amplification test.Results1H-MRS analysis revealed an elevated GABA concentration in the basal ganglia (2.9 mmol/l). Based on the results of quantitative 1H-MRS and clinical findings, GABA-T deficiency was suspected and confirmed in cultured lymphoblasts. Molecular studies of the GABA-T gene revealed compound heterozygosity for a deletion of one exon and a missense mutation, 275G>A, which was not detected in 210 control chromosomes.ConclusionsOur results suggest that excessive prenatal GABA exposure in the central nervous system (CNS) was responsible for the clinical manifestations of GABA transaminase deficiency. Our findings suggest the dual nature of GABA as an excitatory molecule early in life, followed by a functional switch to an inhibitory species later in development. Furthermore, quantitative 1H-MRS appears to be a useful, noninvasive tool for detecting inborn errors of GABA metabolism in the CNS.

The GABA Transaminase, ABAT, Is Essential for Mitochondrial Nucleoside Metabolism

“…The catabolism of GABA through the GABA shunt is known to take place in the mitochondrial matrix and cellular localization studies confirmed the specific sub-mitochondrial localization of ABAT to be the matrix compartment (Supplemental Figure 2). Subjects from two unrelated families have been clinically described in the literature as having ABAT deficiency (Jaeken et al, 1984; Tsuji et al, 2010). These children showed highly similar clinical presentation to our subjects with severe psychomotor retardation, intractable seizures, hypotonia, and hyperreflexia.…”

“…Clinical reports describe two families with biochemically confirmed ABAT deficiency (Jaeken et al, 1984; Tsuji et al, 2010). The probands in these families display elevated levels of GABA along with severe psychomotor retardation, intractable seizures, hypotonia, and hyperreflexia.…”

Phenotype of GABA-transaminase deficiency

“…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.…”

Phenotyping GABA transaminase deficiency: a case description and literature review

“…Clinical investigation aiming for a diagnosis should not end with the patient's death, as it may allow a more precise genetic counselling for the family. Introduction Gamma-aminobutyric acid transaminase (GABA-T) deficiency (MIM#613163) is an autosomal recessive disorder reported in only three unrelated families (Jaeken et al 1984;Tsuji et al 2010;Besse et al 2015). It is caused by mutations in the ABAT gene (HGNC_ID:23), which encodes 4-aminobutyrate transaminase (EC 2.6.1.19), an enzyme of GABA catabolism and mitochondrial nucleoside salvage (Besse et al 2015).…”

“…It is caused by mutations in the ABAT gene (HGNC_ID:23), which encodes 4-aminobutyrate transaminase (EC 2.6.1.19), an enzyme of GABA catabolism and mitochondrial nucleoside salvage (Besse et al 2015). GABA-T deficiency is usually characterized by elevated levels of GABA in cerebrospinal fluid (CSF), associated with severe psychomotor retardation, intractable seizures, hypotonia with hyperreflexia, accelerated height growth, and a high-pitched cry (Jaeken et al 1984;Tsuji et al 2010;Besse et al 2015).…”