4-aminobutyrate aminotransferase (GABA-transaminase) deficiency

4-Aminobutyrate aminotransferase (GABA-transaminase, GABA-T, EC 2.6.1.19) d eficiency (McKusick 137150), an inborn error of GABA degradation, has until now been documented in only a single Flemish child. Compared to the other defects of GABA degradation, succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.24) deficiency with > 150 patients (McKusick 271980) and pyridoxine- dependent seizures with > 100 patients ('putative' glutamic acid decarboxyl ase (GAD, EC 4.1.1.15) deficiency; McKusick 266100), GABA-T deficiency is v ery rare. We present a summary of the clinical, biochemical, enzymatic and molecular findings on the index proband, and a recently identified second p atient, with GABA-T deficiency. The phenotype in both included psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures and el ectroencephalographic abnormalities. In an effort to elucidate the molecula r basis of GABA-T deficiency, we isolated and characterized a 1.5 kb cDNA e ncoding human GABA-T, in addition to a 41 kb genomic clone which encompasse d the GABA-T coding region. Standard methods of cloning and sequencing reve aled an A-to-G transition at nucleotide 754 of the coding region in lymphob last cDNAs derived from the index proband. This mutation resulted in substi tution of an invariant arginine at amino acid 220 by lysine. Expression of the mutant in E. coli, followed by isolation and enzymatic characterization of the recombinant protein, revealed an enzyme whose V-max was reduced to 25% of wild-type activity. The patient and father were heterozygous for thi s allele; the second allele in the patient remains unidentified. Genomic So uthern analysis revealed that the second proband most likely harbours a del etion in the 3' region of the GABA-T gene.