ABAT – GABA aminotransaminase deficiency

Gamma-aminobutyric acid transaminase (ABAT) deficiency is an ultra-rare autosomal recessive disorder characterized by early-onset epileptic encephalopathy, hypotonia, hyperreflexia, and central hypoventilation, often leading to severe developmental impairment and early childhood mortality (PMID:27376954).

Seven probands across five unrelated families have been reported with biallelic ABAT variants, including homozygous and compound heterozygous changes, establishing autosomal recessive inheritance (PMID:27376954; PMID:29478219; PMID:31133775; PMID:27903293). Notably, the homozygous variant c.888G>T (p.Gln296His) has been shown pathogenic in vitro (PMID:27376954).

The variant spectrum includes missense changes (e.g., c.638T>G (p.Phe213Cys), c.1394G>A (p.Gly465Asp)) and loss-of-function alleles (e.g., c.1031G>A (p.Trp344Ter), c.1323del (p.Phe442fs)), with no recurrent founder effect observed to date (PMID:31133775; PMID:27903293).

Functional studies in patient fibroblasts and heterologous cell systems have demonstrated markedly reduced GABA-transaminase activity and impaired mitochondrial DNA maintenance for multiple ABAT variants, including c.1031G>A (p.Trp344Ter) and c.1172T>C (p.Leu391Ser) (PMID:27903293). A biochemical classification of ten missense variants further confirmed severe catalytic defects in p.Pro152Ser, p.Leu211Phe, and p.Leu478Pro, supporting loss-of-function as the primary mechanism (PMID:40414180).

Metabolomic profiling of four affected individuals revealed consistent elevation of 2-pyrrolidinone and succinimide in plasma and CSF, reflecting GABA accumulation and providing useful diagnostic biomarkers independent of anti-seizure medication effects (PMID:31133775).

No conflicting reports have been documented, and all functional assays align with the clinical phenotype. Together, genetic and experimental data support a moderate to strong clinical validity for ABAT in GABA-transaminase deficiency. Key take-home: biallelic pathogenic ABAT variants cause a distinct neonatal-infantile encephalopathy, and early metabolomic screening for GABA-related biomarkers can expedite diagnosis and management.

References

• Journal of inherited metabolic disease • 2016 • Phenotyping GABA transaminase deficiency: a case description and literature review. PMID:27376954
• JIMD reports • 2019 • Serial Magnetic Resonance Imaging and 1H-Magnetic Resonance Spectroscopy in GABA Transaminase Deficiency: A Case Report. PMID:29478219
• Frontiers in neuroscience • 2019 • 2-Pyrrolidinone and Succinimide as Clinical Screening Biomarkers for GABA-Transaminase Deficiency: Anti-seizure Medications Impact Accurate Diagnosis. PMID:31133775
• Molecular brain • 2016 • Personalized medicine approach confirms a milder case of ABAT deficiency. PMID:27903293
• Molecular genetics and metabolism • 2025 • Biochemical investigation of pathogenic missense mutations of human 4-amino butyrate aminotransferase towards the understanding of the molecular pathogenesis of GABA transaminase deficiency. PMID:40414180

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