A Rare Case of GABA Transaminases Deficiency Diagnosed by Trio-Based Whole Exome Sequencing Analysis

Background: Disorders of gamma-aminobutyric acid (GABA) metabolism are ultra-rare and manifest prominent neurological sequelae; 4-aminobutyrate aminotransferase (γ-aminobutyrate: GABA transaminase, or GABA-T; OMIM 137150) deficiency is caused by a mutation in the ABAT gene (16p13.2) encoding mitochondrial 4-aminobutyrate aminotransferase (GABA-T). The phenotype includes severe psychomotor retardation, hypotonia, hyperreflexia, seizures, high-pitched cry, and growth acceleration, associated with early infantile death, which results in the accumulation of GABA and beta-alanine. Herein, we report a rare infant case of GABA transaminases deficiency diagnosed by trio-based whole exome sequencing analysis.

Case study/Methods: The patient was a Yemeni male infant, born preterm in week 33(+1) by vaginal delivery with maternal polyhydramnios. The baby had an Apgar score of 4/5 and birth weight was 1610 g (13 percentile for gestation). He was the sixth child of consanguineous healthy Yemen parents, the mother was para 13, four sisters were normal and one brother died from respiratory difficulty in the neonatal period. On clinical exam, the baby was hypotonic with dysmorphic features consisting of a long neck, enlarged fontanel, and club feet. Since birth, the baby had no self-respiration and spontaneous movement, progressing to encephalopathy and coma with myoclonic seizures. EEG showed electrical partial seizure and diffuse cerebral dysfunction. Brain USG revealed ventriculomegaly and diffuse increased echogenicity in both periventricular white matter. Additionally, the baby showed central diabetes insipidus.

Results: Tri-based whole exome sequence confirmed the presence of a likely pathogenic homozygous mutation in the ABAT gene with GABA-T deficiency. Both parents were heterozygous for the same mutation.

Conclusion: This is a case which involved the diagnosis of a rare neurometabolic disorder in one of the babies and eventual genetic counselling of the family. The family has been offered pre-implantation genetic diagnosis for future pregnancies.

Keywords: GABA transaminase deficiency, infant, trio-based WES.