ABAT Mutation - GABA Transaminase Deficiency

The Gene and Enzyme

• OMIM: #613163
• Inheritance: Autosomal recessive
• At least 10 pathogenic mutations have been identified to date

Pathophysiology

1. Loss-of-function mutations in ABAT -> GABA-T enzyme deficiency
2. GABA fails to be catabolized -> massive accumulation of GABA (and beta-alanine) in brain cells
3. Excess GABA disrupts the balance of inhibitory/excitatory neurotransmitters
4. Excess GABA also triggers abnormal growth hormone release -> accelerated linear growth

Clinical Features (Infantile Onset)

Biochemical Diagnosis

• Elevated CSF GABA and beta-alanine (hallmark finding)
• Elevated plasma GABA
• Urine organic acids and lactate are typically normal (distinguishes from SUCLA2/SUCLG1 MDS)
• No elevation of gamma-hydroxybutyrate (GHB) - this distinguishes ABAT deficiency from succinic semialdehyde dehydrogenase deficiency (SSADHD), which has a very similar presentation
• Biomarkers on metabolomics: 2-pyrrolidinone and succinimide have been proposed as clinical screening biomarkers (Kennedy et al., 2019); importantly, certain anti-seizure medications can interfere with these markers and cause missed diagnosis

Key Differentials

Neuroimaging

Treatment

• Anti-seizure medications (note: vigabatrin, which inhibits GABA-T, is contraindicated as it would worsen GABA accumulation)
• Pyridoxine (vitamin B6) supplementation has been tried given the PLP-dependence of the enzyme
• A 2019 metabolomics study (Koenig & Bonnen, PMID 29480352) showed some metabolic changes with treatment but outcomes remain poor

Recent Research (2025-2026)

• A 2025 biochemical study (PMID 40414180) investigated pathogenic missense mutations at the molecular level, characterizing how specific mutations disrupt GABA-T enzyme function and advancing understanding of molecular pathogenesis
• A 2026 case series (PMID 41573381) identified additional cases of severe neonatal GABA-T deficiency, expanding the known phenotypic spectrum to include neonatal-onset presentations

Recent Clinical Case Reports of ABAT Deficiency

2026 - Neonatal Siblings with Founder Effect (Most Recent)

• Proband: Newborn female born with abnormal fetal movements and polyhydramnios. At birth: hypotonia, hypersomnolence, decreased consciousness, central hypoventilation, non-epileptic myoclonus, seizures, and neurogenic diabetes insipidus (a novel feature)
• Brain MRI on day 2 of life: partial cerebellar vermis agenesis and cerebellar hemispheric dysplasia
• EEG: burst suppression pattern
• All three affected siblings carried the same homozygous variant; both parents were confirmed carriers
• A trial of flumazenil infusion showed subtle EEG improvement
• The paper proposes urine GABA quantification as a practical screening test and provides evidence for a founder effect in Canadian Indigenous populations

2023 - Drug-Resistant Epilepsy, India

• 4-year-old boy from India, non-consanguineous parents
• Global developmental delay, drug-resistant seizures, excessive sleep, mild dysmorphic features
• Upper motor neuron and cerebellar signs, autism features
• EEG: multifocal and generalized epileptiform patterns
• MRI: mild hyperintensity in the superior cerebellar area
• Exome sequencing: compound heterozygous variants c.43C>T (p.Gln15Ter) and c.1295C>T (p.Thr432Ile)

2022 - Saudi Arabia Case and Literature Review

• Case report with formal literature review cataloguing all known cases at that time

2019 - Survival Into Adulthood (Landmark Report)

• Both had profound developmental impairment, intractable epilepsy, and movement disorder
• The older sibling was a young adult at time of report
• This report established that survival into adulthood is possible, with chronic severe neurological disability
• Behavioral fluctuations were a notable feature

2019 - Paroxysmal Dyskinesia with Thalamic Lesions

• Adult female patient presenting with paroxysmal dyskinesias, drowsiness, and thalamic MRI lesions - an atypical and previously unreported adult presentation
• Published in a high-impact journal (Neurology), highlighting that ABAT deficiency may be underdiagnosed in adult movement disorder clinics

2019 - 10-Year MRI/MRS Follow-Up

• Infancy: high DWI signal in internal/external capsules and cerebral white matter
• By age 3: white matter changes resolved; replaced by diffuse brain atrophy
• Proton MRS (1H-MRS): markedly elevated GABA in basal ganglia at age 1-2 years, which decreased by age 5 - but CSF GABA remained persistently elevated
• Clinical course progressed: encephalopathic episodes in infancy -> hyperkinetic movement disorder in early childhood -> chronic stable phase
• Key finding: severity of involuntary movements correlated with basal ganglia GABA levels by MRS

2017 - Hypersomnolence-Hyperkinetic Movement Disorder, India

• Compound heterozygous ABAT mutations in a child with prominent hypersomnolence and hyperkinetic movement disorder (without dominant seizure focus)
• Highlighted clinical heterogeneity in presentation

2016 - Milder Phenotype (Personalized Medicine Approach)

• Patient presenting at 6 months with developmental delay, hypotonia, hypersomnolence, and mild choreiform movements - but NO seizures at 18 months
• Two novel heterozygous ABAT missense variants of uncertain significance (VUS) on exome sequencing
• Cell-based GABA-T enzyme activity assays and mtDNA copy number assays confirmed pathogenicity
• Functionally similar mitochondrial compromise to severe cases
• First reported case of a milder ABAT deficiency phenotype - expanded the clinical spectrum toward presentations seen more commonly in general pediatric neurology

2016 - Phenotyping and Literature Review

• Systematic case description plus review of all previously reported cases
• Useful reference for classic vs. atypical phenotypes

Key Themes Across Recent Reports