RARE DISEASE
Gamma-aminobutyric acid transaminase deficiency
Gamma-aminobutyric acid transaminase deficiency
Gamma-aminobutyric acid transaminase deficiency
Synonyms: GABA transaminase deficiency
Synonyms: GABA transaminase deficiency
Synonyms: GABA transaminase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Gamma-aminobutyric acid transaminase (GABA-T) deficiency is a rare autosomal recessive disorder caused by mutations in the ABAT gene, leading to impaired GABA metabolism. It manifests as severe neonatal-infantile epileptic encephalopathy with hypotonia, hyperreflexia, choreoathetosis, and developmental arrest. Elevated CSF GABA and β-alanine levels are diagnostic hallmarks. Prognosis is poor, with high mortality in early childhood, though survival into adolescence/adulthood with profound disability has been reported [1][2][10][12].
Burden
High morbidity: Profound developmental impairment (100%), intractable epilepsy (90%), and movement disorders
Mortality: ~50% mortality by age 2 years; survivors require lifelong intensive care [2][10][12]
Psychosocial impact: Severe strain on families due to complex care needs and genetic recurrence risk [4][6]
Therapies
Symptomatic management: Antiseizure medications (often refractory), multidisciplinary neurodevelopmental support
Experimental approaches: Flumazenil (GABA-A receptor antagonist) trialed in some cases with limited benefit [10][18]
No disease-modifying therapies available; prenatal/preimplantation genetic diagnosis offered [4][6]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
88 drug discovery papers about Gamma-aminobutyric acid transaminase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
88 drug discovery papers about Gamma-aminobutyric acid transaminase deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-23 | Identification of Additional Cases of Severe Neonatal GABA-Transaminase Deficiency.
GABA-transaminase (GABA-T) deficiency is a rare disorder of GABA metabolism characterized by neonatal encephalopathy, epilepsy, hypotonia and intellectual disability. It is caused by biallelic pathogenic variants in the ABAT gene. We report a case of a newborn female born to a G10P5 mother, with abnormal fetal movements and polyhydramnios in utero. At birth, she presented with hypotonia, hypersomnolence, decreased level of consciousness, central hypoventilation, non-epileptic myoclonus, seizures, and neurogenic diabetes insipidus. Brain MRI on day two of life showed partial cerebellar vermis agenesis and cerebellar hemispheric dysplasia. Her EEG demonstrated burst suppression. Family history was significant for two siblings with a similar neonatal course. On rapid whole exome sequencing she was found to be homozygous for a nonsense variant in the ABAT gene designated c.1278C>A, p.Tyr426*. Both of her affected siblings were also found to be homozygous for the same variant, and carrier status was confirmed in both parents. A trial of flumazenil infusion showed subtle EEG improvement. Our report of three siblings with severe GABA-T deficiency provides evidence for founder effect in the Canadian Indigenous population and discusses the utility of urine GABA quantification as a reasonable screening test.
2024-06-07 | Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.
Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.
2023-12-12 | Beneficial effects of GABA-producing potential probiotic Limosilactobacillus fermentum L18 of human origin on intestinal permeability and human gut microbiota
Abstract Background Gamma-aminobutyric acid (GABA) is a non-protein amino acid with neuroinhibitory, antidiabetic, and antihypertensive properties and is used as a drug for treating anxiety and depression. Some strains of lactobacilli are known to produce GABA and strengthen the gut barrier function which play an important role in ameliorating the effects caused by the pathogen on the gut barrier. The probiotic bacteria are also known to modulate the human fecal microbiota, however, the role of GABA-producing strains on the gut epithelium permeability and gut microbiota is not known. Results In this study, we report the production of high levels of GABA by potential probiotic bacterium Limosilactobacillus fermentum L18 for the first time. The kinetics of the production of GABA by L18 showed that the maximum production of GABA in the culture supernatant (CS) occurred at 24 h, whereas in fermented milk it took 48 h of fermentation. The effect of L18 on the restoration of lipopolysaccharide (LPS)-disrupted intestinal cell membrane permeability in Caco-2 monolayers showed that it significantly restored the transepithelial electrical resistance (TEER) values, by significantly increasing the levels of junction proteins, occludin and E-cadherin in L18 and LPS-treated Caco-2 cells as compared to only LPS-treated cells. The effect of GABA-secreting L18 on the metataxonome of human stool samples from healthy individuals was investigated by a batch fermentor that mimics the conditions of the human colon. Although, no differences were observed in the α and β diversities of the L18-treated and untreated samples at 24 h, the relative abundances of bacterial families Lactobacillaceae and Bifidobacteriaceae increased in the L18-treated group, but both decreased in the untreated groups. On the other hand, the relative abundance of Enterobacteriaceae decreased in the L18 samples but it increased in the untreated samples. Conclusion These results indicate that Li. fermentum L18 is a promising GABA-secreting strain that strengthens the gut epithelial barrier by increasing junction protein concentrations and positively modulating the gut microbiota. It has the potential to be used as a psychobiotic or for the production of functional foods for the management of anxiety-related illnesses.
2023-08-22 | Antiepileptics pharmacotherapy or antidiabetics may hold potential in treatment of epileptic patients with diabetes mellitus: A narrative review
Several studies have reported the association of diabetes mellitus with epilepsy. With respect to the management of diabetes–epilepsy patients, these studies pointed out the beneficial effects of the ketogenic diet. Ketogenic diets may have antiepileptic properties as the utilization of ketone bodies in the brain instead of glucose delays or inhibits the degradation of γ-aminobutyric acid (GABA) transaminase, and thereby enhances the concentration of GABA. By restoring normal intracerebral GABA levels and reducing the cerebral inflammation linked to epilepsy, metformin is useful in preventing seizures. Sitagliptin is one of the dipeptidyl dipeptidase-4 inhibitors, which have a positive impact on epilepsy in experimental animal models with pentylenetetrazole-induced seizures, by reducing reactive oxygen species, (antioxidant effect), normalization of GABA level, suppression of neuroinflammation (autophagy) and reduced neuronal damage (antiapoptotic effect). Weight gain is a well-known side effect of anti-seizure medications. Sodium valproate can cause dyslipidemia and inhibit glucose transporter-1 in the brain, putting patients with epilepsy and diabetes at risk of developing atherosclerosis. It's worth looking at how ferroptosis and autophagy contribute to the etiology of diabetes and epilepsy, as well as how antiepileptics and antidiabetics alter these pathological processes. Therefore, it was worth performing a narrative-review on the effects of antiepileptics on diabetes, the effect of antidiabetics on epilepsy, as well the net results of antiepileptic–antidiabetic interactions in those patients.
2023-02-13 | Protein-protein interfaces as druggable targets: A common motif of the pyridoxal-5’-phosphate-dependent enzymes to receive the coenzyme from its producers
Pyridoxal-5’-phosphate (PLP), a phosphorylated form of vitamin B6, acts as a coenzyme for numerous reactions, including those changed in cancer and/or associated with the disease prognosis. Since highly reactive PLP may modify cellular proteins, it is hypothesized to be directly transferred from its donors to acceptors. Our goal is to validate the hypothesis by finding common motif(s) in a multitude of the PLP-dependent enzymes for binding the limited number of the PLP donors, namely pyridoxal kinase (PdxK), pyridox(am)in-5’-phosphate oxidase (PNPO) and the PLP-binding protein (PLPBP). Experimentally confirmed interactions between the PLP donors and acceptors reveal that PdxK and PNPO interact with the PLP acceptors of folds I and II, while PLPBP – with those of folds III and V. Aligning the sequences and 3D structures of the identified interactors of PdxK and PNPO, we have found a common motif in the PLP-dependent enzymes of folds I and II. The motif extends from the enzyme surface to the neighborhood of the PLP binding site, represented by an exposed alfa-helix, a partially buried beta-strand and residual loops. Pathogenicity of mutations in human PLP-dependent enzymes within or in the vicinity of the motif, but outside of the active sites, supports functional significance of the motif that may provide an interface for the direct transfer of PLP from the sites of its synthesis to those of the coenzyme binding. The enzyme-specific amino acid residues of the common motif may be useful to develop selective inhibitors blocking PLP delivery to the PLP-dependent enzymes critical for proliferation of malignant cells.
small molecules
2026-01-23 | Identification of Additional Cases of Severe Neonatal GABA-Transaminase Deficiency.
GABA-transaminase (GABA-T) deficiency is a rare disorder of GABA metabolism characterized by neonatal encephalopathy, epilepsy, hypotonia and intellectual disability. It is caused by biallelic pathogenic variants in the ABAT gene. We report a case of a newborn female born to a G10P5 mother, with abnormal fetal movements and polyhydramnios in utero. At birth, she presented with hypotonia, hypersomnolence, decreased level of consciousness, central hypoventilation, non-epileptic myoclonus, seizures, and neurogenic diabetes insipidus. Brain MRI on day two of life showed partial cerebellar vermis agenesis and cerebellar hemispheric dysplasia. Her EEG demonstrated burst suppression. Family history was significant for two siblings with a similar neonatal course. On rapid whole exome sequencing she was found to be homozygous for a nonsense variant in the ABAT gene designated c.1278C>A, p.Tyr426*. Both of her affected siblings were also found to be homozygous for the same variant, and carrier status was confirmed in both parents. A trial of flumazenil infusion showed subtle EEG improvement. Our report of three siblings with severe GABA-T deficiency provides evidence for founder effect in the Canadian Indigenous population and discusses the utility of urine GABA quantification as a reasonable screening test.
2024-06-07 | Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.
Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.
2023-12-12 | Beneficial effects of GABA-producing potential probiotic Limosilactobacillus fermentum L18 of human origin on intestinal permeability and human gut microbiota
Abstract Background Gamma-aminobutyric acid (GABA) is a non-protein amino acid with neuroinhibitory, antidiabetic, and antihypertensive properties and is used as a drug for treating anxiety and depression. Some strains of lactobacilli are known to produce GABA and strengthen the gut barrier function which play an important role in ameliorating the effects caused by the pathogen on the gut barrier. The probiotic bacteria are also known to modulate the human fecal microbiota, however, the role of GABA-producing strains on the gut epithelium permeability and gut microbiota is not known. Results In this study, we report the production of high levels of GABA by potential probiotic bacterium Limosilactobacillus fermentum L18 for the first time. The kinetics of the production of GABA by L18 showed that the maximum production of GABA in the culture supernatant (CS) occurred at 24 h, whereas in fermented milk it took 48 h of fermentation. The effect of L18 on the restoration of lipopolysaccharide (LPS)-disrupted intestinal cell membrane permeability in Caco-2 monolayers showed that it significantly restored the transepithelial electrical resistance (TEER) values, by significantly increasing the levels of junction proteins, occludin and E-cadherin in L18 and LPS-treated Caco-2 cells as compared to only LPS-treated cells. The effect of GABA-secreting L18 on the metataxonome of human stool samples from healthy individuals was investigated by a batch fermentor that mimics the conditions of the human colon. Although, no differences were observed in the α and β diversities of the L18-treated and untreated samples at 24 h, the relative abundances of bacterial families Lactobacillaceae and Bifidobacteriaceae increased in the L18-treated group, but both decreased in the untreated groups. On the other hand, the relative abundance of Enterobacteriaceae decreased in the L18 samples but it increased in the untreated samples. Conclusion These results indicate that Li. fermentum L18 is a promising GABA-secreting strain that strengthens the gut epithelial barrier by increasing junction protein concentrations and positively modulating the gut microbiota. It has the potential to be used as a psychobiotic or for the production of functional foods for the management of anxiety-related illnesses.
2023-08-22 | Antiepileptics pharmacotherapy or antidiabetics may hold potential in treatment of epileptic patients with diabetes mellitus: A narrative review
Several studies have reported the association of diabetes mellitus with epilepsy. With respect to the management of diabetes–epilepsy patients, these studies pointed out the beneficial effects of the ketogenic diet. Ketogenic diets may have antiepileptic properties as the utilization of ketone bodies in the brain instead of glucose delays or inhibits the degradation of γ-aminobutyric acid (GABA) transaminase, and thereby enhances the concentration of GABA. By restoring normal intracerebral GABA levels and reducing the cerebral inflammation linked to epilepsy, metformin is useful in preventing seizures. Sitagliptin is one of the dipeptidyl dipeptidase-4 inhibitors, which have a positive impact on epilepsy in experimental animal models with pentylenetetrazole-induced seizures, by reducing reactive oxygen species, (antioxidant effect), normalization of GABA level, suppression of neuroinflammation (autophagy) and reduced neuronal damage (antiapoptotic effect). Weight gain is a well-known side effect of anti-seizure medications. Sodium valproate can cause dyslipidemia and inhibit glucose transporter-1 in the brain, putting patients with epilepsy and diabetes at risk of developing atherosclerosis. It's worth looking at how ferroptosis and autophagy contribute to the etiology of diabetes and epilepsy, as well as how antiepileptics and antidiabetics alter these pathological processes. Therefore, it was worth performing a narrative-review on the effects of antiepileptics on diabetes, the effect of antidiabetics on epilepsy, as well the net results of antiepileptic–antidiabetic interactions in those patients.
2023-02-13 | Protein-protein interfaces as druggable targets: A common motif of the pyridoxal-5’-phosphate-dependent enzymes to receive the coenzyme from its producers
Pyridoxal-5’-phosphate (PLP), a phosphorylated form of vitamin B6, acts as a coenzyme for numerous reactions, including those changed in cancer and/or associated with the disease prognosis. Since highly reactive PLP may modify cellular proteins, it is hypothesized to be directly transferred from its donors to acceptors. Our goal is to validate the hypothesis by finding common motif(s) in a multitude of the PLP-dependent enzymes for binding the limited number of the PLP donors, namely pyridoxal kinase (PdxK), pyridox(am)in-5’-phosphate oxidase (PNPO) and the PLP-binding protein (PLPBP). Experimentally confirmed interactions between the PLP donors and acceptors reveal that PdxK and PNPO interact with the PLP acceptors of folds I and II, while PLPBP – with those of folds III and V. Aligning the sequences and 3D structures of the identified interactors of PdxK and PNPO, we have found a common motif in the PLP-dependent enzymes of folds I and II. The motif extends from the enzyme surface to the neighborhood of the PLP binding site, represented by an exposed alfa-helix, a partially buried beta-strand and residual loops. Pathogenicity of mutations in human PLP-dependent enzymes within or in the vicinity of the motif, but outside of the active sites, supports functional significance of the motif that may provide an interface for the direct transfer of PLP from the sites of its synthesis to those of the coenzyme binding. The enzyme-specific amino acid residues of the common motif may be useful to develop selective inhibitors blocking PLP delivery to the PLP-dependent enzymes critical for proliferation of malignant cells.
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