GABA Transaminase Deficiency With Survival Into Adulthood

Hegde, Anaita Udwadia; Karnavat, Purva Keni; Vyas, Rashmi; DiBacco, Melissa L.; Grant, P. Ellen; Pearl, Phillip L.

doi:10.1177/0883073818823359

Cited by 12 publications

(7 citation statements)

References 9 publications

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“…The variant is pathogenic, resulting in the ABAT deficiency phenotype observed in our case. In comparison to the previous reports, 3,4,8,10,[12][13][14][15][16][17][18] our patient had a previously unreported homozygous missense mutation in the ABAT gene.…”

Section: Discussioncontrasting

confidence: 76%

“…To date, only 14 patients worldwide have been reported in the published literature with GABA-T deficiency. 3 4 8 10 12 13 14 15 16 17 18 Six of these patients survived for more than 3 years, compared with the previously reported mortality rate within the first 2 years of life. 8 Our patient died at 30 months, which is consistent with previous data.…”

Section: Discussionmentioning

confidence: 72%

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Gamma-Aminobutyric Acid Transaminase (GABA-T) Deficiency in a Consanguineous Saudi Family: A Case Report and Literature Review

Kentab

2022

Journal of Pediatric Epilepsy

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Gamma-aminobutyric acid transaminase (GABA-T) deficiency is a rare, autosomal recessive disorder caused by mutations in the 4-aminobutyrate aminotransferase (ABAT) gene, which encodes an enzyme involved in GABA catabolism. It is characterized by severe psychomotor retardation, early-onset epileptic encephalopathy, intractable seizures, hypotonia, hyperreflexia, movement disorder, hypersomnolence, and early childhood mortality. It is associated with elevated free GABA in cerebrospinal fluid (CSF), GABA-T deficiency in cultured lymphoblasts, hypomyelination on brain magnetic resonance imaging (MRI), and elevated GABA level in the basal ganglia on proton magnetic resonance spectroscopy (MRS). Only 14 cases have been published in the literature. A rare case of infantile epileptic encephalopathy caused by GABA-T deficiency resulting from a previously unreported homozygous missense mutation in the ABAT gene is described. Our findings add to the phenotypic, neuroradiological, and genetic spectrum of ABAT mutations.

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Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 72%

Gamma-Aminobutyric Acid Transaminase (GABA-T) Deficiency in a Consanguineous Saudi Family: A Case Report and Literature Review

Kentab

2022

Journal of Pediatric Epilepsy

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“…In conclusion, there is no doubt that the GABA shunt is imperative for health, and its impairment triggers the development of several disease phenotypes, most of which are related to neurological disturbances [13,14,[76][77][78][79]. In this study, we showed that the GABA shunt is a promising route involved in the mitochondrial redox metabolism of cortical and hypothalamic synaptosomes and is linked to glucose metabolism by increasing HK activity at the mitochondrial level.…”

Section: Discussionmentioning

confidence: 62%

Coupling of GABA Metabolism to Mitochondrial Glucose Phosphorylation

Cavalcanti-de-Albuquerque

de‐Souza‐Ferreira

Carvalho

et al. 2021

Neurochem Res

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Glucose and oxygen (O 2 ) are vital to the brain. Glucose metabolism and mitochondria play a pivotal role in this process, culminating in the increase of reactive O 2 species. Hexokinase (HK) is a key enzyme on glucose metabolism and is coupled to the brain mitochondrial redox modulation by recycling ADP for oxidative phosphorylation (OXPHOS). GABA shunt is an alternative pathway to GABA metabolism that increases succinate levels, a Krebs cycle intermediate. Although glucose and GABA metabolisms are intrinsically connected, their interplay coordinating mitochondrial function is poorly understood. Here, we hypothesize that the HK and the GABA shunt interact to control mitochondrial metabolism differently in the cortex and the hypothalamus. The GABA shunt stimulated mitochondrial O 2 consumption and H 2 O 2 production higher in hypothalamic synaptosomes (HSy) than cortical synaptosomes (CSy). The GABA shunt increased the HK coupled to OXPHOS activity in both population of synaptosomes, but the rate of activation was higher in HSy than CSy. Significantly, malonate and vigabatrin blocked the effects of the GABA shunt in the HK activity coupled to OXPHOS. It indicates that the glucose phosphorylation is linked to GABA and Krebs cycle reactions. Together, these data shed light on the HK and SDH role on the metabolism of each region fed by GABA turnover, which depends on the neurons' metabolic route. KeywordsBrain • Synaptosome • Mitochondria • GABA shunt • Hexokinase • Bioenergetics Abbreviations α-KG Alpha ketoglutarate ΔΨm Mitochondrial membrane potential 2-DG 2-Deoxyglucose Ap5A P1,P5-Di(adenosine-5') pentaphosphate CSy Cortical synaptosome ETS Electron transport system FCCP Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone GABA-t Gamma transaminase GAD Glutamate decarboxylase GDH Glutamate dehydrogenase Glc Glucose G6P Glucose-6-phosphate HK Hexokinase HSy Hypothalamic synaptosome mROS Mitochondrial reactive oxygen species mt-HK Mitochondrial-bound hexokinase NAG N-Acetyl-Glucosamine OXPHOS Oxidative phosphorylation SDH Succinate dehydrogenase SSADH Succinic semialdehyde dehydrogenase Succ Succinate TCA Tricarboxylic acid cycle * Joao Paulo Cavalcanti-de-Albuquerque

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“…Increased expression of this degrading enzyme could shorten the availability of GABA, causing a disinhibitory effect. Increased ABAT expression could underlie manic symptoms in BP and SCHIZ, as ABAT deficiency has been associated with inconsolable crying, dullness, and lethargy (98) and increased ABAT expression has been associated with aggression in a preclinical model (99).…”

Section: Astrocyte-related Gene Expression In Bp and Schizmentioning

confidence: 99%

“…Increased ABAT expression could underlie manic symptoms in BP, as ABAT deficiency has been associated with inconsolable crying, dullness, and lethargy in case studies 107 and increased ABAT has been associated with aggression in rodents 108 .…”

Section: Astrocyte-related Gene Expression In Bp and Schizmentioning

confidence: 99%

Neurotransmission-Related Gene Expression in the Frontal Pole (Brodmann Area 10) is Altered in Subjects with Bipolar Disorder and Schizophrenia

Medina

Hagenauer

Krolewski

et al. 2022

Preprint

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Background: Broadmann Area 10 (BA10) is the largest cytoarchitectonic region of the human cortex and perhaps the most evolutionarily advanced, yet it remains poorly understood, in part due to the complexity of its integrative functions. Bipolar disorder (BP) and schizophrenia (SCHIZ) are two disorders that share symptomatology and genetic risk. The average onset of BP and SCHIZ coincides with the adolescent pruning of BA10 grey matter, suggesting a potential role for BA10 dysfunction in the disorders. In this study, we investigated the role of neurotransmission-related gene expression in BA10 in BP and SCHIZ. Methods: We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ post-mortem samples (n=72). We chose this method for its high sensitivity to detect low-level expression. We then bolstered our findings by performing a meta-analysis of publicly-released BA10 microarray data (n=101) and identified sources of convergence with our qPCR results. To improve our interpretation of diagnosis effects, we compiled an unusually large database of clinical metadata for our qPCR samples. We used this data to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these exploratory findings with publicly-available datasets. Results: Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results include a large down-regulation in BP and SCHIZ of two important therapeutic targets with low-levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABA-ergic and astrocytic function. We also found evidence that therapeutics may produce differential expression that opposes the effects of diagnosis. In contrast, substances of abuse may be associated with similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.

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GABA Transaminase Deficiency With Survival Into Adulthood

Cited by 12 publications

References 9 publications

Gamma-Aminobutyric Acid Transaminase (GABA-T) Deficiency in a Consanguineous Saudi Family: A Case Report and Literature Review

Gamma-Aminobutyric Acid Transaminase (GABA-T) Deficiency in a Consanguineous Saudi Family: A Case Report and Literature Review

Coupling of GABA Metabolism to Mitochondrial Glucose Phosphorylation

Neurotransmission-Related Gene Expression in the Frontal Pole (Brodmann Area 10) is Altered in Subjects with Bipolar Disorder and Schizophrenia

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