Phenotype of GABA-transaminase deficiency

Koenig, Mary Kay; Hodgeman, Ryan; Riviello, James J.; Chung, Wendy K.; Bain, Jennifer; Chiriboga, Claudia A.; Ichikawa, Kazushi; Osaka, Hitoshi; Tsuji, Megumi; Gibson, K. Michael; Bonnen, Penelope E.; Pearl, Phillip L.

doi:10.1212/wnl.0000000000003936

Cited by 48 publications

(57 citation statements)

References 20 publications

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“…A recently published spectrum of GABA transaminase deficiency reviewed 10 cases of the disorder, five of which had infantile deaths and the surviving subjects were under 10 years of age. 2 Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and is synthesized from glutamic acid in a reaction catalyzed by glutamic acid decarboxylase. The action of GABA transaminase is to convert GABA to succinic semialdehyde, which leads to the oxidative metabolism of GABA through the tricarboxylic acid cycle.…”

Section: Introductionmentioning

confidence: 99%

GABA Transaminase Deficiency With Survival Into Adulthood

Hegde

Karnavat

Vyas³

et al. 2019

J Child Neurol

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GABA-transaminase deficiency is an ultra-rare disorder of GABA metabolism that was described for decades as an early onset epileptic encephalopathy plus movement disorder and hypersomnolence with mortality in early childhood. We report two affected siblings in adolescence and adulthood, both with profound developmental impairment, intractable epilepsy, movement disorder, and behavioral fluctuations. This considerably expands the phenotype and longevity of this inherited neurotransmitter disease.

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Section: Introductionmentioning

confidence: 99%

GABA Transaminase Deficiency With Survival Into Adulthood

Hegde

Karnavat

Vyas³

et al. 2019

J Child Neurol

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“…Through study of multiple patient tissues we confirm that 2pyrrolidinone is accessible and informative by noninvasive sampling of plasma and urine. Additionally, we show GABA metabolite levels pre-and posttreatment with flumazenil, the only available treatment for this disorder (Koenig et al 2017).…”

Section: Introductionmentioning

confidence: 76%

Metabolomics Profile in ABAT Deficiency Pre- and Post-treatment

Koenig¹,

Bonnen

2018

JIMD Reports

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Metabolomic profiling is an emerging technology in the clinical setting with immediate diagnostic potential for the population of patients with Inborn Errors of Metabolism. We present the metabolomics profile of two ABAT deficiency patients both pre- and posttreatment with flumazenil. ABAT deficiency, also known as GABA-transaminase deficiency, is caused by recessive mutations in the gene ABAT and leads to encephalopathy of variable severity with hypersomnolence, hypotonia, hypomyelination, and seizures. Through metabolomics screening of multiple patient tissues, we identify 2-pyrrolidinone as a biomarker for GABA that is informative in plasma, urine, and CSF. These data will enable noninvasive diagnostic testing for the population of patients with disorders of GABA metabolism.

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“…Evidence is increasing that disturbed biosynthesis or breakdown of amino acid neurotransmitters and hence pre-and/or postsynaptic dysfunction play an important role in many other inherited metabolic diseases. For instance, significant dysfunction of glutamatergic and/or GABAergic metabolism and signaling is known or thought to be involved in urea cycle disorders (Braissant 2010), isolated sulfite oxidase and molybdenum cofactor deficiency (Kumar et al 2017), homocystinurias (Poddar et al 2017;Sibarov et al 2016), branched-chain 2-ketoacid dehydrogenase kinase (Novarino et al 2012), maple syrup urine disease (Zinnanti et al 2009), GABA transaminase deficiency (Koenig et al 2017), glutamine synthetase deficiency (Häberle et al 2005), pyridoxine-dependent epilepsy (Mills et al 2006), guanidinoacetate methyltransferase deficiency (Schulze et al 2016), mucopolysaccharidosis IIIA (Dwyer et al 2017), and disorders of energy metabolism such as pyruvate carboxylase deficiency (Ortez et al 2013). Although amino acid disorders are among the earliest identified inherited metabolic diseases, the delineation of the synaptic disorder underlying the metabolic diseases has long been neglected and remains more fully examined.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

Kölker

2018

J of Inher Metab Disea

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Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of L-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of L-glycine and D-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasma L-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebral L-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γ-hydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABA and GABA receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated by L-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis of L-serine, an important neurotrophic factor, and the neurotransmitters D-serine and L-glycine. Supplementation with L-serine and L-glycine has a positive effect on seizure frequency and spasticity, while neurocognitive development can only be improved if treatment starts in utero or immediately postnatally. With novel techniques, the study of synaptic dysfunction in inherited metabolic diseases has become an emerging research field. More and better therapies are needed for these difficult-to-treat diseases.

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Phenotype of GABA-transaminase deficiency

Abstract: Objective: We report a case series of 10 patients with g-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype.Methods: Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil.

Cited by 48 publications

References 20 publications

GABA Transaminase Deficiency With Survival Into Adulthood

GABA Transaminase Deficiency With Survival Into Adulthood

Metabolomics Profile in ABAT Deficiency Pre- and Post-treatment

Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

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