scholarly journals Neurological Syndromes Associated with Anti-GAD Antibodies

2020 ◽  
Vol 21 (10) ◽  
pp. 3701 ◽  
Author(s):  
Maëlle Dade ◽  
Giulia Berzero ◽  
Cristina Izquierdo ◽  
Marine Giry ◽  
Marion Benazra ◽  
...  
Keyword(s):  
Unmet Need ◽  
Acid Decarboxylase ◽  
Gamma Aminobutyric Acid ◽  
Gad Antibodies ◽  
Intracellular Enzyme ◽  
Inhibitory Neurotransmitter ◽  
Predictors Of Response ◽  
Physiologic Function ◽  
The Central Nervous System ◽  
Relative Rarity

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

scholarly journals An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2678 ◽  
Author(s):  
Dai-Hung Ngo ◽  
Thanh Sang Vo
Keyword(s):  
Neuronal Development ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Peripheral Tissues ◽  
Inhibitory Neurotransmitter ◽  
Anti Cancer ◽  
The Central Nervous System ◽  
Potential Alternative ◽  
Pharmaceutical Properties ◽  
Anti Inflammation

Gamma-aminobutyric acid (Gaba) is a non-proteinogenic amino acid that is widely present in microorganisms, plants, and vertebrates. So far, Gaba is well known as a main inhibitory neurotransmitter in the central nervous system. Its physiological roles are related to the modulation of synaptic transmission, the promotion of neuronal development and relaxation, and the prevention of sleeplessness and depression. Besides, various pharmaceutical properties of Gaba on non-neuronal peripheral tissues and organs were also reported due to anti-hypertension, anti-diabetes, anti-cancer, antioxidant, anti-inflammation, anti-microbial, anti-allergy, hepato-protection, reno-protection, and intestinal protection. Therefore, Gaba may be considered as potential alternative therapeutics for prevention and treatment of various diseases. Accordingly, this updated review was mainly focused to describe the pharmaceutical properties of Gaba as well as emphasize its important role regarding human health.

scholarly journals Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2388-2397 ◽  
Author(s):  
Caroline Neuray ◽  
Reza Maroofian ◽  
Marcello Scala ◽  
Tipu Sultan ◽  
Gurpur S Pai ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Epileptic Encephalopathy ◽  
Neurological Dysfunction ◽  
Acid Decarboxylase ◽  
Gamma Aminobutyric Acid ◽  
Inhibitory Neurotransmitter ◽  
Base Level ◽  
Excitatory Neurotransmitters ◽  
New Gene ◽  
Brain Gaba

Abstract Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.

scholarly journals Two distinct mechanisms target GAD67 to vesicular pathways and presynaptic clusters

2010 ◽  
Vol 190 (5) ◽  
pp. 911-925 ◽  
Author(s):  
Jamil Kanaani ◽  
Julia Kolibachuk ◽  
Hugo Martinez ◽  
Steinunn Baekkeskov
Keyword(s):  
Neuroendocrine Cells ◽  
Acid Decarboxylase ◽  
Inhibitory Neurotransmitter ◽  
Golgi Membranes ◽  
The Central Nervous System ◽  
Hydrophobic Lipid ◽  
Rapid Modulation ◽  
Axonal Targeting ◽  
Membrane Anchoring ◽  
Constitutively Active

The inhibitory neurotransmitter γ-amino butyric acid (GABA) is synthesized by two isoforms of the enzyme glutamic acid decarboxylase (GAD): GAD65 and GAD67. Whereas GAD67 is constitutively active and produces >90% of GABA in the central nervous system, GAD65 is transiently activated and augments GABA levels for rapid modulation of inhibitory neurotransmission. Hydrophobic lipid modifications of the GAD65 protein target it to Golgi membranes and synaptic vesicles in neuroendocrine cells. In contrast, the GAD67 protein remains hydrophilic but has been shown to acquire membrane association by heterodimerization with GAD65. Here, we identify a second mechanism that mediates robust membrane anchoring, axonal targeting, and presynaptic clustering of GAD67 but that is independent of GAD65. This mechanism is abolished by a leucine-103 to proline mutation that changes the conformation of the N-terminal domain but does not affect the GAD65-dependent membrane anchoring of GAD67. Thus two distinct mechanisms target the constitutively active GAD67 to presynaptic clusters to facilitate accumulation of GABA for rapid delivery into synapses.

Sequence and chromosomal assignment of a human novel cDNA: similarity to gamma-aminobutyric acid transporter

2001 ◽  
Vol 79 (12) ◽  
pp. 977-984 ◽  
Author(s):  
Yuewen Gong ◽  
Manna Zhang ◽  
Li Cui ◽  
Gerald Y Minuk
Keyword(s):  
Cdna Probe ◽  
Human Kidney ◽  
The Body ◽  
Aminobutyric Acid ◽  
Mammalian Brain ◽  
Chromosomal Assignment ◽  
Gamma Aminobutyric Acid ◽  
Gaba Transporter ◽  
Inhibitory Neurotransmitter ◽  
The Central Nervous System

Gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the mammalian brain. Although initially thought to be confined to the central nervous system, GABAergic activity has also been described in other tissues throughout the body. In the present study, we report the cloning and localization of human GABA transporter cDNA and document its expression in various human tissues. A human liver cDNA library was initially screened by a 32P-labeled murine brain GABA transporter 3 (GAT-3) cDNA probe, and full-length cDNA was cloned by employing Marathon-Ready(tm) human kidney cDNA. The human GABA transporter cDNA encoded a 569 amino acid hydrophobic protein with 12 transmembrane domains (TMs). Search of published sequences revealed high homology with rat GAT-2, murine GAT-3 cDNA, human solute carrier family 6 member 13 (SLC6A13), and a human peripheral betaine/GABA transporter. Northern blot analyses demonstrated that the human GABA transporter is expressed strongly in the kidney and to a lesser extent in the liver and brain. The sequence was well matched with human chromosome 12p13.3, suggesting the human GABA transporter contains 14 exons. The above findings confirm the existence of and further characterize a specific GABA transporter in human tissues.Key words: sequence, chromosome, GABA, GABA transporter.

scholarly journals Case reports of unexplained weight loss in autoimmune central neurological syndromes with anti-GAD antibodies

2019 ◽  
Vol 6 (2) ◽  
pp. 5
Author(s):  
James Broadley ◽  
Mastura Monif
Keyword(s):  
Central Nervous System ◽  
Weight Loss ◽  
Neurological Disorders ◽  
Case Reports ◽  
Acid Decarboxylase ◽  
Gad Antibodies ◽  
Unexplained Weight Loss ◽  
Immune Mediated ◽  
Disease Associations ◽  
The Central Nervous System

Glutamic acid decarboxylase (GAD) is becoming increasingly recognised as an antigenic target in autoimmune disorders of the central nervous system. There are currently no reports of weight loss being a manifestation in such disorders. We describe two cases of anti-GAD associated neurological disorders with profound and otherwise unexplained weight loss. Both patients had incomplete response to immunotherapy, as is becoming typical of these disorders. The variable disease associations of anti-GAD antibodies is incompletely understood, and leads us to question whether weight loss in these patients could possibly be immune-mediated.

scholarly journals Cerebellar Ataxia Followed by Stiff Person Syndrome in a Patient with Anti-GAD Antibodies

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Sinali O. Seneviratne ◽  
Katherine A. Buzzard ◽  
Belinda Cruse ◽  
Mastura Monif
Keyword(s):  
Cerebellar Ataxia ◽  
Acid Decarboxylase ◽  
Stiff Person Syndrome ◽  
Gamma Aminobutyric Acid ◽  
Neurological Manifestations ◽  
Rare Occurrence ◽  
Gad Antibodies ◽  
Long Term Follow Up

Anti-GAD antibody syndrome is a result of the production of antibodies against glutamic acid decarboxylase (GAD), the main enzyme responsible for the production of gamma-aminobutyric acid (GABA). Several neurological manifestations including cerebellar ataxia and stiff person syndrome have been reported in association with anti-GAD antibodies. In this paper, we present a case of a young woman with anti-GAD antibodies who initially presented with cerebellar ataxia followed by stiff person syndrome three and a half years later. Having both cerebellar ataxia and stiff person syndrome is a rare occurrence in anti-GAD antibody syndrome. We emphasise the importance of long-term follow-up of patients with anti-GAD antibody syndrome, as delayed neurological manifestations can occur.

Case reports of unexplained weight loss in autoimmune central neurological syndromes with anti-GAD antibodies

2018 ◽  
pp. 1-4
Keyword(s):  
Central Nervous System ◽  
Weight Loss ◽  
Neurological Disorders ◽  
Case Reports ◽  
Acid Decarboxylase ◽  
Gad Antibodies ◽  
Unexplained Weight Loss ◽  
Immune Mediated ◽  
Disease Associations ◽  
The Central Nervous System

Glutamic acid decarboxylase (GAD) is becoming increasingly recognised as an antigenic target in autoimmune disorders of the central nervous system. There are currently no reports of weight loss being a manifestation in such disorders. We describe two cases of anti-GAD associated neurological disorders with profound and otherwise unexplained weight loss. Both patients had incomplete response to immunotherapy, as is becoming typical of these disorders. The variable disease associations of anti-GAD antibodies is incompletely understood, and leads us to question whether weight loss in these patients could possibly be immune-mediated.

POSSIBLE ROLE OF GAMMA-AMINOBUTYRIC ACID SYNTHESIS IN THE MECHANISM OF DEXAMETHASONE FEEDBACK ACTION

1978 ◽  
Vol 77 (1) ◽  
pp. 137-141 ◽  
Author(s):  
Z. ÁCS ◽  
E. STARK
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glutamic Acid Decarboxylase ◽  
Acid Synthesis ◽  
Aminobutyric Acid ◽  
Acid Decarboxylase ◽  
Specific Inhibition ◽  
Gamma Aminobutyric Acid ◽  
The Central Nervous System

Specific inhibition of glutamic acid decarboxylase (GAD, EC 4.1.1.15; the main enzyme involved in the synthesis of γ-aminobutyric acid) by mercaptopropionic acid interferes with the effect of dexamethasone on both the resting and stress-induced secretion of ACTH. It is postulated that dexamethasone may, at least in part, inhibit the secretion of ACTH via the induction of GAD, thereby raising the level of γ-aminobutyric acid in the central nervous system.

scholarly journals Stiff-Person Syndrome: Seeing Past Comorbidities to Reach the Correct Diagnosis

2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
Jared Hicken ◽  
Daniel Ramirez ◽  
Mark Rigby ◽  
Aram Minasian
Keyword(s):  
Correct Diagnosis ◽  
Acid Decarboxylase ◽  
Muscle Rigidity ◽  
African American Female ◽  
Stiff Person Syndrome ◽  
Gamma Aminobutyric Acid ◽  
Axial Muscle ◽  
History Of ◽  
The Central Nervous System ◽  
Psychotic Features

Stiff-person syndrome (SPS) is a rare disorder seen in approximately one in one million people. Although it is rare, the symptoms and findings of a typical case should paint a clear clinical picture for those who are familiar with the disease. The primary findings in SPS include progressive axial muscle rigidity as well as muscle spasms. These symptoms most commonly occur in the setting of antibodies against Glutamic Acid Decarboxylase (GAD), the rate-limiting enzyme in the production of Gamma-Aminobutyric Acid (GABA), which is the primary inhibitory enzyme in the central nervous system. Here, we report the case of a 65-year-old African-American female with a past medical history of hypothyroidism, anxiety, and depression with psychotic features who presented with axial muscle rigidity and lactic acidosis. She had been symptomatic for several months and reported extensive workups performed at two previous hospitals without a definitive diagnosis. A complete neurological and musculoskeletal investigation yielded no positive findings except for the presence of GAD antibodies. The patient was treated with diazepam, tizanidine, and Intravenous Immunoglobulin (IVIG) with significant improvement, thus solidifying the diagnosis of SPS, a rare autoimmune and/or paraneoplastic syndrome.

scholarly journals Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 530
Author(s):  
Oliviero Bruni ◽  
Luigi Ferini-Strambi ◽  
Elena Giacomoni ◽  
Paolo Pellegrino
Keyword(s):  
Gaba Receptors ◽  
Herbal Medicines ◽  
Well Being ◽  
Herbal Remedies ◽  
Gamma Aminobutyric Acid ◽  
Systematic Analysis ◽  
Inhibitory Neurotransmitter ◽  
Alternative Medicines ◽  
Molecular Components ◽  
The Brain

Sleep is an essential component of physical and emotional well-being, and lack, or disruption, of sleep due to insomnia is a highly prevalent problem. The interest in complementary and alternative medicines for treating or preventing insomnia has increased recently. Centuries-old herbal treatments, popular for their safety and effectiveness, include valerian, passionflower, lemon balm, lavender, and Californian poppy. These herbal medicines have been shown to reduce sleep latency and increase subjective and objective measures of sleep quality. Research into their molecular components revealed that their sedative and sleep-promoting properties rely on interactions with various neurotransmitter systems in the brain. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a major role in controlling different vigilance states. GABA receptors are the targets of many pharmacological treatments for insomnia, such as benzodiazepines. Here, we perform a systematic analysis of studies assessing the mechanisms of action of various herbal medicines on different subtypes of GABA receptors in the context of sleep control. Currently available evidence suggests that herbal extracts may exert some of their hypnotic and anxiolytic activity through interacting with GABA receptors and modulating GABAergic signaling in the brain, but their mechanism of action in the treatment of insomnia is not completely understood.

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