Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrahydroisoxazolopyridinol (THIP), a GABA receptor agonist, gamma-acetylenic-GABA(GAG) and gamma-vinyl-GABA(GVG), two GABA transaminase inhibitors were given in single parenteral doses to three Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol. High doses of THIP temporarily abolished dyskinesias but also caused bradykinesia, ataxia, dystonia and myoclonic jerks. GAG and GVG reduced dyskinesias to a lesser extent and with fewer side effects. Whether the observed antidyskinetic effect is secondary to the concomitant general toxic effects or if these drugs have a specific antidyskinetic action remains an open question.
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PMID:GABA agonists in cebus monkeys with neuroleptic-induced persistent dyskinesias. 289 37

The irreversible GABA transaminase inhibitor vigabatrin (VGB) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. The median number of CPS per month decreased from 11.0 to 5.0 after addition of VGB, and 51% of patients had a 50% or greater decrease in CPS frequency (p less than 0.001). Side effects (principally drowsiness, ataxia, and headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on VGB, side effects significantly interfered with functioning in only 13% of patients, and the efficacy:toxicity ratio warranted continued administration in 74% of patients. Coadministration of VGB resulted in a mean decrease of 20% in phenytoin serum concentration (p less than 0.001). Sixty-six patients with a favorable response to VGB during the single-blind study have been followed for a median of 16.7 months on VGB. No serious systemic or neurologic toxicity has been detected, and most patients have retained their initial favorable CPS control.
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PMID:Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up. 380 98

Pyrithiamine, a thiamine phosphokinase inhibitor, was fed to rats on a thiamine-deficient diet, producing weight loss, ataxia and loss of righting reflex in 10 days. Some rats were then sacrificed; others were returned to a normal diet, to be sacrificed only when their weight had returned to pre-experimental levels. Rats were sacrificed for assay of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in homogenates of eight brain regions or were perfused for gamma-aminobutyric acid transaminase (GABA-T) histochemistry. GAD activity was significantly reduced in symptomatic rats in the thalamus greater than cerebellum greater than midbrain greater than pons/medulla. GABA-T staining was similarly reduced, with greatest losses in the thalamus greater than inferior colliculus greater than pons greater than medulla. ChAT activity was not significantly altered in any brain area. Following return to a normal diet. GAD activity was significantly recovered in all areas except the thalamus. GABA-T staining recovered, at least partially, in all areas affected.
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PMID:GABA-transaminase and glutamic acid decarboxylase changes in the brain of rats treated with pyrithiamine. 408 35

Seven patients with Huntington disease were treated with aminooxyacetic acid (AOAA), an inhibitor of gamma-aminobutyric acid aminotransferase (GABA-T), in an effort to alleviate symptoms by increasing brain GABA content. AOAA was given orally in a placebo-controlled crossover trial in which patients, relatives, and three of the evaluating physicians remained blind. Toxic symptoms occurred in all seven patients when AOAA dosage was increased beyond 2 mg per kilogram per day, and included drowsiness, ataxia, seizures, and psychotic behavior. In five patients who took AOAA for 4 months, no clinical improvement was observed. Biochemical monitoring showed that less inhibition of hepatic GABA-T enzyme activity was achieved than in patients treated with large doses of isoniazid. Results of this trial neither support nor exclude the possible therapeutic usefulness of increasing brain GABA content in Huntington disease.
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PMID:Failure of aminooxyacetic acid therapy in Huntington disease. 644 91

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included.
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PMID:Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency. 1289 56

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal-recessively inherited disorder of gamma-aminobutyrate (GABA) catabolism characterized by ataxia and epilepsy. Since SSADH is responsible for GABA break-down downstream of GABA transaminase, patients manifest high extracellular levels of GABA, as well as the GABA(B) receptor (GABA(B)R) agonist gamma-hydroxybutyrate (GHB). SSADH knockout (KO) mice display absence seizures, which progress into lethal tonic-clonic seizures at around 3weeks of age. It is hypothesized that desensitization of GABA(B)Rs plays an important role in the disease, although detailed studies of pre- and postsynaptic GABA(B)Rs are not available. We performed patch-clamp recordings from layer 2/3 pyramidal neurons in neocortical brain slices of wild-type (WT) and SSADH KO mice. Electrical stimulation of GABAergic fibers during wash in of the GABA(B)R agonist baclofen revealed no difference in presynaptic GABA(B)R mediated inhibition of GABA release between WT and SSADH KO mice. In contrast, a significant decrease in postsynaptic baclofen-induced potassium currents was seen in SSADH KO mice. This reduction was unlikely to be caused by accumulation of potassium, GABA or GHB in the brain slices, or an altered expression of regulators of G-protein signaling (RGS) proteins. Finally, adenosine-induced potassium currents were also reduced in SSADH KO mice, which could suggest heterologous desensitization of the G-protein dependent effectors, leading to a reduction in G-protein coupled inwardly rectifying potassium (GIRK) channel responses. Our findings indicate that high GABA and GHB levels desensitize postsynaptic, but not certain presynaptic, GABA(B)Rs, promoting a decrease in GIRK channel function. These changes could contribute to the development of seizures in SSADH KO mice and potentially also in affected patients.
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PMID:Plasticity of postsynaptic, but not presynaptic, GABAB receptors in SSADH deficient mice. 2057 Jun 75