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

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

GHB is a naturally occurring compound in the central nervous system (CNS) whose tissue concentration are highly increased during drug abuse and in the inherited deficiency of succinic semialdehyde dehydrogenase (SSADH) activity. SSADH deficiency is a neurometabolic-inherited disorder of the degradation pathway of gamma-aminobutyric acid (GABA). It is biochemically characterized by increased concentrations of gamma-hydroxybutyric acid (GHB) in tissues, cerebrospinal fluid (CSF), blood and urine of affected patients. Clinical manifestations are variable, ranging from mild retardation of mental, motor, and language development to more severe neurological symptoms, such as hypotonia, ataxia and seizures, whose underlying mechanisms are practically unknown. In the present study, the in vitro and in vivo effects of GHB was investigated on some parameters of oxidative stress, such as chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR), as well as the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) in homogenates from cerebral cortex of 15-day-old Wistar rats. In vitro, GHB significantly increased chemiluminescence and TBA-RS levels, while TRAP and TAR measurements were markedly diminished. In contrast, the activities of the antioxidant enzymes SOD, CAT and GPX were not altered by GHB in vitro. Acute administration of GHB provoked a significant enhance of TBA-RS levels and a decrease of TRAP and TAR measurements. These results indicate that GHB induces oxidative stress by stimulating lipid peroxidation and decreasing the non-enzymatic antioxidant defenses in cerebral cortex of young rats. If these effects also occur in humans, it is possible that they might contribute to the brain damage found in SSADH-deficient patients and possibly in individuals who consume GHB or its prodrug gamma-butyrolactone.
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PMID:Gamma-hydroxybutyric acid induces oxidative stress in cerebral cortex of young rats. 1719 55

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound in the central nervous system (CNS) whose tissue concentration are highly increased in the neurometabolic-inherited deficiency of succinic semialdehyde dehydrogenase (SSADH) activity or due to intoxication. SSADH deficiency is biochemically characterized by increased concentrations of GHB in tissues, cerebrospinal fluid, blood and urine of affected patients. Clinical manifestations are variable and include retardation of mental, motor, and language development along with other neurological symptoms, such as hypotonia, ataxia and seizures, whose underlying mechanisms are practically unknown. The precursor of GHB, 1,4-butanediol (1,4-BD) has been used to study the mechanisms of in vivo GHB neurotoxicity. Therefore, in the present work, the effect of acute administration of 20 or 120 mg/Kg 1,4-BD was investigated on various parameters of oxidative stress, such as spontaneous chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total antioxidant reactivity (TAR), sulfhydryl and protein carbonyl contents, as well as the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in homogenates from cerebral cortex of 14-day-old Wistar rats. Acute administration of 120 mg/Kg 1,4-BD significantly increased spontaneous chemiluminescence and TBA-RS levels, while TAR measurement was markedly diminished, whereas injection of a lower dose (20 mg/Kg) did not change the parameters examined. Other parameters of oxidative stress evaluated were not affected by administration of 1,4-BD. These results indicate that 1,4-BD induces in vivo oxidative stress by stimulating lipid peroxidation and decreasing the non-enzymatic antioxidant defenses in cerebral cortex of young rats. If these effects also occur in humans, it is possible that they might contribute to the brain damage found in SSADH-deficient patients and possibly in individuals intoxicated by GHB or its prodrugs (gamma-butyrolactone or 1,4-BD).
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PMID:Effects of 1,4-butanediol administration on oxidative stress in rat brain: study of the neurotoxicity of gamma-hydroxybutyric acid in vivo. 1929 10