sodium-oxybate and Ataxia

The U.S. Consumer Product Safety Commission announced a recall of Aqua Dots (Spin Master Ltd.; Toronto, Canada) on November 7, 2007 due to children becoming ill after swallowing beads from these toy craft kits. Reports suggested that the beads contained 1,4-butanediol (1,4-BD), a precursor to gamma-hydroxybutyrate (GHB), rather than the intended, but more expensive 1,5-pentanediol (1,5-PD). We measured the 1,4-BD and 1,5-PD content of Aqua Dots beads to determine if 1,5-PD had been completely substituted with 1,4-BD by the manufacturer, and if the reported clinical effects from swallowing Aqua Dots beads were consistent with the estimated ingested 1,4-BD dose.. In vitro bench research using gas chromatography-mass spectroscopy (GC-MS) was performed. Dilute samples of pure 1,4-BD and 1,5-PD in water were used for the calibration of the GC-MS instrument. We then soaked Aqua Dots beads in water for varying durations, and the resultant solutions were analyzed for 1,4-BD and 1,5-PD content.. Aqua Dots beads weighed 79.3 mg each (+/- 0.6 mg, SD), and contained 13.7% (+/- 2.4%, SD) 1,4-BD by weight; this corresponds to a 1,4-BD content of 10.8 mg (+/- 1.9 mg, SD) per bead. No 1,5-PD was detected in any beads.. Aqua Dots beads contained a surprisingly high amount (nearly 14%) of extractable 1,4-BD. No 1,5-PD was detected, corroborating reports that this chemical had been completely replaced with a substitute that is metabolized into GHB after ingestion. Reports of ataxia, vomiting, seizure activity, and self-limited coma in children are consistent with the ingestion of several dozen Aqua Dots beads.

Topics: Ataxia; Butylene Glycols; Calibration; Child; Coma; Consumer Product Safety; Gas Chromatography-Mass Spectrometry; Glycols; Humans; Pentanes; Play and Playthings; Seizures; Sodium Oxybate; Solubility; Vomiting

Succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria) is a rare neurometabolic disorder of gamma-aminobutyric acid degradation. While neurological manifestations, such as developmental delay, are typical during infancy, limited data are available on adolescent and adult symptomatology.. We overview the phenotype of 33 adolescents and adults (10.1-39.5 years of age, mean: 17.1 years, 48% females) with SSADH deficiency. For this purpose, we applied a database with systematic questionnaire-based follow-up data.. Sixty-six percent of patients (n=21) presented by 6 months of age, 14% from 6-12 months of age, 5% from 1-2 years of age, and 14% from 2-4 years of age, mean age at first symptoms was 11+/-12 months. However, mean age at diagnosis was 6.6+/-6.4 years of age. Presenting symptoms encompassed motor delay, hypotonia, speech delay, autistic features, seizures, and ataxia. Eighty-two percent demonstrated behavioral problems, such as attention deficit, hyperactivity, anxiety, or aggression, and 33% had >or=3 behavior problems. Electroencephalograms showed background slowing or epileptiform discharges in 40% of patients. Treatment approaches are then summarized.. The variable phenotype in SSADH deficiency suggests the likelihood that this disease may be under-diagnosed. Families of patients with SSADH deficiency should be counseled and supported regarding the anticipated persistence of various neuropsychiatric symptoms into adulthood.

Topics: Adolescent; Adult; Amino Acid Metabolism, Inborn Errors; Ataxia; Behavioral Symptoms; Child; Child, Preschool; Cohort Studies; Developmental Disabilities; Electroencephalography; Female; Follow-Up Studies; gamma-Aminobutyric Acid; Humans; Intellectual Disability; Language Development Disorders; Male; Seizures; Sleep Wake Disorders; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Surveys and Questionnaires

Gamma-hydroxybutyrate (GHB) is a gamma-aminobutyric acid (GABA) analog that is used to treat narcolepsy but that is also abused. GHB has many actions in common with the GABA(B) receptor agonist baclofen, but their underlying GABA(B) receptor mechanisms may be different.. The aim of this study is to further investigate a possible differential role of glutamate in GABA(B) receptor-mediated effects of GHB and baclofen.. The experiments examined the effects of non-competitive antagonists at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors on GHB-induced catalepsy and compared these effects with those on baclofen-induced catalepsy.. In C57BL/6J mice, ketamine, phencyclidine (PCP), and dizocilpine (MK-801) all enhanced GHB-induced catalepsy. They did so with a potency order (i.e., MK-801 > PCP > ketamine) consistent with their relative potencies as NMDA antagonists but not as inhibitors of dopamine or organic cation transporters. Ketamine, PCP, and MK-801 enhanced catalepsy along inverted U-shaped dose-response curves likely because higher doses affected motor coordination, which limited their catalepsy-enhancing effects. Doses that were maximally effective to enhance GHB-induced catalepsy did not affect the cataleptic effects of baclofen.. The finding that NMDA receptor antagonists enhance the cataleptic effects of GHB but not those of baclofen is further evidence that the GABA(B) receptor mechanisms mediating the effects of GHB and GABA(B) agonists are not identical. Differential interactions of glutamate with the GABA(B) receptor mechanisms mediating the effects of GHB and baclofen may explain why GHB is effective for treating narcolepsy and is abused, whereas baclofen is not.

Topics: Anesthetics, Intravenous; Animals; Area Under Curve; Ataxia; Baclofen; Catalepsy; Data Interpretation, Statistical; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Male; Mice; Mice, Inbred C57BL; Muscle Relaxants, Central; Phencyclidine; Receptors, GABA-B; Receptors, N-Methyl-D-Aspartate; Sodium Oxybate

GABA(B) receptor agonists produce hypothermia and motor incoordination. Two GABA(B(1)) receptor subunit isoforms exist, but because of lack of specific molecular or pharmacological tools, the relevance of these isoforms in controlling basal body temperature, locomotor activity, or in vivo responses to GABA(B) receptor agonists has been unknown. Here, we used mice deficient in the GABA(B(1a)) and GABA(B(1b)) subunit isoforms to examine the influence of these isoforms on both baseline motor behavior and body temperature and on the motor-incoordinating and hypothermic responses to the GABA(B) receptor agonists l-baclofen and gamma-hydroxybutyrate (GHB). GABA(B(1b))(-/-) mice were hyperactive in a novel environment and showed slower habituation than either GABA(B(1a))(-/-) or wild-type mice. GABA(B(1b))(-/-) mice were hyperactive throughout the circadian dark phase. Hypothermia in response to l-baclofen (6 and 12 mg/kg) or GHB (1 g/kg), baclofen-induced ataxia as determined on the fixed-speed Rotarod, and GHB-induced hypolocomotion were significantly, but for the most part similarly, attenuated in both GABA(B(1a))(-/-) and GABA(B(1b))(-/-) mice. We conclude that l-baclofen and GHB are nonselective for either GABA(B(1)) receptor isoform in terms of in vivo responses. However, GABA(B(1)) receptor isoforms have distinct and different roles in mediating locomotor behavioral responses to a novel environment. Therefore, GABA(B(1a)) and GABA(B(1b)) isoforms are functionally relevant molecular variants of the GABA(B(1)) receptor subunit, which are differentially involved in specific neurophysiological processes and behaviors.

Topics: Animals; Ataxia; Baclofen; Body Temperature; Darkness; Female; GABA Agonists; GABA-B Receptor Agonists; Hypothermia; Isomerism; Light; Male; Mice; Mice, Knockout; Motor Activity; Postural Balance; Receptors, GABA-B; Sensation Disorders; Sex Characteristics; Sodium Oxybate

In the present study, the development of tolerance to the motor impairing effects of gamma-hydroxybutyric acid (GHBA) and ethanol was compared (Experiment 1). Rats were required to perform a motor coordination task daily shortly after ethanol (3.5 g/kg) and GHBA (1.0 g/kg) administration for 9 consecutive days. Tolerance to the motor impairing effects of ethanol and GHBA developed to a similar extent but with different patterns. On the tenth day, the presence of cross-tolerance to the motor impairing effects of GHBA and ethanol was assessed (Experiment 2). Administration of 1.0 g/kg GHBA produced a significantly lower impairment in ethanol-tolerant rats than in ethanol-naive rats. Similarly, administration of 3.5 g/kg ethanol induced a significantly lower impairment in GHBA-tolerant rats than in GHBA-naive rats. The presence of cross-tolerance between GHBA and ethanol is discussed in terms of common pathways of neuroadaptation to chronic GHBA and ethanol.

Topics: Animals; Ataxia; Dose-Response Relationship, Drug; Drug Tolerance; Ethanol; Male; Postural Balance; Rats; Rats, Sprague-Dawley; Sodium Oxybate

A child presenting with mild psychomotor retardation, hypotonia, microcephaly and hyperkinesis is described. Urinary organic acid analysis by combined gas chromatography-mass spectrometry revealed 4-hydroxybutyric aciduria. Succinic semialdehyde dehydrogenase activity in extracts of white cells derived from the patient was less than 10% of control values.

Topics: Ataxia; Child; Female; Humans; Hydroxybutyrates; Hyperkinesis; Intellectual Disability; Muscle Hypotonia; Seizures; Sodium Oxybate

Topics: Adolescent; Ataxia; Child; Female; gamma-Aminobutyric Acid; Humans; Hydroxybutyrate Dehydrogenase; Hydroxybutyrates; Male; Metabolism, Inborn Errors; Sodium Oxybate