sodium-oxybate and Metabolism--Inborn-Errors

SSADH deficiency, a rare inborn error of human metabolism, disrupts the normal metabolism of the inhibitory neurotransmitter GABA. In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Clinical and bio-chemical findings in patients are contrasted with existing neuropharmacologic data on GHB in animals and men. We conclude that GHB contributes to the pathogenesis of SSADH deficiency; whether this effect is mediated by GHB, by GABA following metabolic interconversion, or via synergistic mechanisms by both compounds, remains to be determined. An animal model of SSADH deficiency should further define the role of GHB in the pathogenesis of SSADH deficiency, and provide a useful vehicle for the evaluation of new therapeutic intervention.

Topics: Aldehyde Oxidoreductases; Animals; Anticonvulsants; Child; Developmental Disabilities; Disease Models, Animal; Electroencephalography; gamma-Aminobutyric Acid; Humans; Illicit Drugs; Metabolism, Inborn Errors; Phenotype; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Vigabatrin

Topics: Biomarkers; Cardiomyopathy, Dilated; Central Nervous System Diseases; Diagnosis, Differential; gamma-Aminobutyric Acid; Glutarates; Humans; Metabolism, Inborn Errors; Muscular Diseases; Prognosis; Sodium Oxybate

We report two adult patients with succinic semialdehyde dehydrogenase deficiency, manifesting as gamma-hydroxybutyric aciduria. For both, the clinical presentation included significant behavioral disturbances and psychosis (hallucinations, disabling anxiety, aggressive behavior, and sleep disorder), leading to multiple therapeutic attempts. Intervention with benzodiazepines appeared most efficacious, resulting in decreased aggression and agitation and improvement in anxiety. A review of 56 published and unpublished studies of SSADH-deficient patients revealed that 42% manifested behavioral disturbances, whereas 13% (predominantly adults) displayed psychotic symptomatology. To explore the potential biochemical basis of these behavioral abnormalities, we studied cerebrospinal fluid derived from 13 patients, which revealed significantly elevated GHB (65- to 230-fold), high free and total GABA (up to threefold), and low glutamine. Although within the control range, homovanillic and 5-hydroxyindoleacetic acids (end products of dopamine and serotonin metabolism, respectively) showed a significant linear correlation with increasing GHB concentration, suggesting enhanced dopamine and serotonin turnover. We conclude that elevated GABA combined with low glutamine suggest disruption of the glial-neuronal glutamine/GABA/glutamate shuttle necessary for replenishment of neuronal neurotransmitters, whereas altered dopamine and serotonin metabolism may be causally linked to the hyperkinetic movement disorders and behavioral disturbances seen in SSADH-deficient patients.

Topics: Adult; Aldehyde Oxidoreductases; Atrophy; Cerebellum; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Female; gamma-Aminobutyric Acid; Globus Pallidus; Glutamic Acid; Hallucinations; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Intellectual Disability; Magnetic Resonance Imaging; Male; Metabolism, Inborn Errors; Sodium Oxybate; Statistics as Topic; Succinate-Semialdehyde Dehydrogenase

To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients.. The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families.. The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients.. Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

Topics: Adolescent; Adult; Aldehyde Oxidoreductases; Child; Child, Preschool; Developmental Disabilities; Diagnosis, Differential; Enzyme Inhibitors; Female; gamma-Aminobutyric Acid; Humans; Infant; Intellectual Disability; Language Development Disorders; Male; Metabolism, Inborn Errors; Motor Skills; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Vigabatrin

Topics: Adolescent; Aldehyde Oxidoreductases; Child; Family; Female; Humans; Intellectual Disability; Leukocytes; Male; Metabolism, Inborn Errors; New Caledonia; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase

Topics: 4-Aminobutyrate Transaminase; Aldehyde Oxidoreductases; Brain Diseases, Metabolic; GABA Antagonists; gamma-Aminobutyric Acid; Humans; Metabolism, Inborn Errors; Seizures; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Treatment Outcome; Vigabatrin

We report our cumulative experience for the prenatal diagnosis of succinic semialdehyde dehydrogenase (SSADH) deficiency in seven 'at-risk' pregnancies from four unrelated families. Prenatal diagnosis was performed by determination of 4-hydroxybutyric acid (4-HBA) concentration in amniotic fluid using isotope-dilution gas chromatography-mass spectrometry in conjunction with assay of SSADH activity in biopsied chorionic villus and/or cultured amniocytes. In three of four pregnancies predicted as affected, confirmation was obtained by demonstration of deficient SSADH activity in fetal tissues. Our results suggest that determination of 4-HBA concentration in amniotic fluid combined with enzyme determination in cultured or biopsied tissue represents a reliable method for the prenatal diagnosis of SSADH deficiency.,

Topics: Aldehyde Oxidoreductases; Amniotic Fluid; Female; Humans; Immunoblotting; Metabolism, Inborn Errors; Pregnancy; Prenatal Diagnosis; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase

The number of known inherited metabolic disorders resulting in an organic aciduria has increased steadily over the past two decades. Prompt and reliable detection is both clinically and technically demanding but is essential if appropriate treatment is to be undertaken. This is the first study of laboratory performance in the detection of these disorders to be undertaken in the UK. Some conditions were accurately identified by most laboratories: for example for maple syrup urine disease, 12 of 14 laboratories provided an appropriate response and medium chain acyl-CoA dehydrogenase deficiency was correctly identified by 15 of 17 laboratories. However, accuracy of detection was poorer for other conditions: for example, only eight of 17 laboratories detected tyrosinaemia type 1 and nine of 18 laboratories detected 4-hydroxybutyric aciduria. The strongest correlation with good performance was obtained by comparison with the extent of peak identification: r = 0.62, P = 0.002. The need for regular attendance at scientific symposia was also supported by a weaker positive correlation with the average score achieved, P = 0.08. Evidence also suggested that some of the laboratories with a low workload performed less well. No significant difference in performance could be demonstrated between the 17 laboratories who used gas chromatography-mass spectrometry and the six participants who used gas chromatography alone.

Topics: Acyl-CoA Dehydrogenase; Acyl-CoA Dehydrogenases; Carboxylic Acids; Chromatography, Gas; Gas Chromatography-Mass Spectrometry; Glutarates; Humans; Metabolism, Inborn Errors; Methylmalonic Acid; Quality Control; Sodium Oxybate; United Kingdom

Topics: Aldehyde Oxidoreductases; Anticonvulsants; Child; Female; gamma-Aminobutyric Acid; Gas Chromatography-Mass Spectrometry; Humans; Metabolism, Inborn Errors; Nervous System Diseases; Phenotype; Sodium Oxybate; Spectrometry, Fluorescence; Succinate-Semialdehyde Dehydrogenase; Vigabatrin

Topics: Aldehyde Oxidoreductases; Amniocentesis; Amniotic Fluid; Female; Fetal Diseases; Humans; Metabolism, Inborn Errors; Pregnancy; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase

Topics: Adult; Child; Child, Preschool; Female; Humans; Infant; Metabolism, Inborn Errors; Pedigree; Sodium Oxybate

Topics: Aldehyde Oxidoreductases; Aminocaproates; Anticonvulsants; Child, Preschool; Humans; Male; Metabolism, Inborn Errors; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Vigabatrin

Topics: Aldehyde Oxidoreductases; Child; Child, Preschool; Dicarboxylic Acids; Female; Humans; Hydroxybutyrates; Infant; Metabolism, Inborn Errors; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase

Topics: Aldehyde Oxidoreductases; Humans; Hydroxybutyrates; Metabolism, Inborn Errors; Muscle Hypotonia; Psychomotor Disorders; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase; Syndrome

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

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

Topics: Carboxy-Lyases; Female; gamma-Aminobutyric Acid; Genes, Recessive; Humans; Hydroxybutyrate Dehydrogenase; Hydroxybutyrates; Male; Metabolism, Inborn Errors; Methylmalonyl-CoA Decarboxylase; Sodium Oxybate

A coupled assay using [14C]4-aminobutyric acid and a direct assay using [14C]succinic semialdehyde have been designed to assay te activity of succinic semialdehyde dehydrogenase in a patient with 4-hydroxybutyric aciduria and family members. In the coupled assay less than 3% of control succinic semialdehyde dehydrogenase activity was found in lysates of lymphocytes isolated from whole blood of the patient. In the direct assay there was no detectable activity of the enzyme in lysates of isolated lymphocytes or cultured lymphoblasts. Results indicated the parents to be heterozygous carriers carriers of the abnormal gene, consistent with an autosomal recessive inheritance.

Topics: Adult; Carbon Radioisotopes; Female; Follow-Up Studies; Humans; Hydroxybutyrate Dehydrogenase; Hydroxybutyrates; Lymphocytes; Male; Metabolism, Inborn Errors; Sodium Oxybate