sodium-oxybate and Developmental-Disabilities

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

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation.. Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements.. Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

Topics: Amino Acid Metabolism, Inborn Errors; Aminobutyrates; Child; Developmental Disabilities; Epilepsy; gamma-Aminobutyric Acid; Humans; Seizures; Sodium Oxybate

SSADH deficiency (SSADHD) is a rare autosomal recessively inherited metabolic disorder. It is associated with mutations of ALDH5A1 gene, coding for the homotetrameric enzyme SSADH. This enzyme is involved in γ-aminobutyric acid (GABA) catabolism, since it oxidizes succinic semialdehyde (SSA) to succinate. Mutations in ALDH5A1 gene result in the abnormal accumulation of γ-hydroxybutyrate (GHB), which is pathognomonic of SSADHD. In the present report, diagnosis of SSADHD in a three-month-old female was achieved by detection of high levels of GHB in urine. Sequence analysis of ALDH5A1 gene showed that the patient was a compound heterozygote for c.1226G > A (p.G409D) and the novel missense mutation, c.1498G > C (p.V500 L). By ALDH5A1 gene expression in transiently transfected HEK293 cells and enzyme activity assays, we demonstrate that the p.V500 L mutation, despite being conservative, produces complete loss of enzyme activity. In silico protein modelling analysis and evaluation of tetramer destabilizing energies suggest that structural impairment and partial occlusion of the access channel to the active site affect enzyme activity. These findings add further knowledge on the missense mutations associated with SSADHD and the molecular mechanisms underlying the loss of the enzyme activity.

Topics: Amino Acid Metabolism, Inborn Errors; Binding Sites; Computer Simulation; Developmental Disabilities; DNA; Female; gamma-Aminobutyric Acid; HEK293 Cells; Heterozygote; Humans; Infant; Models, Molecular; Mutation; Mutation, Missense; Pedigree; Sodium Oxybate; Succinate-Semialdehyde Dehydrogenase

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

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