Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (Gamma-Hydroxybutyric aciduria)

• Published in: Biological psychiatry (1969) Vol. 54; no. 7; pp. 763 - 768
• Main Authors: Gibson, K.Michael, Gupta, Maneesh, Pearl, Phillip L., Tuchman, Mendel, Vezina, L.Gilbert, Snead, O.Carter, Smit, Leo M.E., Jakobs, Cornelis
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.2003; Elsevier Science
• Subjects: 5-hydroxyindoleacetic acid; Adult; Adult and adolescent clinical studies; Aldehyde Oxidoreductases - cerebrospinal fluid; Aldehyde Oxidoreductases - deficiency; Atrophy - pathology; Behavioral disturbance; benzodiazepines; Biological and medical sciences; Cerebellum - anatomy & histology; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; dopamine; Female; GABA; gamma-Aminobutyric Acid - metabolism; Globus Pallidus - anatomy & histology; Glutamic Acid - metabolism; Hallucinations; homovanillic acid; Homovanillic Acid - cerebrospinal fluid; Humans; Hydroxyindoleacetic Acid - cerebrospinal fluid; Intellectual Disability; Investigative techniques, diagnostic techniques (general aspects); Magnetic Resonance Imaging - instrumentation; Magnetic Resonance Imaging - methods; Male; Medical sciences; Metabolism, Inborn Errors - cerebrospinal fluid; Metabolism, Inborn Errors - physiopathology; Metabolism, Inborn Errors - psychology; Nervous system; Other psychotic disorders; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; psychosis; serotonin; Sodium Oxybate - urine; Statistics as Topic; Succinate-Semialdehyde Dehydrogenase; succinic semialdehyde dehydrogenase deficiency; γ-hydroxybutyric acid (GHB); serotonin; 5-hydroxyindoleacetic acid; benzodiazepines; succinic semialdehyde dehydrogenase deficiency; GABA; homovanillic acid; γ-hydroxybutyric acid (GHB); dopamine; psychosis; Behavioral disturbance; Human; Dopamine; Pathophysiology; Serotonin; Enzyme; Etiopathogenesis; Exploration; Nuclear magnetic resonance imaging; Behavioral disorder; Case study; Psychosis; Succinate-semialdehyde dehydrogenase; Medical imagery; Adult; Benzodiazepine derivatives; Oxidoreductases; Neurotransmission
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/S0006-3223(03)00113-6

We report two adult patients with succinic semialdehyde dehydrogenase deficiency, manifesting as γ-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.