Case Report| Volume 54, ISSUE 7, P763-768, October 01, 2003

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



      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 A review of 56 published and unpublished studies of SSADH-deficient patients revealed that 42% manifested behavioral disturbances, whereas 13% (predominantly adults) displayed psychotic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.


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      1. Anderson D, Bottiglieri T, Gibson KM (2002): Pargyline antagonizes the effect of gamma-hydroxybutyrate (GHB) on locomotor activity in the rat (Program No. 749 15). Abstract Viewer/Itinerary Planner. Online at Washington, DC: Society for Neuroscience

      2. Anderson D, Gibson KM, Froestl W, Diaz-Arrastia R, Bottiglieri T (2001): Effect of gamma-hydroxybutyrate (GHB) and GABAB receptor antagonists on locomotor activity and brain dopamine metabolism in the rat. Neurosci Abstracts 27: Program No.971.7

        • Banerjee P.K.
        • Snead O.C.
        Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB).
        J Pharmacol Exp Ther. 1995; 273: 1534-1543
        • Behar K.L.
        • Rothman D.L.
        • Petersen K.F.
        • Hooten M.
        • Delaney R.
        • Petroff O.A.
        • et al.
        Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients.
        Am J Psychiatr. 1999; 156: 952-954
        • Borgen L.A.
        • Cook H.N.
        • Hornfeldt C.S.
        • Fuller D.E.
        Sodium oxybate (GHB) for treatment of cataplexy.
        Pharmacotherapy. 2002; 22: 798-799
        • Bowles T.M.
        • Sommi R.W.
        • Amiri M.
        Successful management of prolonged gamma-hydroxybutyrate and alcohol withdrawal.
        Pharmacotherapy. 2001; 21: 254-257
        • Carai M.A.
        • Colombo G.
        • Brunetti G.
        • Melis S.
        • Serra S.
        • Vacca G.
        • et al.
        Role of GABAB receptors in the sedative/hypnotic effect of gamma-hydroxybutyric acid.
        Eur J Pharmacol. 2001; 428: 315-321
        • Colombo G.
        • Agabio R.
        • Carai M.A.
        • Lobina C.
        • Pani M.
        • Reali R.
        • Gessa G.L.
        Characterization of the discriminative stimulus effects of gamma-hydroxybutyric acid as a means for unraveling the neurochemical basis of gamma-hydroxybutyric acid actions and its similarities to those of ethanol.
        Alcohol. 2000; 20: 237-245
        • Colombo G.
        • Agabio R.
        • Lobina C.
        • Reali R.
        • Gessa G.L.
        Involvement of GABAA and GABAB receptors in the mediation of the discriminative stimulus effects of gamma-hydroxybutyric acid.
        Physiol Behav. 1998; 64: 293-302
        • Colombo G.
        • Gessa G.L.
        Gamma-hydroxybutyric acid in alcohol preference, dependence and withdrawal.
        Addiction Biol. 2000; 5: 389-403
        • De Vivo D.C.
        • Gibson K.M.
        • Resor L.D.
        • Steinschneider M.
        • Aramaki S.
        • Cote L.
        4-Hydroxybutyric acidemia.
        Ann Neurol. 1988; 24: 304
        • Gessa G.L.
        • Agabio R.
        • Carai M.A.M.
        • Lobina C.
        • Pani M.
        • Reali R.
        • Colombo G.
        Mechanism of the antialcohol effect of gamma-hydroxybutyric acid.
        Alcohol. 2000; 20 (abstract): 271-276
        • Gibson K.M.
        • Aramaki S.
        • Sweetman L.
        • Nyhan W.L.
        • De Vivo D.C.
        • Hodson A.K.
        • Jakobs C.
        Stable isotope dilution analysis of 4-hydroxybutyric acid.
        Biomed Environ Mass Spectrom. 1990; 19: 89-93
        • Gibson K.M.
        • Christensen E.
        • Jakobs C.
        • Fowler B.
        • Clarke M.A.
        • Hammersen G.
        • et al.
        The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria).
        Pediatrics. 1997; 99: 567-574
        • Gibson K.M.
        • Goodman S.I.
        • Frerman F.E.
        • Glasgow A.M.
        Succinic semialdehyde dehydrogenase deficiency associated with combined 4-hydroxybutyric and dicarboxylic acidurias.
        J Pediatr. 1989; 114: 607-610
        • Gibson K.M.
        • Hoffmann G.F.
        • Hodson A.K.
        • Bottiglieri T.
        • Jakobs C.
        4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism.
        Neuropediatrics. 1998; 29: 14-22
        • Gibson K.M.
        • Jakobs C.
        Disorders of beta- and gamma-amino acids in free and peptide-linked forms.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill, New York2001: 2079-2105
        • Gibson K.M.
        • Jakobs C.
        • Ogier H.
        • Hagenfeldt L.
        • Eeg-Olofsson K.E.
        • Eeg-Olofsson O.
        • et al.
        Vigabatrin therapy in six patients with succinic semialdehyde dehydrogenase deficiency.
        J Inher Metab Dis. 1995; 18: 143-146
        • Gibson K.M.
        • Schor D.S.M.
        • Gupta M.
        • Guerand W.S.
        • Senephansiri H.
        • Burlingame T.G.
        • et al.
        Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase.
        J Neurochem. 2002; 81: 71-79
        • Gobaille S.
        • Schleef C.
        • Hechler V.
        • Viry S.
        • Aunis D.
        • Maitre M.
        Gamma-hydroxybutyrate increases tryptophan availability and potentiates serotonin turnover in rat brain.
        Life Sci. 2002; 70: 2101-2112
        • Haan E.A.
        • Brown G.K.
        • Mitchell D.
        • Danks D.M.
        Succinic semialdehyde dehydrogenase deficiency—A further case.
        J Inher Metab Dis. 1985; 8: 99
        • Hogema B.M.
        • Gupta M.
        • Senephansiri H.
        • Burlingame T.G.
        • Taylor M.
        • Jakobs C.
        • et al.
        Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase.
        Nat Genet. 2001; 29: 212-216
        • Hyland K.
        Disorders of neurotransmitter metabolism.
        in: Blau N. Duran M. Blaskovics M.E. Gibson K.M. Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. 2nd ed. Springer, Heidelberg2002: 107-122
        • Jakobs C.
        • Smit L.M.E.
        • Kneer J.
        • Michael T.
        • Gibson K.M.
        The first adult case with 4-hydroxybutyric aciduria.
        J Inher Metab Dis. 1990; 13: 341-344
        • Kok R.M.
        • Howells D.W.
        • van den Heuvel C.C.
        • Guerand W.S.
        • Thompson G.N.
        • Jakobs C.
        Stable isotope dilution analysis of GABA in CSF using simple solvent extraction and electron-capture negative-ion mass fragmentography.
        J Inher Metab Dis. 1993; 16: 508-512
        • Larnaout A.
        • Mongalgi M.A.
        • Kaabachi N.
        • Khiari D.
        • Debbabi A.
        • Mebazza A.
        • et al.
        Methylmalonic acidaemia with bilateral globus pallidus involvement. A neuropathological study.
        J Inherit Metab Dis. 1998; 21: 639-644
        • Maitre M.
        The gamma-hydroxybutyrate signalling system in brain.
        Prog Neurobiol. 1997; 51: 337-361
        • Maitre M.
        • Andriamampandry C.
        • Kemmel V.
        • Schmidt C.
        • Hode Y.
        • Hechler V.
        • Gobaille C.
        Gamma-hydroxybutyric acid as a signalling molecule in brain.
        Alcohol. 2000; 20: 277-283
      3. Mehta AK, Gupta M, Gibson KM, Ticku MK (2002): Decreased GHB and GABA receptor binding in succinate semialdehyde dehydrogenase (SSADH:Aldh5a1) deficient mouse brain. Program No. 431.15. Abstract Viewer/Itinerary Planner. Online at Washington, DC: Society for Neuroscience

        • Muller C.
        • Viry S.
        • Miehe M.
        • Andriamampandry C.
        • Aunis D.
        • Maitre M.
        Evidence for a gamma-hydroxybutyrate (GHB) uptake by rat brain synaptic vesicles.
        J Neurochem. 2002; 80: 899-904
        • Nava F.
        • Carta G.
        • Bortolato M.
        • Gessa G.L.
        Gamma-hydroxybutyric acid and baclofen decrease extracellular acetylcholine levels in the hippocampus via GABAB receptors.
        Eur J Pharmacol. 2001; 430: 261-263
        • Neu P.
        • Seyfert S.
        • Brockmoeller J.
        • Dettling M.
        • Marx P.
        Neuroleptic malignant syndrome in a patient with succinic semialdehyde dehydrogenase deficiency.
        Pharmacopsychiatr. 2002; 35: 26-28
        • Pearl P.L.
        • Tuchman M.
        • Gibson K.M.
        • Lavenstein B.L.
        • McClintock W.M.
        • Gropman A.
        • et al.
        Succinic semialdehyde dehydrogenase deficiency.
        Ann Neurol. 2001; 50: S115
        • Schneir A.B.
        • Ly B.T.
        • Clark R.F.
        A case of withdrawal from the GHB precursors gamma-butyrolactone and 1,4-butanediol.
        J Emerg Med. 2001; 21: 31-33
        • Slocum R.H.
        • Cummings J.G.
        Amino acid analysis of physiological samples.
        in: Hommes F.A. Techniques in Diagnostic Human Biochemical Genetics. 1st ed. Wiley-Liss, New York1991: 87-126
        • Snead O.C.
        Evidence for a G protein-coupled gamma-hydroxybutyric acid receptor.
        J Neurochem. 2000; 75: 1986-1996
        • Sonnewald U.
        • McKenna M.
        Metabolic compartmentation in cortical synaptosomes.
        Neurochem Res. 2002; 27: 43-50
        • Wallace R.H.
        • Marini C.
        • Petrou S.
        • Harkin L.A.
        • Bowser D.N.
        • Panchal R.G.
        • et al.
        Mutant GABAA receptor gamma2-subunit in childhood absence epilepsy and febrile seizures.
        Nature Genet. 2001; 28: 49-52