title: Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development.
abstract: BACKGROUND
  SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1); gamma-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development.
  
  
  METHODS
  Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10-13, 14-15, 16-17, 18-19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5-15 subjects, Aldh5a1+/+ and Aldh5a1-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95th centile.
  
  
  RESULTS
  GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA.
  
  
  CONCLUSIONS
  Our findings indicate early GABAergic alterations in Aldh5a1-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Children's Hospital & the University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. eew.jansen@vumc.nl
authors.forename: Erwin E W
authors.initials: EE
authors.lastname: Jansen
authors.forename: Eduard
authors.initials: E
authors.lastname: Struys
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hager
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010795:Phthalic Acids / Q000378:metabolism; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D010795:Phthalic Acids; D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C036016:4,5-dihydroxyphthalic acid; D050644:Succinate-Semialdehyde Dehydrogenase