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Cited by 41Metabolism and Genetic DisordersAmino Acid Enzymes and MetabolismMetabolomics and Mass Spectrometry Studies

Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development

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Jansen, Erwin EW, Struys, Eduard, Jakobs, Cornelis, Hager, Elizabeth, Snead, O Carter, Gibson, K Michael·2008·BMC Developmental Biology
DOI 10.1186/1471-213x-8-112PMC PMC2642797
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Abstract

Background: SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1); γ-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 95 th 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. Conclusion: 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.

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  • Early and sustained disruptions of GABA signaling are likely a key factor of perturbed oligodendrocyte development and faulty myelination in SSADH deficiency.

    “As GABA already accumulate during embryonic development in SSADH deficiency (Jansen et al., 2008), early and sustained disruptions of GABA signaling is likely a key factor of perturbed oligodendrocyte development and faulty myelination in SSADH deficiency.”

    From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Jansen et al., 2008

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Research works printed but not linked: 41

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Authors
Jansen, E. E., Struys, E., Jakobs, C., Hager, E., Snead, O. C., & Gibson, K. M.
Affiliations
  • University of Pittsburgh (US)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • University of Toronto (CA)
Corresponding author
Gibson, K Michael
ORCID
Venue
BMC Developmental Biology
Publisher
Springer Science and Business Media LLC
Published
2008-11-28
Volume
8
Issue
1
Pages
112-112
ISSN
1471-213X (ISSN-L)
DOI
10.1186/1471-213x-8-112
PMC
PMC2642797
OpenAlex
W2128482306
Cited by
41
References
0
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 4 · 2021: 1 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 2
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS040270, NS 40270-07)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
ALDH5A1, gamma-hydroxybutyric acid, GABA metabolism, homocarnosine, D-2-hydroxyglutarate, embryonic development, globus pallidus, amniotic fluid
MeSH terms
Amniotic Fluid, Animals, Animals, Newborn, Embryo, Mammalian, Female, gamma-Aminobutyric Acid, Glutamine, Humans, Male, Mice, Inbred C57BL, Phthalic Acids, Time Factors, Mice, Knockout, Neurotransmitter Agents, Glutamic Acid, Succinate-Semialdehyde Dehydrogenase, Mice

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