d-2-Hydroxyglutaric aciduria in three patients with proven SSADH deficiency: Genetic coincidence or a related biochemical epiphenomenon?

E. A. Struys, N. M. Verhoeven, G. S. Salomons, J. Berthelot, C. Vianay-Saban, S. Chabrier, J. A. Thomas, Anne Tsai, K. M. Gibson, C. Jakobs

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency and d-2-hydroxyglutaric aciduria (d-2-HGA) are rare inborn errors of metabolism primarily revealed by urinary organic acid screening. Three patients with proven SSADH deficiency excreted, in addition to GHB considerable amounts of d-2-HG. We examined whether these patients suffered from two inborn errors of metabolism by measuring d-2-HG concentrations in the culture medium of cells from these patients. In addition, mutation analysis of the d-2-hydroxyglutarate dehydrogenase gene was performed. Normal concentrations of d-2-HG were measured in the culture media of fibroblasts or lymphoblasts derived from the three patients. In one patient, we found a heterozygous likely pathogenic mutation in the d-2-hydroxyglutarate dehydrogenase gene. These combined results argue against the hypothesis that the patients are affected with "primary" d-2-HGA in combination with their SSADH deficiency. Moderately increased levels of d-2-HG were also found in urine, plasma, and cerebrospinal fluid samples derived from 12 other patients with SSADH deficiency, revealing that d-2-HG is a common metabolite in this disease. The increase of d-2-HG in SSADH deficiency can be explained by the action of hydroxyacid-oxoacid transhydrogenase, a reversible enzyme that oxidases GHB in the presence of 2-ketoglutarate yielding SSA and d-2-HG.

Original languageEnglish (US)
Pages (from-to)53-57
Number of pages5
JournalMolecular Genetics and Metabolism
Volume88
Issue number1
DOIs
StatePublished - May 2006
Externally publishedYes

Fingerprint

Succinate-Semialdehyde Dehydrogenase
Metabolism
Inborn Errors Metabolism
Culture Media
Genes
Cerebrospinal fluid
Organic acids
Fibroblasts
Metabolites
Mutation
Screening
Oxidoreductases
2-Hydroxyglutaricaciduria
succinic semialdehyde dehydrogenase deficiency
Plasmas
Cerebrospinal Fluid
Enzymes
Urine
Acids

Keywords

  • 4-Hydroxybutyrate
  • Combined
  • d-2-Hydroxyglutarate
  • d-2-Hydroxyglutaric aciduria
  • GHB
  • Hydroxyacid-oxoacid transhydrogenase
  • SSADH

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism

Cite this

d-2-Hydroxyglutaric aciduria in three patients with proven SSADH deficiency : Genetic coincidence or a related biochemical epiphenomenon? / Struys, E. A.; Verhoeven, N. M.; Salomons, G. S.; Berthelot, J.; Vianay-Saban, C.; Chabrier, S.; Thomas, J. A.; Tsai, Anne; Gibson, K. M.; Jakobs, C.

In: Molecular Genetics and Metabolism, Vol. 88, No. 1, 05.2006, p. 53-57.

Research output: Contribution to journalArticle

Struys, EA, Verhoeven, NM, Salomons, GS, Berthelot, J, Vianay-Saban, C, Chabrier, S, Thomas, JA, Tsai, A, Gibson, KM & Jakobs, C 2006, 'd-2-Hydroxyglutaric aciduria in three patients with proven SSADH deficiency: Genetic coincidence or a related biochemical epiphenomenon?', Molecular Genetics and Metabolism, vol. 88, no. 1, pp. 53-57. https://doi.org/10.1016/j.ymgme.2005.12.002
Struys, E. A. ; Verhoeven, N. M. ; Salomons, G. S. ; Berthelot, J. ; Vianay-Saban, C. ; Chabrier, S. ; Thomas, J. A. ; Tsai, Anne ; Gibson, K. M. ; Jakobs, C. / d-2-Hydroxyglutaric aciduria in three patients with proven SSADH deficiency : Genetic coincidence or a related biochemical epiphenomenon?. In: Molecular Genetics and Metabolism. 2006 ; Vol. 88, No. 1. pp. 53-57.
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AU - Salomons, G. S.

AU - Berthelot, J.

AU - Vianay-Saban, C.

AU - Chabrier, S.

AU - Thomas, J. A.

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AU - Gibson, K. M.

AU - Jakobs, C.

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