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, A. Chun Hui Tsai, K. M. Gibson, C. Jakobs

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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
Issue number1
StatePublished - May 2006


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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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