D-2-hydroxyglutaric aciduria in three patients with proven SSADH deficiency: genetic coincidence or a related biochemical epiphenomenon?

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.

• Authors: 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
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 88 Issue 1 Pg. 53-7 (May 2006) ISSN: 1096-7192 [Print] United States
• PMID: 16442322 (Publication Type: Case Reports, Journal Article)

Chemical References

• Glutarates
• Hydroxybutyrates
• Mitochondrial Proteins
• alpha-hydroxyglutarate
• 4-hydroxybutyric acid
• Alcohol Oxidoreductases
• 2-hydroxyglutarate dehydrogenase
• hydroxyacid-oxoacid transhydrogenase
• Succinate-Semialdehyde Dehydrogenase

Topics

• Alcohol Oxidoreductases (genetics, metabolism)
• Amino Acid Metabolism, Inborn Errors (genetics, urine)
• Child, Preschool
• Female
• Glutarates (blood, cerebrospinal fluid, urine)
• Humans
• Hydroxybutyrates (blood, cerebrospinal fluid, urine)
• Infant
• Mitochondrial Proteins
• Succinate-Semialdehyde Dehydrogenase (deficiency)