D-2-hydroxyglutaric aciduria in three patients with proven SSADH deficiency: genetic coincidence or a related biochemical epiphenomenon?
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.
Struys
E A
EA
Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands. e.struys@VUMC.nl
Verhoeven
N M
NM
Salomons
G S
GS
Berthelot
J
J
Vianay-Saban
C
C
Chabrier
S
S
Thomas
J A
JA
Tsai
A Chun-Hui
AC
Gibson
K M
KM
Jakobs
C
C
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000652:urine*; D002675:Child, Preschool; D005260:Female; D005977:Glutarates / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine*; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D007223:Infant; D024101:Mitochondrial Proteins; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency*
D005977:Glutarates; D006885:Hydroxybutyrates; D024101:Mitochondrial Proteins; C019417:alpha-hydroxyglutarate; C111420:4-hydroxybutyric acid; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase; C072878:hydroxyacid-oxoacid transhydrogenase; D050644:Succinate-Semialdehyde Dehydrogenase