Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria.
We performed molecular, enzyme, and metabolic studies in 50 patients with D-2-hydroxyglutaric aciduria (D-2-HGA) who accumulated D-2-hydroxyglutarate (D-2-HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D-2-hydroxyglutarate dehydrogenase (D-2-HGDH). Enzyme assay of D-2-HGDH confirmed that all patients with mutations had impaired enzyme activity, whereas patients with D-2-HGA whose enzyme activity was normal did not have mutations. Significantly lower D-2-HG concentrations in body fluids were observed in mutation-positive D-2-HGA patients than in mutation-negative patients. These results imply that multiple genetic loci may be associated with hyperexcretion of D-2-HG. Accordingly, we suggest a new classification: D-2-HGA Type I associates with D-2-HGDH deficiency, whereas idiopathic D-2-HGA manifests with normal D-2-HGDH activity and higher D-2-HG levels in body fluids compared with Type I patients. It remains possible that several classifications for idiopathic D-2-HGA patients with diverse genetic loci will be revealed in future studies.
Kranendijk
Martijn
M
Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Struys
Eduard A
EA
Gibson
K Michael
KM
Wickenhagen
Wjera V
WV
Abdenur
Jose E
JE
Buechner
Jochen
J
Christensen
Ernst
E
de Kremer
Raquel Dodelson
RD
Errami
Abdellatif
A
Gissen
Paul
P
Gradowska
Wanda
W
Hobson
Emma
E
Islam
Lily
L
Korman
Stanley H
SH
Kurczynski
Thaddeus
T
Maranda
Bruno
B
Meli
Concetta
C
Rizzo
Cristiano
C
Sansaricq
Claude
C
Trefz
Friedrich K
FK
Webster
Rachel
R
Jakobs
Cornelis
C
Salomons
Gajja S
GS
D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000465:Algorithms; D001826:Body Fluids; D004252:DNA Mutational Analysis; D005838:Genotype; D005977:Glutarates / Q000097:blood* / Q000134:cerebrospinal fluid / Q000652:urine*; D006720:Homozygote; D006801:Humans; D008957:Models, Genetic; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000235:genetics*; D009154:Mutation; D015203:Reproducibility of Results; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000235:genetics
D005977:Glutarates; C019417:alpha-hydroxyglutarate; D005680:gamma-Aminobutyric Acid; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase; C009338:succinic semialdehyde