title: Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria.
abstract: 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.
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Kranendijk
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: Wjera V
authors.initials: WV
authors.lastname: Wickenhagen
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
authors.forename: Jochen
authors.initials: J
authors.lastname: Buechner
authors.forename: Ernst
authors.initials: E
authors.lastname: Christensen
authors.forename: Raquel Dodelson
authors.initials: RD
authors.lastname: de Kremer
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Errami
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Wanda
authors.initials: W
authors.lastname: Gradowska
authors.forename: Emma
authors.initials: E
authors.lastname: Hobson
authors.forename: Lily
authors.initials: L
authors.lastname: Islam
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Korman
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Kurczynski
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.forename: Concetta
authors.initials: C
authors.lastname: Meli
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rizzo
authors.forename: Claude
authors.initials: C
authors.lastname: Sansaricq
authors.forename: Friedrich K
authors.initials: FK
authors.lastname: Trefz
authors.forename: Rachel
authors.initials: R
authors.lastname: Webster
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
mesh_terms: 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
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D005680:gamma-Aminobutyric Acid; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase; C009338:succinic semialdehyde