An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

Marjan E Steenweg, Cornelis Jakobs, Abdellatif Errami, Silvy J M van Dooren, Maria T Adeva Bartolomé, Peter Aerssens, Persephone Augoustides-Savvapoulou, Ivo Baric, Matthias Baumann, Luisa Bonafé, Brigitte Chabrol, Joe T R Clarke, Peter Clayton, Mahmut Coker, Sarah Cooper, Tzipora Falik-Zaccai, Mark Gorman, Andreas Hahn, Alev Hasanoglu, Mary D KingHans B C de Klerk, Stanley H Korman, Céline Lee, Allan Meldgaard Lund, Vlatka Mejaski-Bosnjak, Ignacio Pascual-Castroviejo, Aparna Raadhyaksha, Terje Rootwelt, Agathe Roubertie, Maria L Ruiz-Falco, Emmanuel Scalais, Ulf Schimmel, Manuel Seijo-Martinez, Mohnish Suri, Jolanta Sykut-Cegielska, Friedrich K Trefz, Graziella Uziel, Vassili Valayannopoulos, Christine Vianey-Saban, Stefan Vlaho, Julia Vodopiutz, Moacir Wajner, John Walter, Claudia Walter-Derbort, Zuhal Yapici, Dimitrios I Zafeiriou, Marieke D Spreeuwenberg, Jacopo Celli, Johan T den Dunnen, Marjo S van der Knaap, Gajja S Salomons

93 Citations (Scopus)


L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants ( Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.
Original languageEnglish
JournalHuman Mutation
Issue number4
Pages (from-to)380-90
Number of pages11
Publication statusPublished - 1 Apr 2010


Dive into the research topics of 'An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study'. Together they form a unique fingerprint.

Cite this