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Steenweg, M.E.; Jakobs, C.; Errami, A.; Dooren, S.J.M. van; Bartolome, M.T.A.; Aerssens, P.; ... ; Salomons, G.S. (2010)

An Overview of L-2-Hydroxyglutarate Dehydrogenase Gene (L2HGDH) Variants: A Genotype-Phenotype Study

Article / Letter to editor
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...Show moreL-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 (http://www.LOVD.nl/L2HGDH). 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. Hum Mutat 31:380-390, 2010. (C) 2010 Wiley-Liss, Inc.Show less
L-2-hydroxyglutaric aciduria L2HGDH phenotype mutational analysis LOVD database metabolite repair aciduria brain mutations acidemia defect tumors mri
All authors
Steenweg, M.E.; Jakobs, C.; Errami, A.; Dooren, S.J.M. van; Bartolome, M.T.A.; Aerssens, P.; Augoustides-Savvapoulou, P.; Baric, I.; Baumann, M.; Bonafe, L.; Chabrol, B.; Clarke, J.T.R.; Clayton, P.; Coker, M.; Cooper, S.; Falik-Zaccai, T.; Gorman, M.; Hahn, A.; Hasanoglu, A.; King, M.D.; Klerk, H.B.C. de; Korman, S.H.; Lee, C.; Lund, A.M.; Mejaski-Bosnjak, V.; Pascual-Castroviejo, I.; Raadhyaksha, A.; Rootwelt, T.; Roubertie, A.; Ruiz-Falco, M.L.; Scalais, E.; Schimmel, U.; Seijo-Martinez, M.; Suri, M.; Sykut-Cegielska, J.; Trefz, F.K.; Uziel, G.; Valayannopoulos, V.; Vianey-Saban, C.; Vlaho, S.; Vodopiutz, J.; Wajner, M.; Walter, J.; Walter-Derbort, C.; Yapici, Z.; Zafeiriou, D.I.; Spreeuwenberg, M.D.; Celli, J.; Dunnen, J.T. den; Knaap, M.S. van der; Salomons, G.S.
Date
2010-04-30
Journal
Human Mutation
Volume
31
Issue
4
Pages
380 - 390
DOI
doi:10.1002/humu.21197