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 King; Hans 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

doi:10.1002/humu.21197

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

63 Citations (Scopus)

Abstract

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 (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. (c) 2010 Wiley-Liss, Inc.

Original language	English
Journal	Human Mutation
Volume	31
Issue number	4
Pages (from-to)	380-90
Number of pages	11
ISSN	1059-7794
DOIs	https://doi.org/10.1002/humu.21197
Publication status	Published - 1 Apr 2010

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Steenweg, M. E., Jakobs, C., Errami, A., van Dooren, S. J. M., Adeva Bartolomé, M. T., Aerssens, P., Augoustides-Savvapoulou, P., Baric, I., Baumann, M., Bonafé, L., Chabrol, B., Clarke, J. T. R., Clayton, P., Coker, M., Cooper, S., Falik-Zaccai, T., Gorman, M., Hahn, A., Hasanoglu, A., ... Salomons, G. S. (2010). An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study. Human Mutation, 31(4), 380-90. https://doi.org/10.1002/humu.21197

Steenweg, ME, Jakobs, C, Errami, A, van Dooren, SJM, Adeva Bartolomé, MT, Aerssens, P, Augoustides-Savvapoulou, P, Baric, I, Baumann, M, Bonafé, L, Chabrol, B, Clarke, JTR, Clayton, P, Coker, M, Cooper, S, Falik-Zaccai, T, Gorman, M, Hahn, A, Hasanoglu, A, King, MD, de Klerk, HBC, Korman, SH, Lee, C, Meldgaard Lund, A, Mejaski-Bosnjak, V, Pascual-Castroviejo, I, Raadhyaksha, A, Rootwelt, T, Roubertie, A, Ruiz-Falco, ML, Scalais, E, Schimmel, U, Seijo-Martinez, M, Suri, M, Sykut-Cegielska, J, Trefz, FK, Uziel, G, Valayannopoulos, V, Vianey-Saban, C, Vlaho, S, Vodopiutz, J, Wajner, M, Walter, J, Walter-Derbort, C, Yapici, Z, Zafeiriou, DI, Spreeuwenberg, MD, Celli, J, den Dunnen, JT, van der Knaap, MS & Salomons, GS 2010, 'An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study', Human Mutation, vol. 31, no. 4, pp. 380-90. https://doi.org/10.1002/humu.21197

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

abstract = "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 (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. (c) 2010 Wiley-Liss, Inc.",

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T1 - An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study

AU - Steenweg, Marjan E

AU - Jakobs, Cornelis

AU - Errami, Abdellatif

AU - van Dooren, Silvy J M

AU - Adeva Bartolomé, Maria T

AU - Aerssens, Peter

AU - Augoustides-Savvapoulou, Persephone

AU - Baric, Ivo

AU - Baumann, Matthias

AU - Bonafé, Luisa

AU - Chabrol, Brigitte

AU - Clarke, Joe T R

AU - Clayton, Peter

AU - Coker, Mahmut

AU - Cooper, Sarah

AU - Falik-Zaccai, Tzipora

AU - Gorman, Mark

AU - Hahn, Andreas

AU - Hasanoglu, Alev

AU - King, Mary D

AU - de Klerk, Hans B C

AU - Korman, Stanley H

AU - Lee, Céline

AU - Meldgaard Lund, Allan

AU - Mejaski-Bosnjak, Vlatka

AU - Pascual-Castroviejo, Ignacio

AU - Raadhyaksha, Aparna

AU - Rootwelt, Terje

AU - Roubertie, Agathe

AU - Ruiz-Falco, Maria L

AU - Scalais, Emmanuel

AU - Schimmel, Ulf

AU - Seijo-Martinez, Manuel

AU - Suri, Mohnish

AU - Sykut-Cegielska, Jolanta

AU - Trefz, Friedrich K

AU - Uziel, Graziella

AU - Valayannopoulos, Vassili

AU - Vianey-Saban, Christine

AU - Vlaho, Stefan

AU - Vodopiutz, Julia

AU - Wajner, Moacir

AU - Walter, John

AU - Walter-Derbort, Claudia

AU - Yapici, Zuhal

AU - Zafeiriou, Dimitrios I

AU - Spreeuwenberg, Marieke D

AU - Celli, Jacopo

AU - den Dunnen, Johan T

AU - van der Knaap, Marjo S

AU - Salomons, Gajja S

PY - 2010/4/1

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N2 - 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 (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. (c) 2010 Wiley-Liss, Inc.

AB - 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 (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. (c) 2010 Wiley-Liss, Inc.

U2 - 10.1002/humu.21197

DO - 10.1002/humu.21197

M3 - Journal article

SN - 1059-7794

VL - 31

SP - 380

EP - 390

JO - Human Mutation

JF - Human Mutation

IS - 4

ER -

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

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