Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

Martijn Kranendijk; Eduard A Struys; K Michael Gibson; Wjera V Wickenhagen; Jose E Abdenur; Jochen Buechner; Ernst Christensen; Raquel Dodelson de Kremer; Abdellatif Errami; Paul Gissen; Wanda Gradowska; Emma Hobson; Lily Islam; Stanley H Korman; Thaddeus Kurczynski; Bruno Maranda; Concetta Meli; Cristiano Rizzo; Claude Sansaricq; Friedrich K Trefz; Rachel Webster; Cornelis Jakobs; Gajja S Salomons

doi:10.1002/humu.21186

Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

Martijn Kranendijk, Eduard A Struys, K Michael Gibson, Wjera V Wickenhagen, Jose E Abdenur, Jochen Buechner, Ernst Christensen, Raquel Dodelson de Kremer, Abdellatif Errami, Paul Gissen, Wanda Gradowska, Emma Hobson, Lily Islam, Stanley H Korman, Thaddeus Kurczynski, Bruno Maranda, Concetta Meli, Cristiano Rizzo, Claude Sansaricq, Friedrich K TrefzRachel Webster, Cornelis Jakobs, Gajja S Salomons

Afdeling for Genetik

54 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Human Mutation
Vol/bind	31
Udgave nummer	3
Sider (fra-til)	279-83
Antal sider	5
ISSN	1059-7794
DOI	https://doi.org/10.1002/humu.21186
Status	Udgivet - 1 mar. 2010

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Kranendijk, M., Struys, E. A., Gibson, K. M., Wickenhagen, W. V., Abdenur, J. E., Buechner, J., Christensen, E., de Kremer, R. D., Errami, A., Gissen, P., Gradowska, W., Hobson, E., Islam, L., Korman, S. H., Kurczynski, T., Maranda, B., Meli, C., Rizzo, C., Sansaricq, C., ... Salomons, G. S. (2010). Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria. Human Mutation, 31(3), 279-83. https://doi.org/10.1002/humu.21186

Kranendijk, M, Struys, EA, Gibson, KM, Wickenhagen, WV, Abdenur, JE, Buechner, J, Christensen, E, de Kremer, RD, Errami, A, Gissen, P, Gradowska, W, Hobson, E, Islam, L, Korman, SH, Kurczynski, T, Maranda, B, Meli, C, Rizzo, C, Sansaricq, C, Trefz, FK, Webster, R, Jakobs, C & Salomons, GS 2010, 'Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria', Human Mutation, bind 31, nr. 3, s. 279-83. https://doi.org/10.1002/humu.21186

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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.",

author = "Martijn Kranendijk and Struys, {Eduard A} and Gibson, {K Michael} and Wickenhagen, {Wjera V} and Abdenur, {Jose E} and Jochen Buechner and Ernst Christensen and {de Kremer}, {Raquel Dodelson} and Abdellatif Errami and Paul Gissen and Wanda Gradowska and Emma Hobson and Lily Islam and Korman, {Stanley H} and Thaddeus Kurczynski and Bruno Maranda and Concetta Meli and Cristiano Rizzo and Claude Sansaricq and Trefz, {Friedrich K} and Rachel Webster and Cornelis Jakobs and Salomons, {Gajja S}",

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T1 - Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

AU - Kranendijk, Martijn

AU - Struys, Eduard A

AU - Gibson, K Michael

AU - Wickenhagen, Wjera V

AU - Abdenur, Jose E

AU - Buechner, Jochen

AU - Christensen, Ernst

AU - de Kremer, Raquel Dodelson

AU - Errami, Abdellatif

AU - Gissen, Paul

AU - Gradowska, Wanda

AU - Hobson, Emma

AU - Islam, Lily

AU - Korman, Stanley H

AU - Kurczynski, Thaddeus

AU - Maranda, Bruno

AU - Meli, Concetta

AU - Rizzo, Cristiano

AU - Sansaricq, Claude

AU - Trefz, Friedrich K

AU - Webster, Rachel

AU - Jakobs, Cornelis

AU - Salomons, Gajja S

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

AB - 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.

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VL - 31

SP - 279

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JO - Human Mutation

JF - Human Mutation

IS - 3

ER -

Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

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