Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

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

doi:10.1002/humu.21186

Cited by 69 publications

(57 citation statements)

References 24 publications

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“…To this end, the R55Q variant of the D2HGDH gene was more frequently detected in cases with high 2-HG and wild-type IDH1/2 (Fig. S1B), which reminds us of the fact that the genetic disease caused by the mutation of D2HGDH was associated with a high serum 2-HG level (26). Given that accumulation of high 2-HG might require not only a neoenzymatic activity of the IDH1/2 mutant but also the availability of α-KG as a substrate, it was interesting to note that the serum level of α-KG was increased in AML cases with high 2-HG, especially in those with wild-type IDH1/2.…”

Section: (Top Row) Os (A) and Efs (B) Curves Of The Patients Accordinmentioning

confidence: 75%

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

Wang

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

132

104

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The 2-hydroxyglutarate (2-HG) has been reported to result from mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes and to function as an "oncometabolite." To evaluate the clinical significance of serum 2-HG levels in hematologic malignancies, acute myeloid leukemia (AML) in particular, we analyzed this metabolite in distinct types of human leukemia and lymphoma and established the range of serum 2-HG in appropriate normal control individuals by using gas chromatograph-time-of-flight mass spectrometry. Aberrant serum 2-HG pattern was detected in the multicenter group of AML, with 62 of 367 (17%) patients having 2-HG levels above the cutoff value (2.01, log 2 -transformed from 4.03 μg/mL). IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation. Indeed, glutamine-related metabolites exhibited a pattern in favor of 2-HG synthesis in the high 2-HG group. In AML patients with cytogenetically normal AML (n = 234), high 2-HG represented a negative prognostic factor in both overall survival and event-free survival. Univariate and multivariate analyses confirmed high serum 2-HG as a strong prognostic predictor independent of other clinical and molecular features. We also demonstrated distinct gene-expression/DNA methylation profiles in AML blasts with high 2-HG compared with those with normal ones, supporting a role that 2-HG plays in leukemogenesis.biomarker | prognosis

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Section: (Top Row) Os (A) and Efs (B) Curves Of The Patients Accordinmentioning

confidence: 75%

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

Wang

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

132

104

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“…This model is supported by the observation that in patients with type I (D)-2-hydroxyglutaric aciduria (D2HGA), an inborn neurometabolic disorder caused by germline mutations in D2HGDH, levels of (R)-2HG are elevated but to a much lesser extent than is observed in IDH mutant tumors (Wickenhagen et al 2009). Type II D2HGA, which is caused by germline IDH2 R140Q and IDH2 R140G mutations, is associated with higher levels of (R)-2HG and a more severe clinical course (Kranendijk et al 2010(Kranendijk et al , 2011. Interestingly, D2HGA is not associated with an increased incidence of cancer.…”

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confidence: 96%

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

2013

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Mutations in metabolic enzymes, including isocitrate dehydrogenase 1 (IDH1) and IDH2, in cancer strongly implicate altered metabolism in tumorigenesis. IDH1 and IDH2 catalyze the interconversion of isocitrate and 2-oxoglutarate (2OG). 2OG is a TCA cycle intermediate and an essential cofactor for many enzymes, including JmjC domain-containing histone demethylases, TET 5-methylcytosine hydroxylases, and EglN prolyl-4-hydroxylases. Cancer-associated IDH mutations alter the enzymes such that they reduce 2OG to the structurally similarHere we review what is known about the molecular mechanisms of transformation by mutant IDH and discuss their implications for the development of targeted therapies to treat IDH mutant malignancies.Cellular metabolism has been hypothesized to play a central role in cancer since the observation made almost a century ago by Otto Warburg (Warburg 1956) that cancer cells preferentially generate energy by metabolizing glucose to lactate. Even in the presence of oxygen, cancer cells switch from generating ATP by the highly energy-efficient process of oxidative phosphorylation to the much less efficient process of glycolysis (Vander Heiden et al. 2009;Dang 2012). Why this switch occurs has long been a mystery, although the observation that normal cells use ''aerobic glycolysis'' during periods of increased proliferation supports the hypothesis that this metabolic switch is an important feature of rapidly dividing cells (Locasale and Cantley 2011;Lunt and Vander Heiden 2011). Recent work suggests that aerobic glycolysis facilitates cellular transformation by producing the high levels of glycolytic intermediates that proliferating cells need for the biosynthesis of lipids, amino acids, and nucleic acids. Moreover, metabolic reprogramming appears to be sufficient to mediate tumorigenesis in some systems (Lyssiotis and Cantley 2012;Sebastian et al. 2012). Nevertheless, whether altered cellular metabolism is a cause of cancer or merely an adaptive response of cancer cells in the face of accelerated cell proliferation is still a topic of some debate.The recent identification of cancer-associated mutations in three metabolic enzymes suggests that altered cellular metabolism can indeed be a cause of some cancers (Pollard et al. 2003;King et al. 2006;Raimundo et al. 2011). Two of these enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are bone fide tumor suppressors, and loss-of-function mutations in FH and SDH have been identified in various cancers, including renal cell carcinomas and paragangliomas. The third mutated enzyme, isocitrate dehydrogenase (IDH), is a more complicated case. Mutations in two isoforms of IDH, IDH1 and IDH2, are common in a diverse array of cancers, including gliomas and acute myelogenous leukemia (AML) (Dang et al. 2010). The mutant enzymes are not catalytically inactive. Rather, the cancer-associated mutations alter the catalytic activity of the enzymes such that they produce high levels of a metabolite, (R)-2-hydroxyglutarate [(R)-2HG], which is normally ...

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“…One of these is D-2-hydroxyglutarate (Fig. 8), a species detected at elevated levels in another heritable neurological disorder, D-2-hydroxyglutaric aciduria (101). D-2-hydroxyglutarate is believed to arise from the action of D-2-hydroxyglutarate transhydrogenase, an NAD þ -independent enzyme that converts GHB to SSA with stoichiometric generation of D-2-hydroxyglutarate from 2-oxoglutarate (95).…”

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confidence: 99%

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Kim

Pearl

Jensen

et al. 2011

Antioxidants & Redox Signaling

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Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADHdeficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation=reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691-718.

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Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

Cited by 69 publications

References 24 publications

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

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