"Isocitrate dehydrogenases are enzymes that catalyse the oxidative decarboxylation of isocitrate to 2-oxoglutarate (also known as α-ketoglutarate) which occurs within mitochondria, cytoplasm and peroxisomes. This reaction also produces NADPH (IDH1 and IDH2) or NADH (IDH3) 4,5."
"Isocitrate dehydrogenases are enzymes that catalyse the oxidative decarboxylation of isocitrate to 2-oxoglutarate (also known as α-ketoglutarate) which occurs within mitochondria, cytoplasm and peroxisomes. This reaction also produces NADPH (IDH1 and IDH2) or NADH (IDH3) 4,5."
"In mitochondria, isocitrate dehydrogenase (IDH3) acts at the rate-limiting step of the tricarboxylic acid cycle and results in the production of NADH."
"responsible for production NADPH"
"responsible for the production NADPH"
"essential for the production of NADH"
"A number of genes have been identified that code for isoforms of these enzymes, with IDH1 and IDH2 being most relevant in glioma classification 8."
"IDH1"
"IDH2"
"IDH3"
"MGMT methylation status is also potentially useful in further reducing the chances that an immunohistochemical IDH1 R132H negative tumour actually harbours a less common mutation. Although the literature is heterogeneous, generally IDH mutated (IDH1 and IDH2) tumours are more likely to also have MGMT methylation (80% for IDH-mutant compared to 60% of IDH-wildtype tumours) 9-11."
"Not yet in widespread clinical use, but of tremendous interest, is the assessment of 2-hydroxyglutarate in vivo with MR spectroscopy 3. In tumours with mutated IDH, levels of 2-hydroxyglutarate are elevated, which resonates at 2.25 ppm 3,6."
"If no immunohistochemical reactivity is detected, it is likely but not certain that the tumour is IDH-wildtype. This can only be established with formal genotyping, e.g. using pyrosequencing 3,7. In practice, however, this is not always done, both because it is expensive and in some patient groups (e.g. elderly patients with tumours demonstrating necrosis) it is almost always negative (i.e. these are almost invariably glioblastoma)."
"Although no single absolute age cut-off exists, in individuals over the age of 55 years with a diagnosis of glioma that is IDH1 R132H negative on immunohistochemistry, the chances of an IDH mutation being detected by next-generation sequencing is low and not considered mandatory 12."
Expected headings
"Function"
"Normal function"
"Implications of abnormal function"
"Genetics"
"IDH-mutant"
"IDH-wildtype"
"Detection"
"Therapeutic implications"
"Isocitrate dehydrogenase (IDH) is an enzyme located within the cytoplasm, peroxisomes and mitochondria. Mutations of the IDH genes are important in a variety of diseases. They form the basis of the classification of diffuse adult-type gliomas in the WHO classification of brain tumours 7 with emerging therapeutic implications 13. Somatic mutations of IDH result in enchondromatosis syndromes: Ollier disease and Maffucci syndrome 8."
"Isocitrate dehydrogenases are enzymes that catalyse the oxidative decarboxylation of isocitrate to 2-oxoglutarate (also known as α-ketoglutarate) which occurs within mitochondria, cytoplasm and peroxisomes. This reaction also produces NADPH (IDH1 and IDH2) or NADH (IDH3) 4,5."
"When IDH1 and 2 are mutated they no longer catalyse the formation of 2-oxoglutarate but rather they gain the ability to catalyse the formation of 2-hydroxyglutarate which accumulates (and can in principle be detected using MRS; see below). This compound bears a structural resemblance to glutamate, a key excitatory neurotransmitter in the human brain. Consequently, it has the capability to stimulate N-methyl-D-aspartate (NMDA) receptors. This phenomenon heightens the susceptibility to seizures, elucidating the prevalent occurrence of seizures in diffuse gliomas with IDH mutations, such as astrocytomas and oligodendrogliomas."
"In most instances, IDH status is obtained by performing immunohistochemistry on surgical biopsy specimens. The majority (90%) of IDH mutations in gliomas affect IDH1 with a single amino acid missense mutation at arginine(R)132 replaced by histidine (H); thus denoted as IDH1 R132H. This is the mutation generally tested by immunohistochemistry 7."
"If no immunohistochemical reactivity is detected, it is likely but not certain that the tumour is IDH-wildtype. This can only be established with formal genotyping, e.g. using pyrosequencing 3,7. In practice, however, this is not always done, both because it is expensive and in some patient groups (e.g. elderly patients with tumours demonstrating necrosis) it is almost always negative (i.e. these are almost invariably glioblastoma)."