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Anthony J. Gill - One of the best experts on this subject based on the ideXlab platform.
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Succinate Dehydrogenase sdh deficient neoplasia
Histopathology, 2018Co-Authors: Anthony J. GillAbstract:The Succinate Dehydrogenase (SDH) complex is a key respiratory enzyme composed of four subunits: SDHA, SDHB, SDHC and SDHD. Remarkably, immunohistochemistry for SDHB becomes negative whenever there is bi-alleic inactivation of any component of SDH, which is very rare in the absence of syndromic disease. Therefore, loss of SDHB immunohistochemistry serves as a marker of syndromic disease, usually germline mutation of one of the SDH subunits. Tumours which show loss of SDHB expression are termed Succinate Dehydrogenase-deficient. In addition to loss of SDHB, tumours associated with SDHA mutation also show loss of SDHA expression. Fifteen per cent of pheochromocytoma and paraganglioma (PHEO/PGL) are associated with germline SDH mutation, and therefore SDH-deficient. We recommend screening SDHB immunohistochemistry for all PHEO/PGL. SDH-deficient gastrointestinal stromal tumours (GISTs) show distinctive features, including absent KIT proto-oncogene receptor tyrosine kinase/platelet-derived growth factor receptor A (KIT/PDGFRA) mutations [but positive staining for cKIT and DOG1], virtually exclusive gastric location, lobulated growth, multi-focality, a prognosis not predicted by size and mitotic rate, frequent metastasis to lymph nodes and primary resistance to imatinib therapy. Thirty per cent are associated with SDHA germline mutation and 50% are associated with SDHC epimutation (post-zygotic promoter hypermethylation) - the hallmark of the syndromic but non-hereditary Carney triad (SDH- deficient GIST, SDH-deficient paraganglioma and pulmonary chondroma). SDH-deficient renal carcinoma is newly recognized under the World Health Organization (WHO) 2016 classification and shows vacuolated eosinophilic cytoplasmic and cytoplasmic inclusions. It is particularly associated with SDHB mutation, although SDHC and SDHA mutation occur. SDH-deficient pituitary adenomas are recognized, but appear to be the least common SDH-deficient neoplasm.
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loss of sdha expression identifies sdha mutations in Succinate Dehydrogenase deficient gastrointestinal stromal tumors
The American Journal of Surgical Pathology, 2013Co-Authors: Trisha Dwight, Adele Clarkson, Diana E Benn, Ricardo E Vilain, Lara Lipton, Bruce G Robinson, Roderick J Cliftonbligh, Anthony J. GillAbstract:Succinate Dehydrogenase–deficient gastrointestinal stromal tumors (SDH-deficient GISTs) are a unique class of GIST defined by negative immunohistochemical staining for Succinate Dehydrogenase B (SDHB). SDH-deficient GISTs show distinctive clinical and pathologic features including absence of KIT and
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Succinate Dehydrogenase-deficient GISTs are characterized by IGF1R overexpression.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology Inc, 2012Co-Authors: Angela Chou, Jason Chen, Adele Clarkson, Jaswinder S. Samra, Roderick J. Clifton-bligh, Thomas J. Hugh, Anthony J. GillAbstract:Succinate Dehydrogenase-deficient gastrointestinal stromal tumors (GISTs) demonstrate unique pathological and clinical features, including the absence of activating mutations of KIT and PDGFRA, and primary resistance to imatinib. They arise exclusively in the stomach and account for 5–7.5% of all adult stomach GISTs and the great majority of these tumors in childhood. Insulin-like growth factor 1 receptor (IGF1R) overexpression has been associated with wild-type and pediatric GISTs. We propose that IGF1R overexpression is a feature of Succinate Dehydrogenase-deficient GISTs as a group. We assessed Succinate Dehydrogenase complex subunit B (SDHB) and IGF1R expression by immunohistochemistry in eight known Succinate Dehydrogenase-deficient GISTs, three GISTs arising in the setting of neurofibromatosis type 1 syndrome and 40 unselected GISTs. Selected KIT and PDGFRA exons were amplified and sequenced from formalin-fixed paraffin-embedded tumor samples. All eight Succinate Dehydrogenase-deficient tumors were wild-type for KIT and PDGFRA, Succinate Dehydrogenase B negative and demonstrated IGF1R overexpression. The three neurofibromatosis-related tumors were Succinate Dehydrogenase B positive and IGF1R negative. Of the 40 unselected upper GISTs, five were wild-type for KIT and PDGFRA in the selected exons. Two of the wild-type GISTs were Succinate Dehydrogenase B negative and showed IGF1R overexpression and three were Succinate Dehydrogenase B positive and IGF1R negative. We conclude that IGF1R overexpression is a feature of Succinate Dehydrogenase deficient GIST as a group, rather than pediatric or wild-type GIST per se. Therefore, IGF1R inhibition represents a potential rational therapeutic approach in this recently recognized subgroup of GIST.
Reid R. Heffner - One of the best experts on this subject based on the ideXlab platform.
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Succinate Dehydrogenase Deficiency A Qualitative and Quantitative Assessment in Muscle
Archives of Pathology & Laboratory Medicine, 2000Co-Authors: Georgirene D. Vladutiu, Reid R. HeffnerAbstract:Background.-Partial Succinate Dehydrogenase deficiency (15% to 50% of normal reference enzyme activity) in skeletal muscle causes mitochondrial myopathy with various symptoms, for example, brain involvement, cardiomyopathy, and/or exercise intolerance. The deficiency may be isolated or may coexist with other respiratory-chain enzyme defects. The histopathologic assessment of Succinate Dehydrogenase activity in muscle biopsies of patients with suspected mitochondrial myopathies has focused on the finding of increased staining, usually in ragged-red fibers, rather than on reduced staining. Objectives.-To determine the prevalence of muscle Succinate Dehydrogenase deficiency among patients with respiratory-chain defects and to determine whether the reduced activity is present histochemically and is comparable to the quantitative reduction found in muscle homogenates. Patients and Methods.-One hundred eight muscle biopsies were evaluated from patients with suspected mitochondrial myopathies by qualitative histochemical analysis and quantitative biochemical analyses of respiratory-chain enzymes using standard methodologies. Results.-Fifty-two patients had defects in respiratory-chain complexes; of these patients, 12 (23%) had partial deficiencies in Succinate Dehydrogenase activity either alone or together with reductions in other enzymes. The reduced activity was detectable histochemically in muscle biopsies with residual enzyme activity of up to 34% of the normal reference activity, while 2 biopsies with higher residual activity (49% and 68% of normal) could not be distinguished from normal biopsies. Conclusions-Of the patients with respiratory-chain enzyme defects, 23% had partial deficiencies of Succinate Dehydrogenase activity in muscle biopsies. This reduction could be detected histochemically in biopsies in most cases. The marked prevalence of Succinate Dehydrogenase deficiency among patients with respiratory-chain defects and its detection initially by histochemical analysis are important findings.
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Succinate Dehydrogenase deficiency.
Archives of pathology & laboratory medicine, 2000Co-Authors: Georgirene D. Vladutiu, Reid R. HeffnerAbstract:Abstract Background.—Partial Succinate Dehydrogenase deficiency (15% to 50% of normal reference enzyme activity) in skeletal muscle causes mitochondrial myopathy with various symptoms, for example, brain involvement, cardiomyopathy, and/or exercise intolerance. The deficiency may be isolated or may coexist with other respiratory-chain enzyme defects. The histopathologic assessment of Succinate Dehydrogenase activity in muscle biopsies of patients with suspected mitochondrial myopathies has focused on the finding of increased staining, usually in ragged-red fibers, rather than on reduced staining. Objectives.—To determine the prevalence of muscle Succinate Dehydrogenase deficiency among patients with respiratory-chain defects and to determine whether the reduced activity is present histochemically and is comparable to the quantitative reduction found in muscle homogenates. Patients and Methods.—One hundred eight muscle biopsies were evaluated from patients with suspected mitochondrial myopathies by qualita...
Achim Kröger - One of the best experts on this subject based on the ideXlab platform.
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Reactivity of the Bacillus subtilis Succinate Dehydrogenase complex with quinones.
Biochimica et biophysica acta, 1991Co-Authors: E. Lemma, Cecilia Hägerhäll, Viktor Geisler, Ulrich Brandt, Gebhard Von Jagow, Achim KrögerAbstract:The Succinate Dehydrogenase isolated from Bacillus subtilis was found to catalyze the oxidation of Succinate with hydrophilic quinones. Either naphthoquinones or benzoquinones served as acceptors. The enzyme activity increased with the redox potential of the quinone. The highest turnover number was commensurate with that of the bacterial Succinate respiration in vivo. The Succinate Dehydrogenase was similarly active in fumarate reduction with quinols. The highest activity was obtained with the most electronegative quinol. The fumarate reductase isolated from Wolinella succinogenes catalyzed Succinate oxidation with quinones and fumarate reduction with the corresponding quinols at activities similar to those of the B. subtilis enzyme. Succinate oxidation by the lipophilic quinones, ubiquinone or vitamin K-1, was monitored as cytochrome c reduction using proteoliposomes containing Succinate Dehydrogenase together with the cytochrome bc1 complex. The activity with ubiquinone or vitamin K-1 was commensurate with the Succinate respiratory activity of bacteria or of the bacterial membrane fraction. The results suggest that menaquinone is involved in the Succinate respiration of B. subtilis, although its redox potential is unfavorable.
Henri J L M Timmers - One of the best experts on this subject based on the ideXlab platform.
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MITOCHONDRIA: Succinate Dehydrogenase subunit B-associated phaeochromocytoma and paraganglioma.
The international journal of biochemistry & cell biology, 2021Co-Authors: Margo Dona, Kim Neijman, Henri J L M TimmersAbstract:Abstract Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours. So far, over 20 causative genes have been identified, of which the most frequent and strongest indicator for malignancies are mutations in Succinate Dehydrogenase subunit B. No curative therapy is available for patients with metastases resulting in poor prognosis. Therapy development has been hindered by lack of suitable model systems. The Succinate Dehydrogenase complex is located in the inner membrane of the mitochondria and plays a crucial role in the oxidative phosphorylation chain and the tricarboxylic acid-cycle. Succinate Dehydrogenase deficiency results in accumulation of the oncometabolite Succinate inducing hypoxia inducible factor stabilization, deoxyribonucleic acid and histone methylation inhibition, and impaired production of adenosine triphosphate. It remains unknown which combination of pathways and/or triggers are decisive for metastases development. In this review, the role of mitochondria in malignant Succinate Dehydrogenase subunit B-associated phaeochromocytomas and paragangliomas and implications for mitochondria as therapeutic target are discussed.
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Familial pheochromocytomas and paragangliomas associated with mutations of the Succinate Dehydrogenase genes.
Expert review of endocrinology & metabolism, 2007Co-Authors: Henri J L M Timmers, Karel PacakAbstract:Pheochromocytomas and other sympathetic paragangliomas are rare tumors of the adrenal gland or extra-adrenal chromaffin tissue. Mutations of the genes encoding three subunits of the mitochondrial enzyme Succinate Dehydrogenase give rise to hereditary paraganglioma. We will review the distinct clinical phenotypes of familial paraganglioma syndromes associated with mutations in genes encoding for three different subunits of Succinate Dehydrogenase. The current insights in optimal strategies for biochemical testing, tumor localization and therapy of paraganglioma will be discussed. Furthermore, we provide recommendations regarding genetic testing and tumor screening among relatives of patients with Succinate Dehydrogenase-related paraganglioma.
Ya-mei Wang - One of the best experts on this subject based on the ideXlab platform.
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Succinate Dehydrogenase-deficient gastrointestinal stromal tumors
World journal of gastroenterology, 2015Co-Authors: Ya-mei WangAbstract:Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with Succinate Dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of Succinate Dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without Succinate Dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.
