Functional consequences of succinate dehydrogenase mutations.

To explore the genotype-phenotype correlation among the different forms of hereditary paraganglioma. METHODS: We reviewed the pertinent literature on hereditary paragangliomas, which showed the established classification of types 1, 2, 3, and 4 paraganglioma syndrome (PGL1, PGL2, PGL3, and PGL4, respectively). Germline mutations of succinate dehydrogenase confer susceptibilities as follows: SDHD confers susceptibility to PGL1 syndrome, SDHAF2 to PGL2 syndrome, SDHC to PGL3 syndrome, and SDHB to PGL4 syndrome. Recently, SDHA mutations have been identified in patients with parasympathetic paraganglioma. The 4 paraganglioma syndromes differ in terms of risk of malignancy, secretory activity, and tumor location. RESULTS: Little information is available on the biochemical and functional modifications induced by gene mutations in these tumors. Recent studies provide in vitro and in vivo evidence that succinate, fumarate, or both, which accumulate as a result of succinate dehydrogenase inhibition, lead to the stabilization and activation of hypoxia-inducible factor-1α, which in turn activates cell proliferation and angiogenesis. CONCLUSION: Paraganglia tumors (gross phenotype) are attributable to impairment of the mitochondrial complex II, type of gene mutated, type and position of the mutation, and type of second hit (other genes?) and are the determinants of the clinical phenotype. The relationship among various mutations, a different activity of the mitochondrial complex II, and the clinical phenotype are far from being established.