Succinate Dehydrogenase Gene Analysis

Succinate dehydrogenase (SDH) is a mitochondrial enzyme consisting of 4 subunits: SDHA, SDHB, SDHC, and SDHD. The function of this enzyme is to catalyze the oxidation of succinate to fumarate and the reduction of ubiquinone to ubiquinol.

Homozygous loss-of-function mutations or gene deletions of SDH subunit genes are usually lethal. No diseases have been associated with heterozygous mutations or deletions in the SDHA subunit gene. Heterozygous mutations and deletions in the genes of the SDHB, SDHC, or SDHD subunits result in development of paragangliomas or pheochromocytomas. Mutations in the D subunit are most common, followed by B and then C. SDHB and SDHC mutations show classical autosomal dominant inheritance, while SDHD mutations show a modified autosomal dominant inheritance with chiefly paternal transmission.

SDH-associated paragangliomas and pheochromcytomas usually behave as benign tumors. Because of the germline presence of the mutation or deletion, new primary tumors can occur throughout an individual’s lifetime in different chromaffin tissues. A minority of patients with these mutations develop non-chromaffin tissue tumors including renal cell carcinoma and gastrointestinal stromal tumors (GIST).

Genetic testing for SDHB, SDHC, and SDHD germline mutations and deletions is recommended for all patients presenting with paraganglioma. Mutations and deletions are found in 30% to 50% of sporadic cases and >90% of hereditary cases of paraganglioma. Genetic testing is helpful in  designing optimal follow-up strategies, since the rate of new and recurrent tumors is much higher in patients with SDH mutations or deletions than in truly sporadic cases.

Testing for mutations in SDH genes is not currently recommended for patients with sporadic adrenal pheochromocytoma, because mutations are only detected in 1% to 10% of cases. Patients presenting with a familial history of pheochromocytoma, who do not already have an established diagnosis, should be tested for SDH gene mutations, along with testing for other predisposing mutations including: RET (multiple endocrine neoplasia type 2), VHL (von Hippel-Lindau syndrome), and NF1 (neurofibromatosis type 1). SDH mutations are detected in 20% to 30% of apparent hereditary cases of pheochromocytoma.