Succinate Dehydrogenase Gene Analysis

Succinate dehydrogenase (SDH) is a mitochondrial membrane-bound enzyme complex consisting of 4 subunits: SDHA, SDHB, SDHC, and SDHD. SDH is an oxidoreductase that catalyzes the oxidation of succinate to fumarate (tricarboxylic acid cycle function) and the reduction of ubiquinone to ubiquinol (respiratory chain function).

Homozygous loss-of-function mutations or homozygous deletions of SDH subunit genes are lethal, with the exception of some biallelic mutations in the SDHA gene, which cause Leigh syndrome. No disease-associated heterozygote SDHA mutations or deletions have been reported.

Heterozygous mutations and deletions in the genes of the SDHB, SDHC, or SDHD subunits result in development of paragangliomas or pheochromocytomas. The prevalence of SDHD mutations and deletions is higher than that of SDHB, which in turn exceeds SDHC. 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 pheochromocytomas usually behave as benign tumors. Because of the germline presence of the mutation or deletion, new primary tumors might occur over time 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 assists 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. 

References

1. Young WF Jr: Paragangliomas: clinical overview. Ann NY Acad Sci 2006;1073:21-29.
2. Bornstein SR, Gimenez-Roqueplo AP: Genetic testing in pheochromocytoma: increasing importance for clinical decision making. Ann NY Acad Sci 2006;1073:94-103.
3. Benn DE, Richardson AL, Marsh DJ, Robinson BG: Genetic testing in pheochromocytoma and paraganglioma-associated syndromes. Ann NY Acad Sci 2006;1073:104-111.