Succinate dehydrogenase (SDH, Complex II) differs from all other TCA cycle enzymes in that it is embedded in the inner mitochondrial membrane and directly feeds electrons to the ubiquinone pool. Which of the following is a unique clinical relevance of SDH subunit mutations?

• A SDHB, SDHC, and SDHD mutations cause hereditary paraganglioma-pheochromocytoma syndrome, acting as tumor suppressor genes ✓
• B SDHA mutations cause Leigh syndrome identical to Complex I deficiency
• C SDH deficiency primarily presents as cardiomyopathy and optic atrophy due to myocardial energy failure
• D SDH mutations are the most common cause of mitochondrial diabetes and deafness

Explanation

Mutations in SDH subunits B, C, and D (SDHB, SDHC, SDHD) act as tumor suppressor genes and cause hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome. Loss of SDH function stabilizes HIF-1alpha (pseudo-hypoxia) through succinate accumulation, which inhibits prolyl hydroxylases responsible for HIF degradation. This oncogenic mechanism drives neural crest-derived neoplasms. SDHB mutations are particularly associated with malignant paragangliomas and metastatic pheochromocytomas. This makes SDH testing part of routine workup in all pheochromocytoma cases under age 40.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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