Investigating the clinical utility of plasma succinate with insights from a Sdhb deficient murine model.

SDHB

Succinate dehydrogenase deficiency caused by germline SDHA, SDHB, SDHC and SDHD variants, truncating the citric acid cycle and driving accumulation of the oncometabolite succinate

Germline pathogenic variants in SDHA, SDHB, SDHC and SDHD are the commonest cause of hereditary pheochromocytoma and paraganglioma, carry a higher risk of malignant disease and also predispose to renal cell carcinoma, gastrointestinal stromal tumours and pituitary adenomas; the resulting enzyme deficiency truncates the citric acid cycle and leads to accumulation of the oncometabolite succinate. The authors performed prospective plasma metabolomics and identified succinate as a biomarker for early diagnosis of an underlying SDHx variant. Succinate reflected the deficiency both in individuals with germline predisposition and in a small number of patients with somatic SDHx deficiency, and its levels correlated with tumour burden; longitudinal sampling suggests a possible role in disease surveillance. In a Sdhb-deficient mouse model, succinate was elevated in the adrenal glands, but circulating plasma levels did not mirror the human cohort, which the authors attribute to species-specific cellular thresholds and metabolic regulation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The idea is sound — a circulating marker correlated with tumour burden would be valuable in SDHB carriers facing repeated imaging over decades — but the abstract gives no sample size, no threshold and no sensitivity or specificity, that is, none of the figures needed to judge the claimed diagnostic utility. The mouse validation in fact only validates the tissue side: mouse plasma does not behave like patient plasma, which weakens rather than strengthens the translational argument. At this stage plasma succinate remains a lead to evaluate prospectively, not a test to order.

Analysis by Dr Thibaut Benquey