Hypomagnesemia Due to Transient Receptor Potential Melastatin 6 (TRMP6) Genetic Mutation

Introduction: The TRMP6 channel aids in the absorption of magnesium (Mg) in large intestine and distal convoluted tubule. We present a case report of severe Mg deficiency due to TRMP6 genetic mutation Case Description: A 38-year-old female with hypomagnesemia and hypocalcemia is being followed closely in the nephrology clinic for many years. She was first diagnosed at the age of 3 months with hypomagnesemia due to renal wasting without hypercalciuria after presenting with a seizure. She has been maintained on oral magnesium for most of her life and generally tolerates total Mg levels of 0.7 to 1.0 mg/dL, on 16-20 magnesium tablets per day. A few years ago, she stopped taking Mg supplements and would present to the emergency room periodically with nonspecific symptoms. On one occasion, she presented with perioral numbness and was found to have very low ionized calcium(0.86 mmol/L), low PTH and hypokalemia(3.4 mmol/L) despite a similar total magnesium level(0.7 mg/dL). Her maintenance regimen includes 20 tablets of Mag oxide, 40 meq of potassium chloride, 6 tablets of calcium carbonate 750mg, and 1000 units of vitamin D3 per day. Genetic testing revealed a pathogenic TRMP6 gene mutation which explains the severe hypomagnesemia in the absence of hypercalciuria Discussion: Mg is absorbed via passive, paracellular transport in small intestine and thick ascending limb of the kidney. However, in the colon, and distal tubule of the kidney, active transcellular transport is facilitated by the TRMP6 channel. The most common genetic cause of hypomagnesemia is claudin mutations blocking paracellular absorption and with associated hypercalciuria. In contrast, mutations in the TRMP6 gene can cause hypomagnesemia, with the most severe phenotype as in our patient, with secondary hypoparathyroidism manifesting as hypocalcemia. Although a mild Mg deficiency can lead to stimulation of PTH secretion, a severe Mg deficiency can cause a reduction in PTH secretion. This is referred to as “Paradoxical block of PTH secretion”. The hypocalcemia is restored by magnesium repletion. This case illustrates that severe magnesium deficiency 1) often has an underlying genetic etiology, 2) can present as severe hypocalcemia due to inhibition of PTH secretion, 3) total magnesium levels may not indicate true ionized magnesium levels and therefore this assay should be widely available for clinical use