Genetic causes of hypomagnesemia, a clinical overview

• Published in: Pediatric nephrology (Berlin, West) West), 2017-07, Vol.32 (7), p.1123-1135
• Main Authors: Viering, Daan H. H. M, de Baaij, Jeroen H. F., Walsh, Stephen B., Kleta, Robert, Bockenhauer, Detlef
• Format: Article
• Language: English
• Subjects: Arrhythmia; Arrhythmias, Cardiac - blood; Arrhythmias, Cardiac - etiology; Care and treatment; Child; Complications and side effects; Epithelial Sodium Channel Blockers - therapeutic use; Gene mutations; Homeostasis - genetics; Humans; Hypercalciuria - blood; Hypercalciuria - complications; Hypercalciuria - drug therapy; Hypercalciuria - genetics; Hypokalemia - blood; Hypokalemia - drug therapy; Hypokalemia - etiology; Hypokalemia - genetics; Kidney failure; Kidney Tubules, Distal - physiology; Loop of Henle - physiology; Magnesium - blood; Magnesium - physiology; Magnesium - therapeutic use; Magnesium Deficiency - complications; Magnesium Deficiency - drug therapy; Magnesium Deficiency - genetics; Magnesium deficiency diseases; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mineralocorticoid Receptor Antagonists - therapeutic use; Mitochondria - metabolism; Mutation; Nephrocalcinosis - blood; Nephrocalcinosis - complications; Nephrocalcinosis - drug therapy; Nephrocalcinosis - genetics; Nephrology; Pediatrics; Phenotype; Recommended Dietary Allowances; Renal Elimination - genetics; Renal Reabsorption - drug effects; Renal Reabsorption - genetics; Renal Tubular Transport, Inborn Errors - blood; Renal Tubular Transport, Inborn Errors - complications; Renal Tubular Transport, Inborn Errors - drug therapy; Renal Tubular Transport, Inborn Errors - genetics; Review; Seizures - blood; Seizures - etiology; Urology
• ISSN: 0931-041X; 1432-198X
• DOI: 10.1007/s00467-016-3416-3

Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg 2+ ) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg 2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg 2+ by the thick ascending limb of Henle’s loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg 2+ wasting, as evidenced by an inappropriately high fractional Mg 2+ excretion. Familial renal Mg 2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg 2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16 , CLDN19 , CASR , CLCNKB ), Gitelman-like hypomagnesemias ( CLCNKB , SLC12A3 , BSND , KCNJ10 , FYXD2 , HNF1B , PCBD1 ), mitochondrial hypomagnesemias ( SARS2 , MT-TI , Kearns–Sayre syndrome) and other hypomagnesemias ( TRPM6 , CNMM2 , EGF , EGFR , KCNA1 , FAM111A ). Although identification of these genes has not yet changed treatment, which remains Mg 2+ supplementation, it has contributed enormously to our understanding of Mg 2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.