Genetic causes of hypomagnesemia, a clinical overview

Abstract

Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg²⁺) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg²⁺ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg²⁺ by the thick ascending limb of Henle's loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg²⁺ wasting, as evidenced by an inappropriately high fractional Mg²⁺ excretion. Familial renal Mg²⁺ 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 Mg²⁺ 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 Mg²⁺ supplementation, it has contributed enormously to our understanding of Mg²⁺ 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.

Keywords: Distal convoluted tubule; Hereditary; Homeostasis; Kidney; Magnesium; Thick ascending limb of Henle’s loop.

Fig. 1

Reabsorption of the magnesium cation (Mg ²⁺) in the thick ascending limb of Henle’s loop (TAL) and distal convoluted tubule (DCT). The relevant molecular transport mechanisms of the TAL and DCT are shown. Note that Mg²⁺ is transported via paracellular pathways into the TAL and via transcellular pathways into the DCT. A more detailed explanation of the molecular transport mechanisms can be found in the text. Black text indicates proteins that are mutated in genetic disorders of Mg²⁺ homeostasis. Grey text indicates other proteins

Fig. 2

Diagnostic flowchart for a suspected genetic cause of hypomagnesemia. This diagnostic flowchart is primarily provided to give an impression of the clinical characteristics of all known genetic causes of hypomagnesemia. Genetic testing can confirm or reject a diagnosis. Asterisks indicate dominantly inherited disorders