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.

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin

“…This is in contrast with the hypocalciuria observed in isolated dominant hypomagnesemia [9], and also in the autosomal dominant tubulointerstitial kidney disease with HNF1B mutations [19]. Recently, genetic hypomagnesemic disorders have been classified according to the site in the nephron that handles Mg [21] and where the primary defect resides [7, 22]. There is a distinction between a defect originating in the DCT, which is manifested as a Gitelman-like phenotype, with hypocalciuria, and a defect in a more proximal site such as the thick ascending limb.…”

Afebrile seizures in infants: Never forget magnesium!

“…Hypomagnesaemia can depend on poor intake, increased intestinal loss (typically associated with other electrolytes abnormalities in course of infective or inflammatory diarrhoea) or on genetic abnormalities of its metabolism. These abnormalities can virtually involve each step of magnesium metabolism and can cause an increased renal loss or a decreased intestinal absorption …”

“…These abnormalities can virtually involve each step of magnesium metabolism and can cause an increased renal loss or a decreased intestinal absorption. 8 Increased renal loss is characterised by a magnesium excretion fraction >4% (((urinary magnesium level × blood creatinine level)/(0.7 × blood magnesium level × urinary creatinine level))%) and it is often associated with nephrocalcinosis secondary to HSH and hypercalciuria due to tubular abnormalities. When magnesium excretion fraction is <2% an extrarenal cause of hypomagnesaemia should be suspected.…”

Inherited and acquired disorders of magnesium homeostasis

“…2C)(75). This form of BS can also result in hypomagnesemia but may initially not display hypercalciuria and is therefore typically included in the Gitelman-like forms of hypomagnesemia (Table 2)(76). Mutations in CLCNKB and BSND disturb the intracellular Cl − regulation.…”