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Hereditary etiologies of hypomagnesemia Amir Said Alizadeh Naderi* and Robert F Reilly Jr
S U M M ARY Magnesium ions are essential to all living cells. As the second most abundant intracellular cation, magnesium has a crucial role in fundamental metabolic processes such as DNA and protein synthesis, oxidative phosphorylation, enzyme function, ion channel regulation, and neuromuscular excitability. After presenting an overview of magnesium homeostasis, we review the etiologies of hypomagnesemia, with an emphasis on hereditary causes. keywords Bartter syndrome, Gitelman syndrome, hypomagnesemia, renal Mg2+ handling
Review criteria A literature search was performed in the PubMed and Ovid databases using the following search terms: “hypomagnesemia”, “hereditary causes”, “hypomagnesemia with secondary hypocalcemia”, “TRPM6 mutation”, “Bartter syndrome”, “Gitelman syndrome”, “familial hypomagnesemia with hypercalciuria and nephrocalcinosis”, “paracellin-1”, “autosomal dominant hypomagnesemia with hypocalciuria”, “isolated recessive hypomagnesemia”, “autosomal dominant hypocalcemia”, and “Ca2+/Mg2+-sensing receptor activating mutations”.
cme
Continuing Medical Education online Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please go to http://www.medscape.com/cme/ncp and complete the post-test. Learning objectives Upon completion of this activity, participants should be able to: 1 Identify dietary sources that are high in magnesium. 2 Describe the recommended daily intake of magnesium for adult women and men. 3 Describe the most common clinical presentations of hypomagnesemia. 4 Identify the most likely concurrent electrolyte, endo crine, and metabolic abnormalities occurring with hypomagnesemia. 5 Describe the inheritance patterns of hereditary causes of hypomagnesemia. Competing interests The authors declared no competing interests. Désirée Lie, the CME questions author, declared no relevant financial relationships.
Introduction
ASA Naderi is a Senior Resident in the Department of Internal Medicine, and RF Reilly Jr is Professor of Medicine, Fredric L Coe Professor of Nephrolithiasis Research and Chief of the Division of Nephrology, VA North Texas Heath Care System, both at The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. Correspondence *Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8837, USA
[email protected] Received 4 July 2007 Accepted 20 September 2007 www.nature.com/clinicalpractice doi:10.1038/ncpneph0680
80 nature clinical practice NEPHROLOGY
Magnesium is found in a wide variety of foods, and at particularly high levels in unrefined whole grain cereals, green leafy vegetables, nuts, seeds, peas and beans. A balanced Western diet contains approximately 360 mg of magnesium per day; only about 120 mg of this is absorbed in the intestine. Gastrointestinal magnesium absorption is mediated by a saturable transcellular active pathway, as well as by nonsaturable paracellular passive transport.1 The intestine secretes about 40 mg of magnesium per day and about 20 mg is absorbed in the large bowel. Magnesium homeostasis is maintained by urinary excretion of approximately 100 mg/day. Regulation of renal magnesium excretion maintains physiologic serum concentrations at between 0.75 and february 2008 vol 4 no 2
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0.95 mmol/l (1.8–2.3 mg/dl) in healthy humans. The recommended dietary intake of magnesium, which reflects the amount that meets the needs of almost all (98%) healthy individuals, is 320 mg/day (13.3 mmol/day) for adult females and 420 mg/day (17.5 mmol/day) for adult males.2 Renal magnesium handling
The kidney is the major regulator of total body magnesium homeostasis. Several mechanisms enable the kidney to regulate and maintain serum magnesium concentration within a narrow range. In the setting of hypomagnesemia, the kidney decreases magnesium excretion to as little as 0.5% of the filtered load. Conversely, in the setting of hypermagnesemia, up to 80% of the filtered load can be excreted.3 A proportion of circulating magnesium is protein bound, such that only 70% of total plasma magnesium is ultrafilterable.4 In adults, a small fraction of filtered magnesium is reabsorbed in the proximal tubule. In contrast to most other ions, which are primarily reabsorbed in the proximal tubule, the thick ascending limb of the loop of Henle is the main site of magnesium reabsorption (Figure 1). The Ca2+/Mg2+-sensing receptor (CASR), a member of the G-protein-coupled receptor family, is an important regulator of magnesium homeostasis.5 This receptor is located in the basolateral membrane of thick ascending limb cells and in the distal convoluted tubule, as well as in cells of the parathyroid glands that secrete parathyroid hormone (PTH). In hypomagnesemic or hypocalcemic states, the rates of calcium and magnesium reabsorption in the loop of Henle are increased via CASRmediated stimulation of the Na+–K+–2Cl– cotransporter and the apical ROMK (renal outer medulla potassium) channel.6 By contrast, hypermagnesemia and hypercalcemia inhibit Na+–K+–2Cl– cotransport and activity of the ROMK channel. Magnesium transport in the thick ascending limb is mainly passive in nature, occurring via a paracellular pathway driven by the electrical gradient that results from potassium exit across the apical membrane through ROMK channels.7,8 Paracellin-1 (claudin-16) is expressed in tight junctions of the thick ascending limb of the loop of Henle and is required for selective paracellular magnesium conductance.9 A trans epithelial magnesium transport mechanism in intestine and kidney was identified a few years ago. TRPM6, a member of the transient
Apical membrane
Basolateral membrane Paracellin-1 (claudin-16)
Ca2+, Mg2+ Claudin-19
Tubular lumen
Na+ 2CI– K+
Na+/K+-ATPase 3Na+ 2K+
NKCC2
Ca2+/Mg2+sensing receptor K+ CI– Barttin
ROMK
CLCKA and CLCKB
Figure 1 Magnesium transport in the thick ascending limb of the loop of Henle is passive and paracellular, perhaps mediated by paracellin-1 (claudin‑16) and claudin-19. The lumen-positive electrical gradient is the driving force for paracellular magnesium transport and is dependent on potassium exit via ROMK. Sodium entry and exit are mediated via the furosemide-sensitive NKCC2 and the Na+/K+-ATPase, respectively. The Ca+/Mg2+-sensing receptor expressed in the basolateral membrane is an important regulator of ROMK and NKCC2. Abbreviations: CLCKA and CLCKB, renal chloride channels; NKCC2, Na+–K+–2Cl– cotransporter; ROMK, renal outer medulla potassium channel.
receptor potential family of cation channels, is expressed in the apical membrane of distal convoluted tubule and brush-border membrane of absorptive cells in duodenum; TRPM6 has been characterized as a magnesium-permeable channel.10,11 About 10% of filtered magnesium is reabsorbed in the distal convoluted tubule by transcellular active transport (Figure 2). As there is little magnesium reabsorption beyond the distal tubule, this segment ultimately regulates urinary magnesium excretion. 12 TRPM7 is a recently discovered magnesiumpermeable ion channel, the role of which in cellular magnesium homeostasis is currently being investigated.13 Clinical manifestations of hypomagnesemia
Hypomagnesemia is defined as a serum magnesium concentration of less than 0.74 mmol/l (
