REVIEW REVIEW www.nature.com/clinicalpractice/neph Hereditary etiologies of hypomagnesemia Amir Said Alizadeh Naderi* and Robert F Reilly Jr SUMMARY Continuing Medical Education online Medscape, LLC is pleased to provide online continuing Magnesium ions are essential to all living cells. As the second most medical education (CME) for this journal article, allowing abundant intracellular cation, magnesium has a crucial role in clinicians the opportunity to earn CME credit. Medscape, fundamental metabolic processes such as DNA and protein synthesis, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME oxidative phosphorylation, enzyme function, ion channel regulation, and for physicians. Medscape, LLC designates this educa- neuromuscular excitability. After presenting an overview of magnesium tional activity for a maximum of 1.0 AMA PRA Category 1 homeostasis, we review the etiologies of hypomagnesemia, with an Credits™. Physicians should only claim credit commen- emphasis on hereditary causes. surate with the extent of their participation in the activity. All other clinicians completing this activity will KEYWORDS Bartter syndrome, Gitelman syndrome, hypomagnesemia, be issued a certificate of participation. To receive credit, 2+ renal Mg handling please go to http://www.medscape.com/cme/ncp and complete the post-test. ReVieW CRITERia A literature search was performed in the PubMed and Ovid databases Learning objectives using the following search terms: “hypomagnesemia”, “hereditary causes”, Upon completion of this activity, participants should be “hypomagnesemia with secondary hypocalcemia”, “TRPM6 mutation”, “Bartter able to: syndrome”, “Gitelman syndrome”, “familial hypomagnesemia with hypercalciuria 1 Identify dietary sources that are high in magnesium. and nephrocalcinosis”, “paracellin-1”, “autosomal dominant hypomagnesemia 2 Describe the recommended daily intake of with hypocalciuria”, “isolated recessive hypomagnesemia”, “autosomal dominant magnesium for adult women and men. hypocalcemia”, and “Ca2+/Mg2+-sensing receptor activating mutations”. 3 Describe the most common clinical presentations of hypomagnesemia. CME 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 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 ASA Naderi is a Senior Resident in the Department of Internal Medicine, approximately 360 mg of magnesium per day; and RF Reilly Jr is Professor of Medicine, Fredric L Coe Professor of only about 120 mg of this is absorbed in the Nephrolithiasis Research and Chief of the Division of Nephrology, VA North intestine. Gastrointestinal magnesium absorp- Texas Heath Care System, both at The University of Texas Southwestern tion is mediated by a saturable transcellular Medical Center at Dallas, Dallas, TX, USA. active pathway, as well as by nonsaturable para- cellular passive transport.1 The intestine secretes Correspondence *Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, about 40 mg of magnesium per day and about 5323 Harry Hines Boulevard, Dallas, TX 75390-8837, USA 20 mg is absorbed in the large bowel. Magnesium [email protected] homeostasis is maintained by urinary excretion of approximately 100 mg/day. Regulation of renal Received 4 July 2007 Accepted 20 September 2007 www.nature.com/clinicalpractice magnesium excretion maintains physiologic doi:10.1038/ncpneph0680 serum concentrations at between 0.75 and 80 NATURE CLINICAL PRACTICE NEPHROLOGY FEBRUAry 2008 Vol 4 no 2 NNature.indtature.indt 1 228/11/078/11/07 99:46:50:46:50 aamm REVIEW REVIEW www.nature.com/clinicalpractice/neph 0.95 mmol/l (1.8–2.3 mg/dl) in healthy humans. Apical Basolateral The recommended dietary intake of magnesium, membrane membrane which reflects the amount that meets the needs of Paracellin-1 (claudin-16) almost all (98%) healthy individuals, is 320 mg/day Ca2+, Mg2+ (13.3 mmol/day) for adult females and 420 mg/day (17.5 mmol/day) for adult males.2 Claudin-19 Na+/K+-ATPase ReNal maGNESIUM HANDliNG Na+ 3Na+ – The kidney is the major regulator of total body Tubular lumen 2CI K+ 2K+ magnesium homeostasis. Several mechanisms enable the kidney to regulate and maintain NKCC2 2+ 2+ serum magnesium concentration within a Ca /Mg - sensing receptor narrow range. In the setting of hypomagnesemia, the kidney decreases magnesium excretion to as K+ little as 0.5% of the filtered load. Conversely, – in the setting of hypermagnesemia, up to 80% CI of the filtered load can be excreted.3 A propor- Barttin tion of circulating magnesium is protein bound, ROMK CLCKA and CLCKB such that only 70% of total plasma magnesium Figure 1 Magnesium transport in the thick ascending limb of the loop of Henle is ultrafilterable.4 In adults, a small fraction of is passive and paracellular, perhaps mediated by paracellin-1 (claudin-16) filtered magnesium is reabsorbed in the proximal and claudin-19. The lumen-positive electrical gradient is the driving force for paracellular magnesium transport and is dependent on potassium exit tubule. In contrast to most other ions, which are via ROMK. Sodium entry and exit are mediated via the furosemide-sensitive primarily reabsorbed in the proximal tubule, NKCC2 and the Na+/K+-ATPase, respectively. The Ca+/Mg2+-sensing receptor the thick ascending limb of the loop of Henle expressed in the basolateral membrane is an important regulator of ROMK and is the main site of magnesium reabsorption NKCC2. Abbreviations: CLCKA and CLCKB, renal chloride channels; NKCC2, + + – (Figure 1). The Ca2+/Mg2+-sensing receptor Na –K –2Cl cotransporter; ROMK, renal outer medulla potassium channel. (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 receptor potential family of cation channels, ascending limb cells and in the distal convo- is expressed in the apical membrane of distal luted tubule, as well as in cells of the parathyroid convoluted tubule and brush-border membrane glands that secrete parathyroid hormone (PTH). of absorptive cells in duodenum; TRPM6 has In hypomagnesemic or hypocalcemic states, the been characterized as a magnesium-permeable rates of calcium and magnesium reabsorption channel.10,11 About 10% of filtered magnesium in the loop of Henle are increased via CASR- is reabsorbed in the distal convoluted tubule mediated stimulation of the Na+–K+–2Cl– by transcellular active transport (Figure 2). As cotransporter and the apical ROMK (renal there is little magnesium reabsorption beyond outer medulla potassium) channel.6 By contrast, the distal tubule, this segment ultimately hypermagnesemia and hypercalcemia inhibit regulates urinary magnesium excretion.12 Na+–K+–2Cl– cotransport and activity of the TRPM7 is a recently discovered magnesium- ROMK channel. permeable ion channel, the role of which in Magnesium transport in the thick ascending cellular magnesium homeostasis is currently limb is mainly passive in nature, occurring via being investigated.13 a paracellular pathway driven by the electrical gradient that results from potassium exit across CliNical maNIFESTATIONS the apical membrane through ROMK chan- OF HYPOmaGNESemia nels.7,8 Paracellin-1 (claudin-16) is expressed Hypomagnesemia is defined as a serum magne- in tight junctions of the thick ascending limb sium concentration of less than 0.74 mmol/l of the loop of Henle and is required for selective (<1.8 mg/dl). Early symptoms of hypo- paracellular magnesium conductance.9 A trans- magnesemia are nonspecific and include epithelial magnesium transport mechanism lethargy and weakness. More pronounced in intestine and kidney was identified a few hypomagnesemia presents with symptoms of years ago. TRPM6, a member of the transient increased neuromuscular excitability such as ncpneph_2007_134f1.eps FEBRUAry 2008 Vol 4 no 2 NADERI AND REILLY NATURE CLINICAL PRACTICE NEPHROLOGY 81 NNature.indtature.indt 1 228/11/078/11/07 99:46:50:46:50 aamm REVIEW REVIEW www.nature.com/clinicalpractice/neph Apical Basolateral Hypocalcemia, which is common in patients membrane membrane with severe hypomagnesemia (<1.2 mg/dl [<0.5 mmol/l]), is attributable to several patho- Na+/K+-ATPase physiologic processes. In many individuals the concentration of PTH is inappropriately low, NCCT 3Na+ and bone resistance to the effects of PTH is γ a well-documented phenomenon.16,17 The Na+ 2K+ Tubular lumen kidney is also refractory to PTH, as mani- 2+ ? CI– Mg fested by impaired cyclic AMP generation and CLCKB phosphate reabsorption.18 Administration CI– of magnesium immediately increases PTH Barttin EGF receptor concentration, probably as a result of release of EGF preformed PTH from the parathyroid gland; Mg2+ nevertheless, it can take several days for the serum calcium concentration to normalize, presumably because end-organ resistance is slow to resolve. TRPM6 Mutated pro-EGF Abnormalities of vitamin D metabolism Figure 2 The distal convoluted tubule reabsorbs Mg2+ via an active transcellular route. Mg2+ entry is via the TRPM6 channel.