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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

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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

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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. Mg2+ has to be have also been described in patients with hypo­ extruded at the basolateral membrane against an electrochemical gradient. magnesemia. Serum calcitriol concentration An Na+/Mg2+-dependent exchange mechanism and/or Mg2+-ATPase have is decreased and does not increase when been postulated to facilitate Mg2+ extrusion, but the actual mechanism the diet is low in calcium.19 Calcitriol levels + + remains to be proven. Mutations in the γ subunit of the basolateral Na /K - recover slowly following magnesium reple- 2+ ATPase result in Mg wasting in the distal convoluted tubule. The majority tion. Hypomagnesemia impairs the synthesis of patients with Gitelman syndrome have dysfunctional NCCT; a minority 19 harbor mutated CLCKB, which accounts for the overlap between Gitelman of 1α‑hydroxylase. Increased rates of calcitriol syndrome and classic Bartter syndrome type III. Aberrant targeting of pro-EGF clearance, as well as bone and intestinal to the basolateral membrane reduces EGF production, activation of the EGF resistance to the effects of calcitriol, have also receptor and TRPM6 activity, leading to Mg2+ wasting. Abbreviations: CLCKB, been described.20 Chondrocalcinosis has been renal chloride channel; EGF, epidermal growth factor; NCCT, sodium–chloride described as a complication of chronic hypo- cotransporter; pro-EGF, epidermal growth factor precursor protein; TRPM6, magnesemia, especially in patients with Gitelman transient receptor potential cation channel, subfamily M, member 6. syndrome21–23 and those with autosomal dominant hypomagnesemia with hypocalciuria.

tremor, carpopedal spasm, muscle cramps, tetany Etiology and diagnosis and generalized seizures. Hypomagnesemia can of hypomagnesemia cause cardiac arrhythmias including atrial and Hypomagnesemia results from negative magne- ventricular tachycardia, prolonged QT interval sium balance that develops in the setting of and torsades de pointes. decreased oral intake, increased gastrointestinal Hypomagnesemia is frequently associated with or renal losses, or a shift of magnesium from other electrolyte abnormalities such as hypo­ the extracellular to intracellular compart- kalemia and hypocalcemia. In human volunteers, ment. Most frequently, hypomagnesemia is an hypomagnesemia was found to result in hypo- acquired disorder; only in rare instances does calcemia and hypokalemia despite adequate hypomagnesemia have an underlying hereditary calcium and potassium intake.14 The mechanism etiology.24,25 Box 1 summarizes the etiologies by which hypomagnesemia leads to hypo­ of hypomagnesemia. kalemia is not well understood. Cells in the thick Measurement of urinary magnesium excre- ascending limb of the loop of Henle, as well as tion is helpful in the differentiation of renal in the cortical collecting duct, secrete potassium from extrarenal causes of magnesium wasting. into the lumen via an ATP-inhibitable luminal In the setting of hypomagnesemia, assess- potassium channel. Depletion of intracellular ment of urinary magnesium excretion helps magnesium stores, as in states of hypo­ differentiate renal magnesium wasting from magnesemia, could reduce intracellular ATP extrarenal magnesium loss. The kidney’s concentration and subsequently increase the physiologic response to hypomagnesemia is to rate of potassium secretion.15 increase reabsorption. When sampled via a 24 h ncpneph_2007_134f2.eps

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collection, magnesium excretion in the urine Box 1 Etiologies of hypomagnesemia. is expected to be less than 1 mmol (<24 mg) per day.26 More severe magnesuria indicates Decreased magnesium intake Increased gastrointestinal magnesium loss renal magnesium wasting. It is more conve- ■ Diarrhea65 nient in clinical practice to measure fractional urinary magnesium excretion, as this requires ■ Malabsorption only a spot urine sample. In states of extrarenal ■ Steatorrhea magnesium wasting, the fractional excretion is Small bowel bypass less than 2%, whereas with renal magnesium ■ wasting the fractional excretion exceeds 4%.27 Increased renal magnesium excretion In a patient with renal magnesium wasting, ■ Extracellular fluid volume expansion measurement of urinary magnesium excretion ■ Hypercalcemia might be misleading if it is performed when Medication: loop and thiazide diuretics;66 the patient is in a fasting basal state; the rate of ■ amphotericin; pentamidine; cisplatin; excretion might not be elevated if the kidneys foscarnet; ciclosporin;67,68 proton-pump have reached their low tubular reabsorptive inhibitors69 maximum. In this setting, renal magnesium wasting can be diagnosed on the basis of detec- Other etiologies ■ Acute pancreatitis: magnesium and calcium tion of hypermagnesuria after administration saponification in necrotic fat70 of magnesium. ■ Alcohol-induced tubular dysfunction71

Hereditary causes ■ Hungry bone syndrome72 of hypomagnesemia Diabetes mellitus73 Advances in molecular genetics have led to the ■ identification of several hereditary forms of Hereditary causes24 hypomagnesemia. Although hereditary etiolo- ■ Intestinal and renal: hypomagnesemia with secondary hypocalcemia (HSH; TRPM6 gies are a rare cause of hypomagnesemia, 11,43 characterization of these disorders has mutations ) enhanced understanding of renal and intestinal ■ Renal: Bartter syndrome;36,57 Gitelman magnesium transport. Hereditary forms of syndrome;74 familial hypomagnesemia hypomagnesemia develop in the setting of renal with hypercalciuria and nephrocalcinosis 75 magnesium wasting and/or intestinal magnesium (FHHNC; claudin-16 [paracellin-1] and claudin-19 mutations); autosomal dominant malabsorption (Table 1). hypomagnesemia with hypocalciuria (Na+/K+- ATPase γ subunit mutations);37 isolated Familial hypomagnesemia recessive hypomagnesemia;41 autosomal with hypercalciuria and nephrocalcinosis dominant hypocalcemia (Ca2+/Mg2+-sensing Familial hypomagnesemia with hypercalciuria receptor activating mutations)5,76 and nephrocalcinosis (FHHNC) is an autosomal recessive disorder characterized by excessive renal magnesium and calcium wasting. FHHNC is caused by mutations of the CLDN16 gene, which modulates paracellular conductance by selectively is located on chromosome 3q27–29. The CLDN16 increasing Na+ permeability (without exerting an gene encodes paracellin-1, a renal tight junction effect on Cl–).31 The ratio of the permeability of protein.28 Paracellin-1 is expressed in the thick Na+ over Cl– was 1.21 ± 0.01 in cells expressing ascending limb of the loop of Henle and in the paracellin-1 versus 0.29 ± 0.01 in control cells, distal convoluted tubule, where reabsorption which indicates that expression of paracellin‑1 of magnesium occurs predominantly by para­ preferentially enhances cation permeability cellular flux, a process driven by a lumen-positive across the tight junction. Paracellin‑1 expres- transepithelial potential.29 Results from experi- sion increased the permeability of the tight mental studies show that the association between junction to Na+, Li+, K+, Rb+ and Cs+, to about paracellin-1 and the tight-junction-associated the same degree for each (25.1–29.6 × 10–6 cm/s). cytoplasmic molecule ZO-1 augments magne- Interestingly, the magnitude of the effect on sium reabsorption in renal epithelial cells.30 By these ions was greater than that on Mg2+ contrast, it has been suggested that paracellin-1 (10.7 ± 0.06 × 10–6 cm/s). Analysis of families with

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Table 1 Hereditary causes of hypomagnesemia, and the affected genes and proteins. Hereditary cause OMIM® Gene Chromosome Protein of hypomagnesemia reference Familial hypomagnesemia with 603959 CLDN16 3q27–29 Paracellin-1 (claudin-16), found at tight junctions in hypercalciuria and nephrocalcinosis thick ascending limb of the loop of Henle and distal convoluted tubule Familial hypomagnesemia with 610036 CLDN19 1p34.2 Claudin-19, found at tight junctions in the thick hypercalciuria and nephrocalcinosis ascending limb of the loop of Henle and to a much with ocular manifestation lesser extent in the distal convoluted tubule Autosomal dominant 154020 FXYD2 11q23 γ subunit of basolateral Na+/K+-ATPase in distal hypomagnesemia with hypocalciuria convoluted tubule Isolated recessive hypomagnesemia NA EGF 4q25 The pro-EGF–Pro1070Ala mutation leads to impaired with normocalciuria basolateral sorting of pro-EGF, resulting in decreased stimulation of the EGF receptor, which is localized at the basolateral membrane of distal convoluted tubule Hypomagnesemia with secondary 602014 TRPM6 9q22 TRPM6 is expressed in distal convoluted tubule and hypocalcemia in intestine Activating mutations of the 601199 CASR 3q13.3–q21 Ca2+/Mg2+-sensing receptor in chief cells of extracellular Ca2+/Mg2+-sensing parathyroid gland and basolateral membrane in receptor thick ascending limb of the loop of Henle and distal convoluted tubule Gitelman syndrome 263800 SLC12A3 16q13 NCCT in distal convoluted tubule Antenatal Bartter syndrome type I 601678 SLC12A1 15q15–q21.1 NKCC2 in thick ascending limb of the loop of Henle Antenatal Bartter syndrome type II 241200 KCNJ1 11q24 ROMK in thick ascending limb of the loop of Henle Classic Bartter syndrome type III 607364 CLCNKB 1p36 CLCKB in thick ascending limb of the loop of Henle Bartter syndrome with sensorineural 602522 BSND, or 1p31, 1p36 Barttin acts as an essential β subunit for CLCKA and deafness type IV CLCNKA plus CLCKB, which are located in the basolateral membrane CLCNKB of thick ascending limb of the loop of Henle Abbreviations: CLCKA and CLCKB, renal chloride channels; EGF, epidermal growth factor; NA, not available; NCCT, sodium–chloride cotransporter; NKCC2, Na+–K+–2Cl– cotransporter; OMIM, Online Mendelian Inheritance in Man® (Johns Hopkins University, Baltimore, MD; www.ncbi.nlm.nih.gov/sites/ entrez?db=OMIM); pro-EGF, epidermal growth factor precursor protein; ROMK, renal outer medulla potassium channel; TRPM6, transient receptor potential cation channel, subfamily M, member 6.

FHHNC has identified 12 missense mutations in Symptoms of FHHNC usually become paracellin-1. These mutations were expressed evident in the first few months of life. Affected in LLC-PK1 (pig kidney epithelial) cells, and individuals present with symptoms including several subgroups of defects were identified polyuria, polydipsia, urinary tract infec- including the following: a lack of stable expres- tions, hypomagnesemia, inappropriately high sion; confinement of expressed protein to the rates of urinary magnesium excretion, hyper­ endoplasmic reticulum and Golgi apparatus; calciuria, nephrocalcinosis, nephrolithiasis, and complete or partial loss of function despite hypocitraturia, elevated PTH levels, renal expression at the tight junction.31 insufficiency and, in rare instances, generalized In the thick ascending limb there is a driving seizures.32,33 Incomplete distal renal tubular force for Na+ backflux from the peritubular acidosis, which was corrected by magnesium and paracellular spaces to the tubular lumen. supplementation, has been described in patients The movement of Na+ down its concentration with FHHNC.34 Hypercalciuria and recurrent gradient would serve to augment the lumen- nephrolithiasis were found in 42% of ‘unaffected’ ­positive voltage. Taken together, these data family members of patients with the disorder. indicate that paracellin-1 controls the trans­ The mean age at diagnosis is 15 years, with a epithelial voltage, which is the primary driving range of 5–25 years. In contrast to patients with force for the paracellular movement of Mg2+ hypomagnesemia with secondary hypocalcemia and Ca2+. Whether other claudins also partici- (HSH; see below), the risk of permanent neuro- pate in the paracellular transport of Mg2+ and logic impairment in patients with FHHNC is Ca2+ remains to be determined. relatively low.

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Recently, a study described nine families with a dominant-negative mutation in FXYD2 causes severe hypomagnesemia with mutations of misrouting of the Na+/K+-ATPase γ subunit.40 CLDN19 that share the same renal phenotype Depolarization, reduced levels of intracellular K+ as FHHNC. CLDN19 encodes claudin-19, a tight or increased concentrations of intracellular Na+ junction protein expressed in renal tubules and could then lead to reduced Mg2+ reabsorption eye.35 In contrast to patients with a CLDN16 and Mg2+ wasting.39 defect, affected individuals harboring a CLDN19 mutation had ocular symptoms that included Isolated recessive hypomagnesemia severe visual impairment, macular colobomata, with normocalciuria horizontal nystagmus and marked myopia.36 Isolated recessive hypomagnesemia (IRH) is Therapeutic approaches to management of a rare hereditary disease that was originally patients with severe hypomagnesemia with described in a consanguineous family.41 The mutations of CLDN19 include oral magnesium affected individuals presented with symptoms supplementation, as well as thiazide diuretics of hypomagnesemia during early infancy. IRH to reduce renal calcium excretion and progres- is due to a mutation of the epidermal growth sion of nephrocalcinosis. Renal transplantation factor (EGF) precursor protein pro-EGF, which is curative, as the primary defect resides in is expressed in the basolateral membrane of the the kidney. distal convoluted tubule. Physiologically, pro-EGF is cleaved by extracellular proteases in the baso- Autosomal dominant hypomagnesemia lateral space into the active molecule EGF. EGF with hypocalciuria acts as an autocrine/paracrine magnesiotropic In 1987, Geven et al. described two patients with hormone by activating the basolateral EGF generalized convulsions, hypomagnesemia and receptor, causing an increase in luminal TRPM6 hypocalciuria.37 One of the patients became activity and enhanced luminal magnesium symptomatic during infancy and was treated with uptake in the distal convoluted tubule. In IRH, antiepileptic medication until hypomagnesemia the Pro1070Leu mutation in the cytoplasmic was diagnosed years later. The second developed domain of the pro-EGF precursor protein symptoms during adolescence. Further evalua- prevents EGF secretion into the basolateral tion of the patients revealed hypomagnesemia space. This leads to decreased TRPM6-mediated and hypocalciuria with an autosomal domi- magnesium uptake by the distal convoluted nant mode of inheritance in both families. tubule from the luminal membrane, and to renal Interestingly, other family members remained magnesium wasting.42 asymptomatic. Autosomal dominant hypo­ magnesemia with hypocalciuria was subsequently Hypomagnesemia with secondary linked to a heterozygous mutation (Gly41Arg) hypocalcemia of FXYD2, which is located on chromosome HSH is an autosomal recessive disorder of intes- 11q23.38 FXYD2 encodes a γ subunit of the tinal and renal magnesium transport caused basolateral Na+/K+-ATPase, which is expressed by mutations of TRPM6.11,43 In intestine, in the basolateral membrane of distal convo- magnesium is absorbed by saturable trans­ luted tubule cells, the main sites of active renal cellular transport, as well as by paracellular Mg2+ reabsorption. Mutation of FXYD2 leads passive transport.44 TRPM6 mutations cause to misrouting of the Na+/K+-ATPase γ subunit, a defect in the active transcellular pathway which results in abnormal Mg2+ reabsorption. of intestinal magnesium absorption. HSH is Expression studies in COS-1 cells showed that characterized by extremely low serum magne- the mutated protein accumulated in perinuclear sium levels.45 Patients with HSH present with structures.39 Further analysis by Western blot- generalized seizures due to profound hypo- ting in a Xenopus oocyte expression system magnesemia and hypocalcemia, during the revealed that the mutant subunit lacked post- first months of life. Hypocalcemia is thought translational modifications that were present in to develop in the setting of hypomagnesemia- the wild-type protein.40 In addition, two indi- induced inhibition of PTH synthesis and release viduals who each lacked one copy of FXYD2 from the parathyroid gland.46 Patients with were identified. Interestingly, the serum magne- HSH require intravenous magnesium during sium concentrations of these individuals were convulsive episodes and lifelong high-dose oral normal. Taken together, these data indicate that magnesium replacement.47

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Activating mutations of the patients with Gitelman syndrome have been Ca2+/Mg2+-sensing receptor diagnosed with mutations of CLCNKB, the CASR has an important role in magnesium and gene that encodes the basolaterally located calcium homeostasis. CASR is a G-protein-coupled renal chloride channel CLCKB, which is receptor located in the basolateral membrane of expressed along the thick ascending limb the thick ascending limb of the loop of Henle and distal convoluted tubule and mediates and the distal convoluted tubule, as well as in chloride efflux from tubular epithelial cells to the plasma membrane of cells in the parathyroid the interstitium. This overlap between Gitelman gland.5 CASR senses ionized serum calcium and syndrome and classic Bartter syndrome type III magnesium concentrations and is involved in (see below) is probably related to the fact that renal calcium and magnesium reabsorption as CLCKB is present in both the thick ascending well as in PTH secretion.48 Activating muta- limb of the loop of Henle and the distal tions of CASR result in autosomal dominant convoluted tubule. hypocalcemia (ADH).49–51 The underlying Investigation of patients with Gitelman pathophysiology of ADH is a decreased CASR syndrome has led to the identification of many set point, which leads to decreased PTH different loss-of-function mutations in the release, as well as diminished renal calcium and disorder. The type of mutation, as well as magnesium reabsorption in the setting of low the compound heterozygous versus homo­ serum concentrations of both divalent cations. zygous nature of the mutation, might account Clinically, ADH can be mistaken for primary for the wide clinical and biochemical spectrum hypoparathyroidism, as there is decreased PTH observed in affected patients. Riveira-Munoz secretion in the setting of mild to moderate et al. carried out extensive mutational analysis hypocalcemia. Patients can be asymptomatic or in 27 subjects.54 They identified 26 muta- have symptoms related to hypocalcemia during tions in 25 individuals: 22 missense mutations, childhood. The majority of affected individuals 3 splice-site mutations and 1 duplication. have hypomagnesemia and renal magnesium Heterozygosity was observed for all identified wasting. ADH must be differentiated from mutations. Two mutant alleles were detected in primary hypoparathyroidism because there is an the majority of affected individuals, although increased risk of hypercalciuria, nephrocalcinosis in six patients only one mutated allele was identi­ and even irreversible reduction of renal func- fied. Mutations were distributed throughout tion in individuals with ADH who are treated SLC12A3. The splicing mutations generated with vitamin D. Only patients with ADH with frame-shifted messenger RNA that was degraded symptomatic hypocalcemia should be treated by nonsense-mediated decay. Severe phenotypes with calcium and vitamin D. were associated with at least one mutated allele causing either expression of a protein that was Hereditary renal salt-wasting tubulopathies nonfunctional and intracellularly retained, or Gitelman syndrome and Bartter syndrome are missplicing yielding a short transcript that was two renal salt-wasting disorders characterized degraded by nonsense-mediated decay. Male sex by hypokalemic chloride-resistant metabolic was associated with a more-severe phenotype. alkalosis, elevated plasma levels of renin and Thiazide diuretic abuse and Gitelman syndrome aldosterone, and normal blood pressure. have similar clinical phenotypes, as both inhibit Hypomagnesemia and renal magnesium wasting NCCT and enhance delivery of NaCl to the are distinctive features of Gitelman syndrome. collecting tubule.55 By contrast, there is doubt as to whether magne- Patients with Gitelman syndrome usually sium metabolism is ever markedly abnormal in become symptomatic later in life than those with patients with true Bartter syndrome. Bartter syndrome; that is, during adolescence Gitelman syndrome is an autosomal recessive or early adulthood. In one study, 50 patients disorder caused by mutations in the SLC12A3 with Gitelman syndrome were compared with gene that encodes the sodium–chloride 25 age-matched and sex-matched controls.56 cotransporter NCCT (also known as the thiazide- Symptoms and quality of life were evaluated sensitive NaCl cotransporter), which is with a standardized questionnaire. The most expressed in the distal convoluted tubule.52,53 common symptoms were musculoskeletal (i.e. NCCT reabsorbs approximately 7% of the cramps, muscle weakness, carpopedal spasm, filtered sodium chloride load. A minority of muscle stiffness and arthralgias) and renal (i.e.

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salt craving, nocturia, polydipsia and thirst). Bartter syndrome. Patients usually become Other common symptoms included paresthe- symptomatic during infancy or early child- sias, palpitations, fatigue, dizziness and fainting. hood, and present with polyuria, polydipsia, A substantial fraction of patients (45%) consid- growth retardation and developmental delay. ered their symptoms to be moderately or severely Disturbed magnesium homeostasis is not a problematic. Sixty-five per cent of patients had common finding in patients with antenatal visited an emergency room for treatment of Bartter syndrome. their symptoms; 16–18% had visited the emer- gency room five or more times for intravenous CONCLUSIONS K+ or Mg2+ replacement. Quality of life scores Hypomagnesemia is a common laboratory were lower in patients with Gitelman syndrome finding in clinical practice and affects patients than in controls. The cost of medication and the with a variety of underlying diseases. In most number of pills required to maintain normal cases, hypomagnesemia is a result of renal or electrolyte concentrations contributed to these intestinal magnesium wasting (Box 1), which low scores. Quality of life measures were equally eventually leads to total body magnesium deple- poor in both sexes. Self-perception of physical tion. In the majority of patients, hypomagnesemia health, emotional wellbeing, energy level and is the result of an acquired magnesium-wasting general health were all poorer in affected patients disorder. Hereditary causes of hypomagnesemia than in controls. are less frequently encountered; most patients Classic Bartter syndrome57 is caused by muta- become symptomatic during the first two tions of the CLCNKB gene.58,59 The antenatal decades of life. In the past two decades, advances form of Bartter syndrome is life threatening. in molecular genetics and other basic sciences Antenatal Bartter syndrome type I is caused have contributed much to our understanding of by mutations in the Na+–K+–2Cl– cotrans- the underlying etiology and pathophysiology porter gene (SLC12A1) and is clinically and of inherited forms of hypomagnesemia. The recent biochemically very similar to antenatal Bartter discovery that EGF acts as an autocrine/paracrine syndrome type II, which is caused by muta- magnesiotropic hormone shows how vibrant tion of the potassium channel ROMK1 gene the current research into mammalian Mg2+ (KCNJ1).60–62 In utero, polyuria of the affected homeostasis is. fetus leads to polyhydramnios between 24 and 30 weeks of gestation and premature key points delivery. Postnatally, infants rapidly develop ■ Magnesium deficiency is probably more renal salt wasting, hypokalemic metabolic prevalent than is recognized; this condition alkalosis, hypercalciuria and, as secondary has been linked to common disorders such consequences, nephrocalcinosis and osteopenia. as diabetes, hypertension and cardiovascular Hypermagnesuria is not a characteristic feature disease of this disease. Increased magnesium reabsorp- ■ Hypomagnesemia is frequently associated tion in the distal nephron or increased renal with other electrolyte abnormalities such as prostaglandin synthesis, which is observed in hypokalemia and hypocalcemia; patients antenatal Bartter syndrome, might contribute present with symptoms of increased to increased magnesium reabsorption in the neuromuscular excitability distal convoluted tubule. ■ Hypomagnesemia can cause severe, Bartter syndrome type IV is the combination potentially fatal, cardiac arrhythmias of the infantile variant of Bartter syndrome In most cases, hypomagnesemia results and sensorineural deafness, which can develop ■ from acquired forms of renal and/or intestinal during the first month of life. Bartter syndrome magnesium wasting type IV is caused by mutation of the BSND (infantile Bartter syndrome with sensorineural ■ Hereditary causes of hypomagnesmia are rare; deafness) gene or by simultaneous muta- patients usually become symptomatic during the first two decades of life tion of both the CLCNKA (which encodes the renal chloride channel CLCKA) and ■ Recent advances in characterization of CLCNKB genes.63,64 hereditary magnesium disorders has Hypomagnesemia is detected in only up enhanced understanding of renal and intestinal to 50% of affected individuals with classic magnesium transport mechanisms

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