Review

Continuing Medical EducationNature Clinical Practice Nephrology (2008) 4, 80-89
doi:10.1038/ncpneph0680  
Received 4 July 2007 | Accepted 20 September 2007

Hereditary etiologies of hypomagnesemia

Amir Said Alizadeh Naderi* and Robert F Reilly Jr  About the authors

Correspondence *Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8837, USA

Email anader@parknet.pmh.org

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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 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, endocrine, and metabolic abnormalities occurring with hypomagnesemia.
  5. Describe the inheritance patterns of hereditary causes of hypomagnesemia.

Competing interests

Désirée Lie, the CME questions author, declared no relevant financial relationships.

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Summary

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.

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".

Keywords:

Bartter syndrome, Gitelman syndrome, hypomagnesemia, renal Mg2+ handling

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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 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 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

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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 CASR-mediated 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.

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.
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. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

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.

Full figure and legend (23K)Figures & Tables indexDownload PowerPoint slide (135K)

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 transepithelial magnesium transport mechanism in intestine and kidney was identified a few years ago. TRPM6, a member of the transient 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 magnesium-permeable ion channel, the role of which in cellular magnesium homeostasis is currently being investigated.13

Figure 2 The distal convoluted tubule reabsorbs Mg2+ via an active transcellular route.
Figure 2 : The distal convoluted tubule reabsorbs Mg2+ via an active transcellular route. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Mg2+ entry is via the TRPM6 channel. Mg2+ has to be extruded at the basolateral membrane against an electrochemical gradient. An Na+/Mg2+-dependent exchange mechanism and/or Mg2+-ATPase have been postulated to facilitate Mg2+ extrusion, but the actual mechanism remains to be proven. Mutations in the gamma subunit of the basolateral Na+/K+-ATPase result in Mg2+ wasting in the distal convoluted tubule. The majority of patients with Gitelman syndrome have dysfunctional NCCT; a minority harbor mutated CLCKB, which accounts for the overlap between Gitelman syndrome and classic Bartter syndrome type III. Aberrant targeting of pro-EGF to the basolateral membrane reduces EGF production, activation of the EGF receptor and TRPM6 activity, leading to Mg2+ wasting. Abbreviations: CLCKB, renal chloride channel; EGF, epidermal growth factor; NCCT, sodium–chloride cotransporter; pro-EGF, epidermal growth factor precursor protein; TRPM6, transient receptor potential cation channel, subfamily M, member 6.

Full figure and legend (18K)Figures & Tables indexDownload PowerPoint slide (155K)

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Clinical manifestations of hypomagnesemia

Hypomagnesemia is defined as a serum magnesium concentration of less than 0.74 mmol/l (<1.8 mg/dl). Early symptoms of hypomagnesemia are nonspecific and include lethargy and weakness. More pronounced hypomagnesemia presents with symptoms of increased neuromuscular excitability such as tremor, carpopedal spasm, muscle cramps, tetany and generalized seizures. Hypomagnesemia can cause cardiac arrhythmias including atrial and ventricular tachycardia, prolonged QT interval and torsades de pointes.

Hypomagnesemia is frequently associated with other electrolyte abnormalities such as hypokalemia and hypocalcemia. In human volunteers, hypomagnesemia was found to result in hypocalcemia and hypokalemia despite adequate calcium and potassium intake.14 The mechanism by which hypomagnesemia leads to hypokalemia is not well understood. Cells in the thick ascending limb of the loop of Henle, as well as in the cortical collecting duct, secrete potassium into the lumen via an ATP-inhibitable luminal potassium channel. Depletion of intracellular magnesium stores, as in states of hypomagnesemia, could reduce intracellular ATP concentration and subsequently increase the rate of potassium secretion.15

Hypocalcemia, which is common in patients with severe hypomagnesemia (<1.2 mg/dl [<0.5 mmol/l]), is attributable to several pathophysiologic processes. In many individuals the concentration of PTH is inappropriately low, and bone resistance to the effects of PTH is a well-documented phenomenon.16, 17 The kidney is also refractory to PTH, as manifested by impaired cyclic AMP generation and phosphate reabsorption.18 Administration of magnesium immediately increases PTH concentration, probably as a result of release of preformed PTH from the parathyroid gland; nevertheless, it can take several days for the serum calcium concentration to normalize, presumably because end-organ resistance is slow to resolve.

Abnormalities of vitamin D metabolism have also been described in patients with hypomagnesemia. Serum calcitriol concentration is decreased and does not increase when the diet is low in calcium.19 Calcitriol levels recover slowly following magnesium repletion. Hypomagnesemia impairs the synthesis of 1alpha-hydroxylase.19 Increased rates of calcitriol clearance, as well as bone and intestinal resistance to the effects of calcitriol, have also been described.20 Chondrocalcinosis has been described as a complication of chronic hypomagnesemia, especially in patients with Gitelman syndrome21, 22, 23 and those with autosomal dominant hypomagnesemia with hypocalciuria.

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Etiology and diagnosis of hypomagnesemia

Hypomagnesemia results from negative magnesium balance that develops in the setting of decreased oral intake, increased gastrointestinal or renal losses, or a shift of magnesium from the extracellular to intracellular compartment. Most frequently, hypomagnesemia is an acquired disorder; only in rare instances does hypomagnesemia have an underlying hereditary etiology.24, 25 Box 1 summarizes the etiologies of hypomagnesemia.

Box 1 Etiologies of hypomagnesemia.

 

Decreased magnesium intake

Increased gastrointestinal magnesium loss

  • Diarrhea65
  • Malabsorption
  • Steatorrhea
  • Small bowel bypass

 

Increased renal magnesium excretion

  • Extracellular fluid volume expansion
  • Hypercalcemia
  • Medication: loop and thiazide diuretics;66 amphotericin; pentamidine; cisplatin; foscarnet; ciclosporin;67, 68 proton-pump inhibitors69

 

Other etiologies

  • Acute pancreatitis: magnesium and calcium saponification in necrotic fat70
  • Alcohol-induced tubular dysfunction71
  • Hungry bone syndrome72
  • Diabetes mellitus73

 

Hereditary causes24

  1. Intestinal and renal: hypomagnesemia with secondary hypocalcemia (HSH; TRPM6 mutations11, 43)
  2. Renal: Bartter syndrome;36, 57 Gitelman syndrome;74 familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; claudin-16 [paracellin-1]75 and claudin-19 mutations); autosomal dominant hypomagnesemia with hypocalciuria (Na+/K+-ATPase gamma subunit mutations);37 isolated recessive hypomagnesemia;41 autosomal dominant hypocalcemia (Ca2+/Mg2+-sensing receptor activating mutations)5, 76

Measurement of urinary magnesium excretion is helpful in the differentiation of renal from extrarenal causes of magnesium wasting. In the setting of hypomagnesemia, assessment of urinary magnesium excretion helps differentiate renal magnesium wasting from extrarenal magnesium loss. The kidney's physiologic response to hypomagnesemia is to increase reabsorption. When sampled via a 24 h collection, magnesium excretion in the urine is expected to be less than 1 mmol (<24 mg) per day.26 More severe magnesuria indicates renal magnesium wasting. It is more convenient in clinical practice to measure fractional urinary magnesium excretion, as this requires only a spot urine sample. In states of extrarenal magnesium wasting, the fractional excretion is less than 2%, whereas with renal magnesium wasting the fractional excretion exceeds 4%.27 In a patient with renal magnesium wasting, measurement of urinary magnesium excretion might be misleading if it is performed when the patient is in a fasting basal state; the rate of excretion might not be elevated if the kidneys have reached their low tubular reabsorptive maximum. In this setting, renal magnesium wasting can be diagnosed on the basis of detection of hypermagnesuria after administration of magnesium.

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Hereditary causes of hypomagnesemia

Advances in molecular genetics have led to the identification of several hereditary forms of hypomagnesemia. Although hereditary etiologies are a rare cause of hypomagnesemia, characterization of these disorders has enhanced understanding of renal and intestinal magnesium transport. Hereditary forms of hypomagnesemia develop in the setting of renal magnesium wasting and/or intestinal magnesium malabsorption (Table 1).

Table 1 Hereditary causes of hypomagnesemia, and the affected genes and proteins.
Table 1 - Hereditary causes of hypomagnesemia, and the affected genes and proteins.
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Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Familial hypomagnesemia with hypercalciuria 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 is located on chromosome 3q27–29. The CLDN16 gene encodes paracellin-1, a renal tight junction protein.28 Paracellin-1 is expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule, where reabsorption of magnesium occurs predominantly by paracellular flux, a process driven by a lumen-positive transepithelial potential.29 Results from experimental studies show that the association between paracellin-1 and the tight-junction-associated cytoplasmic molecule ZO-1 augments magnesium reabsorption in renal epithelial cells.30 By contrast, it has been suggested that paracellin-1 modulates paracellular conductance by selectively increasing Na+ permeability (without exerting an effect on Cl-).31 The ratio of the permeability of Na+ over Cl- was 1.21 plusminus 0.01 in cells expressing paracellin-1 versus 0.29 plusminus 0.01 in control cells, which indicates that expression of paracellin-1 preferentially enhances cation permeability across the tight junction. Paracellin-1 expression increased the permeability of the tight junction to Na+, Li+, K+, Rb+ and Cs+, to about the same degree for each (25.1–29.6 times 10-6 cm/s). Interestingly, the magnitude of the effect on these ions was greater than that on Mg2+ (10.7 plusminus 0.06 times 10-6 cm/s). Analysis of families with FHHNC has identified 12 missense mutations in paracellin-1. These mutations were expressed in LLC-PK1 (pig kidney epithelial) cells, and several subgroups of defects were identified including the following: a lack of stable expression; confinement of expressed protein to the endoplasmic reticulum and Golgi apparatus; and complete or partial loss of function despite expression at the tight junction.31

In the thick ascending limb there is a driving force for Na+ backflux from the peritubular and paracellular spaces to the tubular lumen. The movement of Na+ down its concentration gradient would serve to augment the lumen-positive voltage. Taken together, these data indicate that paracellin-1 controls the transepithelial voltage, which is the primary driving force for the paracellular movement of Mg2+ and Ca2+. Whether other claudins also participate in the paracellular transport of Mg2+ and Ca2+ remains to be determined.

Symptoms of FHHNC usually become evident in the first few months of life. Affected individuals present with symptoms including polyuria, polydipsia, urinary tract infections, hypomagnesemia, inappropriately high rates of urinary magnesium excretion, hypercalciuria, nephrocalcinosis, nephrolithiasis, hypocitraturia, elevated PTH levels, renal insufficiency and, in rare instances, generalized seizures.32, 33 Incomplete distal renal tubular acidosis, which was corrected by magnesium supplementation, has been described in patients with FHHNC.34 Hypercalciuria and recurrent nephrolithiasis were found in 42% of 'unaffected' family members of patients with the disorder. The mean age at diagnosis is 15 years, with a range of 5–25 years. In contrast to patients with hypomagnesemia with secondary hypocalcemia (HSH; see below), the risk of permanent neurologic impairment in patients with FHHNC is relatively low.

Recently, a study described nine families with severe hypomagnesemia with mutations of CLDN19 that share the same renal phenotype as FHHNC. CLDN19 encodes claudin-19, a tight junction protein expressed in renal tubules and eye.35 In contrast to patients with a CLDN16 defect, affected individuals harboring a CLDN19 mutation had ocular symptoms that included severe visual impairment, macular colobomata, horizontal nystagmus and marked myopia.36 Therapeutic approaches to management of patients with severe hypomagnesemia with mutations of CLDN19 include oral magnesium supplementation, as well as thiazide diuretics to reduce renal calcium excretion and progression of nephrocalcinosis. Renal transplantation is curative, as the primary defect resides in the kidney.

Autosomal dominant hypomagnesemia with hypocalciuria

In 1987, Geven et al. described two patients with generalized convulsions, hypomagnesemia and hypocalciuria.37 One of the patients became symptomatic during infancy and was treated with antiepileptic medication until hypomagnesemia was diagnosed years later. The second developed symptoms during adolescence. Further evaluation of the patients revealed hypomagnesemia and hypocalciuria with an autosomal dominant mode of inheritance in both families. Interestingly, other family members remained asymptomatic. Autosomal dominant hypomagnesemia with hypocalciuria was subsequently linked to a heterozygous mutation (Gly41Arg) of FXYD2, which is located on chromosome 11q23.38 FXYD2 encodes a gamma subunit of the basolateral Na+/K+-ATPase, which is expressed in the basolateral membrane of distal convoluted tubule cells, the main sites of active renal Mg2+ reabsorption. Mutation of FXYD2 leads to misrouting of the Na+/K+-ATPase gamma subunit, which results in abnormal Mg2+ reabsorption. Expression studies in COS-1 cells showed that the mutated protein accumulated in perinuclear structures.39 Further analysis by Western blotting in a Xenopus oocyte expression system revealed that the mutant subunit lacked post-translational modifications that were present in the wild-type protein.40 In addition, two individuals who each lacked one copy of FXYD2 were identified. Interestingly, the serum magnesium concentrations of these individuals were normal. Taken together, these data indicate that a dominant-negative mutation in FXYD2 causes misrouting of the Na+/K+-ATPase gamma subunit.40 Depolarization, reduced levels of intracellular K+ or increased concentrations of intracellular Na+ could then lead to reduced Mg2+ reabsorption and Mg2+ wasting.39

Isolated recessive hypomagnesemia with normocalciuria

Isolated recessive hypomagnesemia (IRH) is a rare hereditary disease that was originally described in a consanguineous family.41 The affected individuals presented with symptoms of hypomagnesemia during early infancy. IRH is due to a mutation of the epidermal growth factor (EGF) precursor protein pro-EGF, which is expressed in the basolateral membrane of the distal convoluted tubule. Physiologically, pro-EGF is cleaved by extracellular proteases in the basolateral space into the active molecule EGF. EGF acts as an autocrine/paracrine magnesiotropic hormone by activating the basolateral EGF receptor, causing an increase in luminal TRPM6 activity and enhanced luminal magnesium uptake in the distal convoluted tubule. In IRH, the Pro1070Leu mutation in the cytoplasmic domain of the pro-EGF precursor protein prevents EGF secretion into the basolateral space. This leads to decreased TRPM6-mediated magnesium uptake by the distal convoluted tubule from the luminal membrane, and to renal magnesium wasting.42

Hypomagnesemia with secondary hypocalcemia

HSH is an autosomal recessive disorder of intestinal and renal magnesium transport caused by mutations of TRPM6.11, 43 In intestine, magnesium is absorbed by saturable transcellular transport, as well as by paracellular passive transport.44 TRPM6 mutations cause a defect in the active transcellular pathway of intestinal magnesium absorption. HSH is characterized by extremely low serum magnesium levels.45 Patients with HSH present with generalized seizures due to profound hypomagnesemia and hypocalcemia, during the first months of life. Hypocalcemia is thought to develop in the setting of hypomagnesemia-induced inhibition of PTH synthesis and release from the parathyroid gland.46 Patients with HSH require intravenous magnesium during convulsive episodes and lifelong high-dose oral magnesium replacement.47

Activating mutations of the Ca2+/Mg2+-sensing receptor

CASR has an important role in magnesium and calcium homeostasis. CASR is a G-protein-coupled receptor located in the basolateral membrane of the thick ascending limb of the loop of Henle and the distal convoluted tubule, as well as in the plasma membrane of cells in the parathyroid gland.5 CASR senses ionized serum calcium and magnesium concentrations and is involved in renal calcium and magnesium reabsorption as well as in PTH secretion.48 Activating mutations of CASR result in autosomal dominant hypocalcemia (ADH).49, 50, 51 The underlying pathophysiology of ADH is a decreased CASR set point, which leads to decreased PTH release, as well as diminished renal calcium and magnesium reabsorption in the setting of low serum concentrations of both divalent cations. Clinically, ADH can be mistaken for primary hypoparathyroidism, as there is decreased PTH secretion in the setting of mild to moderate hypocalcemia. Patients can be asymptomatic or have symptoms related to hypocalcemia during childhood. The majority of affected individuals have hypomagnesemia and renal magnesium wasting. ADH must be differentiated from primary hypoparathyroidism because there is an increased risk of hypercalciuria, nephrocalcinosis and even irreversible reduction of renal function in individuals with ADH who are treated with vitamin D. Only patients with ADH with symptomatic hypocalcemia should be treated with calcium and vitamin D.

Hereditary renal salt-wasting tubulopathies

Gitelman syndrome and Bartter syndrome are two renal salt-wasting disorders characterized by hypokalemic chloride-resistant metabolic alkalosis, elevated plasma levels of renin and aldosterone, and normal blood pressure. Hypomagnesemia and renal magnesium wasting are distinctive features of Gitelman syndrome. By contrast, there is doubt as to whether magnesium metabolism is ever markedly abnormal in patients with true Bartter syndrome.

Gitelman syndrome is an autosomal recessive disorder caused by mutations in the SLC12A3 gene that encodes the sodium–chloride cotransporter NCCT (also known as the thiazide-sensitive NaCl cotransporter), which is expressed in the distal convoluted tubule.52, 53 NCCT reabsorbs approximately 7% of the filtered sodium chloride load. A minority of patients with Gitelman syndrome have been diagnosed with mutations of CLCNKB, the gene that encodes the basolaterally located renal chloride channel CLCKB, which is expressed along the thick ascending limb and distal convoluted tubule and mediates chloride efflux from tubular epithelial cells to the interstitium. This overlap between Gitelman syndrome and classic Bartter syndrome type III (see below) is probably related to the fact that CLCKB is present in both the thick ascending limb of the loop of Henle and the distal convoluted tubule.

Investigation of patients with Gitelman syndrome has led to the identification of many different loss-of-function mutations in the disorder. The type of mutation, as well as the compound heterozygous versus homozygous nature of the mutation, might account for the wide clinical and biochemical spectrum observed in affected patients. Riveira-Munoz et al. carried out extensive mutational analysis in 27 subjects.54 They identified 26 mutations in 25 individuals: 22 missense mutations, 3 splice-site mutations and 1 duplication. Heterozygosity was observed for all identified mutations. Two mutant alleles were detected in the majority of affected individuals, although in six patients only one mutated allele was identified. Mutations were distributed throughout SLC12A3. The splicing mutations generated frame-shifted messenger RNA that was degraded by nonsense-mediated decay. Severe phenotypes were associated with at least one mutated allele causing either expression of a protein that was nonfunctional and intracellularly retained, or missplicing yielding a short transcript that was degraded by nonsense-mediated decay. Male sex was associated with a more-severe phenotype. Thiazide diuretic abuse and Gitelman syndrome have similar clinical phenotypes, as both inhibit NCCT and enhance delivery of NaCl to the collecting tubule.55

Patients with Gitelman syndrome usually become symptomatic later in life than those with Bartter syndrome; that is, during adolescence or early adulthood. In one study, 50 patients with Gitelman syndrome were compared with 25 age-matched and sex-matched controls.56 Symptoms and quality of life were evaluated with a standardized questionnaire. The most common symptoms were musculoskeletal (i.e. cramps, muscle weakness, carpopedal spasm, muscle stiffness and arthralgias) and renal (i.e. salt craving, nocturia, polydipsia and thirst). Other common symptoms included paresthesias, palpitations, fatigue, dizziness and fainting. A substantial fraction of patients (45%) considered their symptoms to be moderately or severely problematic. Sixty-five per cent of patients had visited an emergency room for treatment of their symptoms; 16–18% had visited the emergency room five or more times for intravenous K+ or Mg2+ replacement. Quality of life scores were lower in patients with Gitelman syndrome than in controls. The cost of medication and the number of pills required to maintain normal electrolyte concentrations contributed to these low scores. Quality of life measures were equally poor in both sexes. Self-perception of physical health, emotional wellbeing, energy level and general health were all poorer in affected patients than in controls.

Classic Bartter syndrome57 is caused by mutations of the CLCNKB gene.58, 59 The antenatal form of Bartter syndrome is life threatening. Antenatal Bartter syndrome type I is caused by mutations in the Na+–K+–2Cl- cotransporter gene (SLC12A1) and is clinically and biochemically very similar to antenatal Bartter syndrome type II, which is caused by mutation of the potassium channel ROMK1 gene (KCNJ1).60, 61, 62 In utero, polyuria of the affected fetus leads to polyhydramnios between 24 and 30 weeks of gestation and premature delivery. Postnatally, infants rapidly develop renal salt wasting, hypokalemic metabolic alkalosis, hypercalciuria and, as secondary consequences, nephrocalcinosis and osteopenia. Hypermagnesuria is not a characteristic feature of this disease. Increased magnesium reabsorption in the distal nephron or increased renal prostaglandin synthesis, which is observed in antenatal Bartter syndrome, might contribute to increased magnesium reabsorption in the distal convoluted tubule.

Bartter syndrome type IV is the combination of the infantile variant of Bartter syndrome and sensorineural deafness, which can develop during the first month of life. Bartter syndrome type IV is caused by mutation of the BSND (infantile Bartter syndrome with sensorineural deafness) gene or by simultaneous mutation of both the CLCNKA (which encodes the renal chloride channel CLCKA) and CLCNKB genes.63, 64

Hypomagnesemia is detected in only up to 50% of affected individuals with classic Bartter syndrome. Patients usually become symptomatic during infancy or early childhood, and present with polyuria, polydipsia, growth retardation and developmental delay. Disturbed magnesium homeostasis is not a common finding in patients with antenatal Bartter syndrome.

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Conclusions

Hypomagnesemia is a common laboratory finding in clinical practice and affects patients with a variety of underlying diseases. In most cases, hypomagnesemia is a result of renal or intestinal magnesium wasting (Box 1), which eventually leads to total body magnesium depletion. In the majority of patients, hypomagnesemia is the result of an acquired magnesium-wasting disorder. Hereditary causes of hypomagnesemia are less frequently encountered; most patients become symptomatic during the first two decades of life. In the past two decades, advances in molecular genetics and other basic sciences have contributed much to our understanding of the underlying etiology and pathophysiology of inherited forms of hypomagnesemia. The recent discovery that EGF acts as an autocrine/paracrine magnesiotropic hormone shows how vibrant the current research into mammalian Mg2+ homeostasis is.

Key points

  • Magnesium deficiency is probably more prevalent than is recognized; this condition has been linked to common disorders such as diabetes, hypertension and cardiovascular disease
  • Hypomagnesemia is frequently associated with other electrolyte abnormalities such as hypokalemia and hypocalcemia; patients present with symptoms of increased neuromuscular excitability
  • Hypomagnesemia can cause severe, potentially fatal, cardiac arrhythmias
  • In most cases, hypomagnesemia results from acquired forms of renal and/or intestinal magnesium wasting
  • Hereditary causes of hypomagnesmia are rare; patients usually become symptomatic during the first two decades of life
  • Recent advances in characterization of hereditary magnesium disorders has enhanced understanding of renal and intestinal magnesium transport mechanisms

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Acknowledgments

Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Genetics of renal disease | Acid-base, fluid and electrolyte disorders

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