Genetics of Hereditary Disorders of Magnesium Homeostasis

Pediatr Nephrol (2004) 19:13–25 DOI 10.1007/s00467-003-1293-z REVIEW Karl P. Schlingmann · Martin Konrad · Hannsjrg W. Seyberth Genetics of hereditary disorders of magnesium homeostasis Received: 28 April 2003 / Revised: 25 July 2003 / Accepted: 28 July 2003 / Published online: 22 November 2003 IPNA 2003 Abstract Magnesium plays an essential role in many transporters and in signal transduction. Under physiolog- biochemical and physiological processes. Homeostasis of ical conditions, serum magnesium levels are maintained magnesium is tightly regulated and depends on the at almost constant values. Homeostasis depends on the balance between intestinal absorption and renal excretion. balance between intestinal absorption and renal excretion. During the last decades, various hereditary disorders of Magnesium deficiency can result from reduced dietary magnesium handling have been clinically characterized intake, intestinal malabsorption, or renal loss. The control and genetic studies in affected individuals have led to the of body magnesium homeostasis primarily resides in the identification of some molecular components of cellular kidney tubules. magnesium transport. In addition to these hereditary A number of acquired and hereditary disorders of forms of magnesium deficiency, recent studies have magnesium handling, most of them due to renal magne- revealed a high prevalence of latent hypomagnesemia in sium loss, have been described, all of them being the general population. This finding is of special interest relatively rare. The phenotypic characterization of clin- in view of the association between hypomagnesemia and ically affected individuals and experimental studies have common chronic diseases such as diabetes, coronary heart allowed the identification of the nephron segments disease, hypertension, and asthma. However, valuable involved in these conditions. Together with the mode of methods for the diagnosis of body and tissue magnesium inheritance this has led to a classification of inherited deficiency are still lacking. This review focuses on magnesium wasting disorders into different subtypes [1, clinical and genetic aspects of hereditary disorders of 2]. During the last few years, genetic studies have resulted magnesium homeostasis. We will review primary defects in the identification of a number of genes involved in the of epithelial magnesium transport, disorders associated pathogenesis of these disorders and provided a first with defects in Ca2+/Mg2+ sensing, as well as diseases insight into the physiology of epithelial magnesium characterized by renal salt wasting and hypokalemic transport at the molecular level. Some of these genotypes alkalosis, with special emphasis on disturbed magnesium are associated with a mild or even asymptomatic clinical homeostasis. course. Consequently, the diagnosis is often delayed and the disease prevalence might be underestimated. Keywords Magnesium · Hypomagnesemia · Magnesium In contrast to hypomagnesemia of hereditary origin, deficiency · Hereditary magnesium loss latent or subclinical hypomagnesemia is relatively fre- quent, with a prevalence of around 14% in the general population [3]. There is growing evidence of an associ- Introduction ation of magnesium deficiency with common chronic diseases such as coronary heart disease, stroke, diabetes Magnesium is the fourth most-abundant cation in the mellitus, and asthma [4, 5]. Whether magnesium supple- body. As a cofactor for many enzymes, it is involved in mentation has a beneficial effect under these conditions energy metabolism and protein and nucleic acid synthesis. remains unknown. It also plays a critical role in the modulation of membrane K. P. Schlingmann · M. Konrad · H. W. Seyberth ()) Magnesium physiology Department of Pediatrics, Philipps University, Deutschhausstrasse 12, 35037 Marburg, Germany Magnesium is the second most-prevalent intracellular e-mail: [email protected] cation. The normal body magnesium content is approx- Tel.: +49-6421-2862789 imately 24 g (1,000 mmol). Magnesium is distributed Fax: +49-6421-2865724 14 mainly in bone and the intracellular compartments of muscle and soft tissues; less than 1% of total body magnesium is located in the blood [6]. Serum magnesium levels are maintained in a narrow range. Circulating magnesium is present in three different states: dissociated/ ionized, bound to albumin, or complexed to phosphate, citrate, or other anions. Ionized and complexed forms account for the ultrafiltrable fraction, the biological active portion is the free, ionized magnesium ([Mg2+]). First studies on body magnesium kinetics were con- ducted in the 1960s with the radioactive isotope 28Mg. Avioli and Berman [7] proposed a multicompartmental model of exchangeable magnesium pools: a magnesium pool mass with a relatively fast turnover comprising ~15% of the estimated body content, representing primarily the extracellular fluid, and a slow-turnover intracellular pool, comprising >70% of total body magnesium. The mechanisms that regulate the exchange between the extracellular and intracellular compartments have not been clearly elucidated. Equilibration between serum magnesium and body stores occurs slowly [6]. Magnesium homeostasis depends on the balance between intestinal absorption and renal excretion. The daily dietary intake of magnesium varies substantially. In 1964, Seelig [8] analyzed a large number of balance studies and concluded that the minimum intake of Fig. 1 a Schematic model of intestinal magnesium absorption via magnesium required to maintain external balance is two independent pathways: passive absorption via the paracellular around 0.25 mmol or 6 mg/kg body weight per day in pathway and active, transcellular transport consisting of an apical entry through a putative magnesium channel and a basolateral exit adults. However, estimations from studies in the United mediated by a putative sodium-coupled exchange. b Kinetics of States and European countries indicate substantially lower human intestinal magnesium absorption. Paracellular transport mean daily magnesium intakes, around 0.16 mmol or linearly rising with intraluminal concentrations (dotted line) and 4 mg/kg body weight per day [9]. For the pediatric saturable active transcellular transport (dashed line) together yield a population, data on daily magnesium requirements are curvilinear function for net magnesium absorption (solid line) sparse. During growth, a positive magnesium balance is expected, but the desirable extent is unknown. For more detailed information on estimated average requirements in different age groups please refer to the 1997 FDA guidelines [10]. Within physiological ranges, diminished magnesium intake is balanced by enhanced magnesium absorption in the intestine and reduced renal excretion. These transport processes are regulated by metabolic and hormonal factors [11, 12]. The principal site of magnesium absorption is the small intestine with smaller amounts being absorbed in the colon. Intestinal magnesium absorption occurs via two different pathways: a saturable active transcellular pathway and a non-saturable paracellular passive transport pathway [11, 13] (Fig. 1a). Satu- ration kinetics of the transcellular transport system indicate a limited active transport capacity. At low intraluminal concentrations magnesium is absorbed primarily via the active transcellular route and with rising concentrations via the paracellular pathway, yielding a curvilinear function for total absorption (Fig. 1b). In the kidney, approximately 80% of total serum magnesium is filtered at the glomeruli, of which more than 95% is reabsorbed along the nephron. In the adult (Fig. 2), 15%–20% is reabsorbed in the proximal tubule. Interestingly, the newborn is able to reabsorb up to 70% Fig. 2 Magnesium reabsorption along the nephron 15 Around 70% of magnesium is reabsorbed in the loop of Henle, especially in the cortical thick ascending limb (TAL). Transport in this segment is passive and paracellular, driven by the lumen-positive voltage (Fig. 3a). Approximately 5%–10% of the filtered magnesium is reabsorbed in the distal convoluted tubule (DCT) via an active, transcellular process (Fig. 3b). The reabsorption rate in the DCT defines the final urinary magnesium excretion, as there is no significant reabsorption of magnesium in the collecting duct. Physiological studies indicate that apical entry into DCT cells is mediated by a specific and regulated magnesium channel driven by a favorable transmembrane voltage [16]. The mechanism of basolateral transport into the interstitium is unknown. Magnesium has to be extruded against an unfavorable electrochemical gradient. Most physiological studies favor a sodium-dependent exchange mechanism [17]. Magnesium entry into DCT cells appears to be the rate- limiting step and the site of regulation. Magnesium transport in the distal tubule has recently been reviewed in detail by Dai et al. [16]. Finally, 3%–5% of the filtered magnesium is excreted in the urine. Diagnosis of magnesium deficiency Magnesium deficiency and hypomagnesemia often re- main asymptomatic. Clinical symptoms are mostly non- specific and magnesium deficiency is frequently associated with additional electrolyte abnormalities, especially hypocalcemia and hypokalemia. Alternatively, the symptoms of hypomagnesemia may be minor compared with the symptoms of the primary disease causing the magnesium depletion. In addition, symptoms do not necessarily correlate with serum magnesium levels, as these do

Load more