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Physiopathology of Potassium Deficiency
Potassium (K + ) deficiency is a common and eventually life-treating condition. Hypokalemia is defined as serum K+ level less than 3.5 mM. This chapter, together with cornerstone mechanisms, reviews the newest molecular regulators of the K + homeostasis, including the feedforward signals recently hypothesized in the gut. The renal and extra-renal diseases leading to hypokalemia are reported here. Newest findings in the mechanism underlying the renal inherited K + -losing syndrome, like Gitelman, Bartter and Liddle syndromes are described in details.
Chronic K + deficiency has been described to induce a kaliopenic nephropathy . This term includes all the morphological and functional changes induced by hypokalemia in the kidneys. The hypokalemia-induced renal morphological alterations in both humans and experimental models are depicted. A segment-detailed analysis of the hypokalemia-induced functional and molecular changes on sodium, water and urea handling and on the acid-base homeostasis is reported. These mechanisms provide the molecular basis underlying the development of metabolic alkalosis, increase urinary ammonium excretion and the urine concentrating defect secondary to K + deficiency. Studies based on a system biology approach to the K + deficiency have been included. These could be suggestive of new experimental hypothesis on the K + deficient states. Finally, we reviewed the new findings on the systemic influence of a K + deficiency pointing on the blood pressure regulation and glucose intolerance.
Keywords
Hypokalemia, Potassium deficiency, glucagon, TTKG, hypokalemic periodic paralysis, Bartter Syndrome, SLC12A1, NKCC2, ROMK, CLCNKA, CLCNKB, BSND, Barttin subunit, CaSR, NCC, Gitelman Syndrome, Liddle Syndrome, ENaC, Kaliopenic Nephropathy, metabolic alkalosis, polyuria, ammonium, hypertension, aldosterone, WNK, glucose intolerance.
Introduction
Hypokalemia is a common clinical disorder that can be the end-result of: (1) potassium (K + ) redistribution between plasma and intracellular fluid (ICF); (2) insufficient K + intake; (3) disproportionate K + excretion. It is commonly defined as a plasma K + concentration less than 3.5 mmol/L, but this level infrequently causes trouble unless it has fallen rapidly: patients are usually symptomatic when plasma K + is lower than 2.5 mmol/L. Major muscle weakness have a tendency to occur at plasma K + less than 2 mmol/L.
The average K + intake in a typical western diet is roughly 70 mmol. The intestine absorbs almost all of the ingested K + ; only negligible quantities of K + are excreted in the feces. The kidney plays an important role in K + balance, which is the result of glomerular filtration, extensive proximal tubule reabsorption, and highly regulated secretory/reabsorbtive processes located along the distal tubule and the collecting duct (CD). Total body K + is roughly 55 mmol/kg of body weight, with 98% distributed to the intracellular fluid (primarily in muscle, liver, and erythrocytes) and 2% in the extracellular fluid. Na/K-ATPase actively pumps K + into the cell and preserves the electrochemical gradient between the intra- and extracellular pool.
New Concepts on the Integrative Control of K + Homeostasis
Feedback Control of K + Homeostasis
A large increase in plasma K + concentration triggers aldosterone release from the adrenal glands. Aldosterone, in turn, stimulates the activity and synthesis of both Na/K-ATPase and luminal K + channels in CD principal cells, thus promoting K + excretion. In addition, aldosterone enhances K + secretion in the distal colon, which can exert an essential role when renal function is reduced.
On the other hand, if plasma K + concentration decreases as a consequence of reduced K + intake or increased K + excretion, then feedback regulation redistributes K + from ICF to plasma. At the same extent, skeletal muscle becomes insulin-resistant to K + (but not glucose) uptake, blocks the entry of K + from plasma into the cell. Hypokalemia also causes a decreased expression of skeletal muscle Na/K-ATPase 2 isoform, thus allowing a leak of K + from ICF to the plasma. The low plasma K + concentration suppresses adrenal aldosterone release so that the kidney reduces urinary K + excretion.
Feedforward Control of K + Homeostasis
However, besides the classic feedback control, some findings suggest a feedforward control. It is clear that plasma K + stimulates aldosterone secretion only at supra-physiological levels, with little effect within the physiological range. Indeed, it has been shown that, in sheep, a meal intake produced a substantial kaliuresis in the absence of changes in plasma aldosterone concentration. From these experiments it was concluded that the increased renal K + excretion following a meal cannot be explained by changes in aldosterone concentration, but it may be dependent on the existence of a kaliuretic reflex arising from sensors in the splanchnic bed (i.e., gut, portal circulation, and/or liver) ( Figure 50.1 ).
One of the potential effectors of the feedforward control of serum K + is glucagon. Glucagon secretion is definitely stimulated after a protein-rich meal, and intraportal glucagon infusion produces significant increases in renal blood flow and glomerular filtration rate (GFR), suggesting the existence of a hepatorenal axis.
The feedforward regulation may act through three different mechanisms: (1) insulin release rapidly stimulates cellular K + uptake into insulin-responsive tissues; (2) glucagon, through cAMP released from the liver, quickly increases renal K + excretion after a protein-rich meal; (3) a yet-unidentified gut factor senses K + ingestion and enhances renal K + excretion. When plasma K + level increases despite these layers of control, feedback regulation is activated. Aldosterone acts only after a certain time, it is not involved in rapid control of K + homeostasis, but it can chronically increase K + secretion until plasma K + is normalized.
Assessment of Urinary K + Excretion
Several urine parameters are used to identify whether hypokalemia is dependent on renal loss. Renal K + excretion can be assessed with a 24 hour urine collection or a spot urine test determining the K + : creatinine ratio. A 24-hour urinary K + excretion lower than 15 mEq or a K + (mmol)/creatinine (mmol) ratio <1 suggests an extrarenal cause of hypokalemia.
In the clinical practise, as an initial test to address the origin of K + losses, a random urine K + is used. However, this approach is hampered by the effect of renal water handling on urine K + concentration. Determining the transtubular K + gradient (TTKG) is still an accepted way to assess renal K + handling:
Tubular fluid K + concentration in the last part of the CD is mainly dependent on aldosterone, because most K + secretion takes place in the CD. Thereafter, urinary K + concentration increases as a consequence of water reabsorption. The TTKG reflects the tubular fluid K + concentration at the end of the cortical CD, by accounting for water reabsorption that takes place distal of where K + secretion has ended.
However, there are few limitations to the clinical use of this formula. First, the calculation assumes that there is no significant solute transport and only water reabsorption along the medullary CD. Any Na + or urea reabsorption in this segment would tend to lower urine osmolality and cause the TTKG to overestimate the gradient for K + secretion in the upstream CD. Second, there must be optimal conditions for K + secretion at the time that the TTKG is measured. In this regard, urinary Na + should be no less than 25 mEq/L, to guarantee that Na + delivery to the CD is not rate-limiting in K + secretion. In addition, urine osmolality should be equal to or higher than the plasma. A higher urine osmolality indicates increased vasopressin release, which is known to stimulate K + secretion in the CD.
Hypokalemia Associated With Intracellular Shift
The regulation of K + distribution between the intracellular and extracellular space is known as internal K + balance. Even though the kidney is in charge of the preservation of total body K + , factors that adjust internal balance are central to the removal of acute K + -loads. A large K + intake could potentially double extracellular K + concentration in the absence of a rapid shift into the cells. This process is mainly regulated by insulin and catecholamines, with a minor role of metabolic and respiratory alkalosis.
Hypokalemic periodic paralysis is a rare disorder characterized by muscle weakness or paralysis as a result of the sudden movement of K + into cells. Measurement of the TTKG at the time of the attacks typically shows values of <1. The attacks may be triggered by exercise, stress, intake of large quantities of carbohydrates, and increased release of catecholamines or insulin.
This disorder is classified as primary, due to a genetic defect or acquired, due to drugs or glandular diseases. The genetic forms are associated with mutations in genes encoding for subunits of muscular sodium, calcium, and potassium channels. Mutations in the α-subunit of the calcium channel [dihydropyridine (DHP)-receptor] (CACNA1S) gene and the α-subunit of the sodium channel (SCN4A) have been described. Loss of function mutations of CACNA1S reduce current density. A mutation in the KCNJ2 gene encoding for the inward-rectifying potassium channel Kir2.1 causes Andersen-Tawil syndrome, characterized by the triad of periodic muscle weakness, cardiac arrhythmias, and multiple dysmorphic features (short stature, hypertelorism, micrognathia). Whether hypokalemia determines the attack is not well-established. The onset of attacks occurs generally between 15 and 35 years of age; the severity of the clinical manifestations range from rare episodes in a lifetime to daily and severe attacks. The attacks can be triggered by all conditions which favor hypokalemia, such as physical exercise, a carbohydrate-rich meal, alcohol, and cold. Myalgia after the attack is a frequent complaint. The acquired form is mainly associated with thyrotoxicosis. Excess thyroid hormone may predispose to paralytic episodes by increasing Na/K-ATPase activity. The activity of this pump is further induced by catecholamines, which are typically increased in this setting. The underlying cause of thyrotoxicosis is most commonly Graves disease, but it can also be a solitary thyroid adenoma (Plummer disease). The acute attacks of hypokalemic periodic paralysis are best treated with intravenous KCl and propranolol.
It is important to administer KCl in non-dextrose-containing solutions, because glucose will stimulate insulin release, potentially exacerbating K + shift into the cells. Propranolol (a nonspecific adrenergic β-blocker) blocks the effects of catecholamines, and inhibits the peripheral conversion of T4 to T3.
Extrarenal K + Loss from the Body
Diarrhea is a common cause of hypokalemia due to gastrointestinal loss. Secretory diarrhea may be the consequence of two processes that can occur either alone or together. First, it may be related to inhibition of active intestinal NaCl and NaHCO 3 reabsorption and, second, it may be dependent on increased active secretion of Cl − coupled to passive secretion of an identical quantity of Na + in order to maintain the electrochemical balance. Under both circumstances, the stool electrolyte composition is analogous to plasma with a high concentration of NaCl and a much lower K + concentration. Despite the low K + concentration in the stool, large K + losses can take place in the setting of large fecal fluid volume.
Hypokalemia may also be associated with infectious diarrhea. In particular, malaria and leptospirosis may cause alterations in fluid and electrolyte balance. Hypokalemia is particularly frequent in children with severe malaria, and may arise within several hours of initiation of therapy. Hypokalemia develops in about one-third of patients with leptospirosis. Such patients are at risk of both gastrointestinal and renal losses. In the outer membrane of the organism there is a substance that has an inhibitory effect on the Na/K-ATPase within the nephron. It has been hypothesized that this inhibitory effect reduces Na + reabsorption along the proximal tubule, thus increasing distal Na + delivery, resulting in kaliuresis. Hypokalemia may also be associated with watery diarrhea and achlorhydria, a condition secondary to hypersecretion of vasoactive intestinal polypeptide (VIP). In adults, this syndrome is most commonly a complication of pancreatic islet cell tumors, and sometimes of bronchogenic carcinoma, medullary thyroid carcinoma or retroperitoneal histiocytoma. There are now few reports describing chronic watery diarrhea and hypokalemia due to adrenal pheochromocytoma containing immunoreactive VIP.
A recent report describes five consecutive patients with acute or subacute colonic pseudo-obstruction suffering a typical secretory diarrhea characterized by very high fecal K + concentrations (over 100 mEq/kg) and low Na + concentration (Ogilvie syndrome). These elevated fecal concentrations of K + in large volume diarrhea induced important outputs of K + salts responsible for profound hypokalemia and decreased urinary excretion of K + .
Renal K + -Losing Syndromes
Bartter Syndrome (BS)
BS results from a defect in any of the major components of NaCl reabsorbtive machinery along the TAL. So far, mutations of five genes have been described. The defect determines renal loss of water and electrolytes resulting in hypovolemia, with a compensatory increase in renin and aldosterone levels.
Genetic and Molecular Biology
BS type I is sustained by mutations of the SLC12A1 gene, encoding the kidney-specific furosemide-sensitive NKCC2. A number of point mutations have been described in homozygosis or compound heterozygosis, mostly frameshift and non-conservative missense mutations. To date, over 30 mutations in the SLC12A1 gene have been reported ; phenotypic variability among patients with SLC12A1 mutations may be due to the effect of genetic mutations on protein function, and milder phenotypes may correlate with residual NKCC2 function.
BS type II depends on inactivating mutations of the KCNJ1 gene, encoding the K + channel ROMK. These channels are the main renal K + secretory channels. Along the TAL, ROMK mediates K + efflux to the lumen, which is critical for supporting Na/K-2Cl absorption via NKCC2. At this level of the nephron, ROMK channels contribute to the generation of the lumen-positive transepithelial voltage which allows paracellular calcium and magnesium absorption. An inactivating mutation of ROMK is thought to inhibit salt reabsorption along the TAL. Over 35 genetic mutations have been described, such as missense mutations, frameshift mutations, and stop codons which result in a truncated protein. The majority of these mutations reduces or eliminates ROMK surface expression, as a consequence of misfolding and/or mistrafficking; others compromise K + permeation and channel regulation. Besides the TAL, ROMK channels are also expressed along the apical membrane of principal cells in the cortical CD, where they mediate K + secretion into the lumen. A defect in ROMK results in the classical BS phenotype, including the presence of hypokalemia. This finding brought attention to its role in K + secretion. Subsequent studies have demonstrated that, in the absence of functional ROMK channels, K + secretion is guaranteed by the upregulation of flux-sensitive Maxi-K channels along the CD in mice.
BS type III depends on the mutation of the kidney-specific Cl − channel, CLC-K. Two genes belonging to the CLC family are involved in Cl − efflux across the basolateral membrane, CLCNKA and CLCNKB. Their products are nearly identical at protein level, and both channels are associated with the Barttin subunit, essential for their insertion on plasma membrane and their activity. These channels differ only in their distribution along the nephron, with CLC-Ka expressed predominantly along the TAL, while CLC-Kb is expressed along the DT. CLCKNB defects are associated with a Bartter phenotype in humans; a high rate of deletions encompassing the entire gene has been described, together with frameshift and splice-site mutations. These mutations are supposed to disrupt the protein, altering its function. The predominant location of CLCKb along the DT explains why this variant of BS is less commonly associated with a defect in concentrating mechanism, and with hypercalciuria. There is no evidence CLCKNA mutations may generate a Bartter like syndrome. ClCk1 (the ortholog of CLC-Ka)-deficient mice show a phenotype of nephrogenic diabetes insipidus. However a combination of defects in both CLCNKA and CLCNKB genes result in a phenotype of antenatal BS.
BS type IV refers to the mutations in the BSND gene product. In contrast to other BS variants, the gene does not encode for an ion channel or transporter, but for an accessory subunit of CLC-Ka and CLC-Kb, defined as Barttin . CLC-K/Barttin Cl − channels also localize in the cochlea, along the basolateral membrane of marginal cells of the stria. Barttin has been found mutated in patients suffering from BS; different mutations generate phenotypes of varying severity. In heterologous expression, CLC-K channels do not yield currents in the absence of a functional Barttin subunit, suggesting that Barttin is essential for their function. As in the TAL, CLC-K channels participate in Cl − reabsorption in the inner ear. Recent studies have shown that the Barttin subunit is essential for the generation of endocochlear potential; in the absence of Barttin, the degeneration of cochlear outer cells and the collapse of endolymphatic space may contribute to the pathogenesis of deafness in this BS subtype.
BS type V depends on the activating mutation of the calcium-sensing receptor (CaSR). The protein is expressed in the parathyroid and in the kidney, and it is mainly involved in calcium and magnesium homeostasis. Along the TAL the CaSR is expressed on the basolateral membrane and it can inhibit salt absorption. A case report showed that activating mutations of the CaSR gene associated with a BS phenotype inhibit ROMK, explaining the inhibition of salt absorption at this site. A number of gain-of-function mutations of the CaSR gene have been identified as causing an inherited form of hypocalcemia/hypoparathyroidism (autosomal-dominant hypoparathyroidism). Whether those disarrangements lead to a different phenotype is still unknown.
Mutations in these five genes do not explain all cases of BS, and many patients do not get a genetic diagnosis. It is presumable that other genes are involved in the pathogenesis of this syndrome. Recently a role has been proposed for claudins, a family of transmembrane proteins expressed within the tight junction. Mutation in claudin-16 is associated with familiar hypomagnesemia with hypercalciuria and nephrocalcinosis. A single nucleotide substitution has been found in the extracellular domain of claudin-8 in four African-American BS patients. The effect of the mutation on protein function has not yet been addressed.
Pathophysiology
The defective NaCl absorption along the TAL caused by mutations in any of these five genes leads to an increased salt delivery to the distal nephron. The subsequent volume-depletion leads to a compensatory hyper-reninemia. Mice models of BS type I and II show early onset of polyuria, metabolic alkalosis, increased calcium and magnesium urinary excretion, and hyper-prostaglandinemia, a phenotype which resembles the abuse of loop diuretics. The activation of RAAS leads to a compensatory increase in Na + absorption along the PT and the aldosterone-sensitive segments of the nephron. The latter favors K + secretion along the CD, enhancing the kaliuretic effect of the increased Na + delivery. Clinical differences among BS subtypes depend on the specific physiological role of the causative gene in the kidney and in other organs.
Type II BS is characterized by relatively mild hypokalemia compared with type I, and by the dual role of ROMK in the kidney in controlling NaCl absorption along the TAL (through K + recycling) and K + secretion along the CD. The presence of hypokalemia is ensured by the activation of the flux-sensitive Maxi-K channels which mediate urinary K + secretion along the distal nephron. However, newborn infants suffering from type II BS show transient hyperkalemia before developing normohypokalemia later in the infancy. This effect may be due to the delay in BK-dependent K + secretion, which later is responsible for urinary K + excretion.
The widespread distribution of CLC-K channels along the distal nephron and the compensatory activation of Cl − absorption through other channels explains why CLCKNB mutations may result in a pure BS phenotype, GS phenotype or a combination of these. Hypercalciuria and nephrocalcinosis are typical signs of type I and II BS, but are rare in type III ; however, a broad spectrum of phenotypes has been associated with mutations of the CLCNKB gene, ranging from antenatal BS to classic BS and Gitelman-like syndrome, without any correlation with the type of genetic mutation. Additional studies are needed for a better understanding of the phenotypic variability.
The presence of deafness is a hallmark of type IV BS. Barttin, as pointed out above, is necessary for CLC-K channels trafficking to the membrane. ClCK-barttin complex is expressed in the kidney and in the inner ear. Mice lacking a functional CLC-Ka have a phenotype resembling nephrogenic diabetes insipidus, with high vasopressin plasma levels, and low osmolality of renal papilla even after water restriction, suggesting a role in the urinary concentrating mechanism. CLCKB-null mice show the classic form of BS, whereas only a defect of Barttin determines deafness. In the inner ear CLC-K/Barttin channels participate in Cl − transcellular extrusion across the basolateral membrane. It is possible that the absence of CLC-Kb could be compensated by the CLC-Ka-Barttin in the inner ear, while the absence of Barttin equals a double defect in CLC-k a and b, leading to deafness. Hypercalciuria and nephrocalcinosis are the main features of type V BS. Activating mutation of the CaSR leads to autosomal dominant hypoparathyroidism, characterized by hypocalcaemia and hyperphosphoremia, with low-normal PTH levels.
Clinical Presentation
Clinically, BS is divided into antenatal and classic BS with or without deafness.
Antenatal BS , or hyper-prostaglandin E BS , is the most severe form, characterized by polyhydramnios for excessive urinary output and premature birth. It is sustained by type I and II, and sometimes type III. After birth, patients have a life-threatening clinical course, with fever, vomiting, and lethargy. Biochemical analysis shows the presence of metabolic alkalosis, hypokalemia, isohypostenuria, and hypercalciuria. Nephrocalcinosis is frequent. High urinary prostaglandin excretion of E2 or its metabolites is typical of the antenatal form, and high levels of renin and aldosterone are secondary to volume-depletion. The reason for the high urinary and plasma prostaglandin levels is still unknown, but it seems to be secondary to the defect of NaCl absorption along the TAL.
Classic BS is sustained more often by type III BS. Clinical appearance occurs during infancy or childhood, in the absence of polyhydramnios and prematurity. The clinical course is milder than the antenatal subtype; patients manifest polyuria, polydipsia, vomiting, and dehydration. Nephrocalcinosis is an infrequent sign, and a less severe defect in urinary concentrating mechanism is present.
BS with sensorineural deafness. The presentation of patients with type IV BS shows remarkable variation, ranging from prenatal diagnosis with severe polyhydramnios and prematurity to late diagnosis.
Gitelman Syndrome
Gitelman syndrome (GS) differs from BS because of the presence of hypocalciuria and hypomagnesaemia. It is often diagnosed in adulthood.
Genetics and Molecular Biology
The syndrome correlates with mutations of the SLC12A3 gene located on chromosome 16q, encoding the thiazide-sensitive sodium-chloride co-transporter (NCC). The transporter is expressed on the apical membrane of distal tubule, and represents the major NaCl transport pathway in this segment. More than 140 mutations have been described; the majority of mutations are missense substitutions, but frameshift and splice-site mutations have also been described. Heterozygous subjects show a tendency for low blood pressure, while the complete GS phenotype occurs only in homozygosis. De Jong et al. have performed, in xenopus laevis oocytes, functional and immunohistochemical analysis of mutant human NCC of GS subjects. This study has found class I mutants, characterized by the absence of significant metazolone-sensitive Na + uptake with undetectable protein distribution on the membrane, and class II mutants, which exhibited significant, albeit low, metazolone-sensitive Na + uptake, while NCC staining was equally present in plasma membrane and cytoplasm. These findings suggest that some mutations compromise NCC abundance in plasma membrane (class I), leading to a defect in protein activity; other mutations only partly impair NCC routing to the membrane, as suggested by the presence of mutant NCC both on plasma membrane and cytoplasm. However, different mechanisms are involved in the impaired trafficking for the two classes of mutations, and the precise mechanism has still to be established. Previous studies suggest the role of defective post-translational changes, such as protein glycosylation, which seems to be required for proper folding and trafficking to plasma membrane. A minority of patients with GS phenotype show mutations in the CLCNKB gene, which is also responsible for BS type III.
Pathophysiology
Both NCC and CLC-Kb dysfunction result in decreased Na + and Cl − absorption along the DT. The volume-contraction resulting from defective NaCl absorption determines a compensatory activation of RAAS, which promotes electrogenic Na + absorption along the CD through ENaC. The latter enhances K + and H + secretion along the CD, favoring hypokalemia and metabolic alkalosis. The pathogenesis of hypocalciuria and hypomagnesemia refers to a not yet completely-elucidated mechanism. Micropuncture experiments have demonstrated an increased Ca 2+ absorption along the proximal tubule (PT) after chronic administration of thiazides, whereas DT calcium absorption was unaffected. This hypothesis is supported by the presence of thiazide-induced hypocalciuria in a mouse model lacking the calcium channel (TRPV5) along the DT. These findings demonstrate that increased calcium absorption parallels a compensatory increased Na + absorption along the PT secondary to volume-contraction. Other studies suggest that enhanced calcium absorption along the DT participates in the generation of hypocalciuria. In a mouse model of GS, the expression of TRPV5 and TRPV6 were increased, and TRPV5 is also overexpressed in renal tissue from patients with GS.
Hypomagnesemia, another hallmark which distinguishes GS from BS, has a controversial origin. Magnesium is freely filtered by the glomerulus, and it is reabsorbed in a small fraction along the PT. The majority of Mg 2+ is reabsorbed along the TAL, via paracellular pathway, and DT, via transcellular pathway. In the latter, Mg 2+ reabsorption is mediated by the transient receptor potential cation channel, TRPM6. In NCC knockout mice a downregulation of TRPM6 in DT has been shown. This effect could explain the defective Mg 2+ absorption, and the subsequent hypomagnesemia.
The clinical phenotype in CLCNKB mutations is extremely variable; several reports have described subjects with phenotypic features of GS without any defect in SLC12A3 gene, carrying homozygous mutations of CLCNKB gene or mixed BS-GS phenotype.
Clinical Presentation
GS is characterized by an extreme inter- and intra-familial phenotype variability, varying from mild or undiagnosed forms to severe conditions complicated by growth retardation, ventricular arrhythmias, and neuromuscular symptoms. In most cases the diagnosis occurs in adulthood. The patients suffer from tetany, especially during conditions which determine further Mg 2+ loss, like vomiting or diarrhea. Some patients experience fatigue which compromises daily activities, in relation to the degree of hypokalemia. In contrast with BS, those patients do not manifest polyuria and growth retardation. Chronic K + and Mg 2+ deficiency may predispose to a higher risk for ventricular arrhythmias. However, lethal arrhythmias have been reported rarely in GS patients, and may be related to underlying triggering mechanisms besides hypokalemia. Riviera et al. have described a subgroup of GS patients with severe phenotype, characterized by early onset, and severe neuromuscular and cardiac symptoms. Almost all patients of the subgroup were male, and showed a higher incidence of splicing mutation leading to a truncated transcript compared with mild and classic GS. This study suggests that male gender and splicing mutations, resulting in a severe protein dysfunction, may account for the clinical severity of GS. Biochemical analysis shows hypocalciuria, hypokalemia, and hypomagnesemia. Although hypocalciuria and hypomagnesemia have been considered necessary for the diagnosis of GS, recently a report of a GS patient with a proven mutation in the GS gene did not manifest those signs. Plasma renin and aldosterone levels are only slightly increased compared with BS.
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