Gitelman Syndrome, Orphanet Journal of Rare Diseases

Etiopathogenesis

In the great majority of cases GS is caused by mutations in the solute carrier family 12, member 3, SLC12A3 gene, which encodes the renal thiazide-sensitive sodium-chloride co-transporter NCC that is specifically expressed in the apical membrane of cells in the first part of the distal convoluted tubule (DCT) (reviewed in [9]). NaCl cotransporter (NCC) is a polypeptide of 1021 amino acids and the 2D-structure is predicted to contain 12 transmembrane domains and long intracellular amino- and carboxytermini. At present, more than 140 different, putative loss-of-function mutations in the SLC12A3 gene have been identified in GS patients. These mutations include missense-, nonsense-, frame-shift-, and splice-site mutations and are distributed throughout the whole protein.

In general, there is extreme inter- and intrafamiliar phenotype variability in GS, the latter emphasizing the lack of a correlation between the severity of symptoms in GS and the type of mutation in the SLC12A3 gene [10]. Recently, however, Riviera-Munoz et al. described a small subgroup of patients with a remarkable severe phenotype, including an early onset, severe neuromuscular manifestations, growth retardation and ventricular arrhythmias [2]. The majority of these patients were male and carried at least one allele of a splice defect, resulting in a truncating transcript, or a non-functional intracellularly retained mutation (see below). They suggested from these data that the nature/position of the SLC12A3 mutation combined with male gender may be a determinant factor in the severity of GS. Studies in lager cohorts are necessary to confirm this assumption.

By functional expression studies and results of immunocytochemistry in Xenopus leavis oocytes, it was shown that most disease-causing NCC mutants are impaired in their routing to the plasma membrane. Thus, the majority of mutations belong to the so-called type 2 mutations which, in contrast to type 1 mutations that impair protein synthesis, lead to fully synthesized proteins. These type 2 mutant proteins, however, do not traffic appropriately to the plasma membrane, primarily due to protein misfolding and retention in the endoplasmic reticulum, followed by rapid proteoasomal degradation. De Jong and co-workers have shown that NCC misfolding resulting in defective trafficking in GS is not uniformly complete [11]. Some mutant NCC proteins are only partially retarded in their trafficking; they do reach the plasma membrane, albeit to a limited extent, and are partially active. Subsequently, it was demonstrated that the intrinsic activity of these partially retarded mutants is unaffected by the mutation [12,13]. This finding opens the possibility of pharmacological chaperones, facilitating the routing of misfolded, trafficking-defective, but otherwise functional NCCs to the apical membrane, for therapeutic use. Indeed, in an additional study, de Jong et al. found prove that the transcriptional regulator 4-phenylbutyrate may be a promising candidate for rescuing partially retarded, but otherwise functional mutant NCCs [14]. Recently, another class of mutations in GS was identified by Riveira-Munoz et al. [15]. This newly identified class includes mutants which are partly retained in the cell, but in contrast to the mutants mentioned above, these mutants do not show any activity when they reach the cell surface.

A minority of patients with the Gitelman phenotype has been shown to have mutations in the CLCNKB gene, encoding the renal chloride channel ClC-Kb, located in basolateral membrane of cells of the thick ascending limb of Henle’s loop (TAL) and the distal tubules. Mutations in the CLCNKB gene were previously found to be the cause of classic Bartter syndrome. It is now evident that the clinical phenotype in patients with CLCNKB mutations can be highly variable, from an antenatal onset of Bartter syndrome on one side of the spectrum, to a phenotype closely resembling Gitelman syndrome at the other side (review in [9]). Therefore, there is an indication to screen the CLCNKB gene in patients with the Gitelman phenotype who do not have mutations in the SLC12A3 gene.

Both loss-of-function mutations in NCC and mutations in CLC-Kb lead to disruption of NaCl reabsorption in the DCT (figure 1). When less NaCl is reabsorped, more sodium will arrive in the collecting duct resulting in mild volume contraction. The reduced vascular volume activates the renin-angiotensin-aldosterone system, increasing renin activity and aldosterone levels. The elevated aldosterone levels give rise to increased electrogenic sodium reabsorption in the cortical collecting duct via the epithelial sodium channel (ENaC), defending salt homeostasis at the expense of increased secretion of potassium and hydrogen ions, thus resulting in hypokalemia and metabolic alkalosis. It has been shown that passive Ca2+ reabsorption in the proximal tubule and reduced abundance of the epithelial Mg2+ channel TRPM6, located in the DCT explains thiazide-induced hypocalciuria and hypomagnesemia, respectively [16]. Since thiazides are known to inhibit NCC, and in view of the phenotypic resemblance between GS and chronic thiazide-treatment, it is very likely that similar mechanisms are involved in the pathogenesis of respectively hypocalciuria and hypomagnesemia seen in GS.

thumbnailFigure 1. A model of transport mechanisms in the DCT. Sodium-chloride (NaCl) enters the cell via the apical thiazide-sensitive NCC and leaves the cell through the basolateral Cl- channel (ClC-Kb), and the Na+/K+-ATPase. Indicated also are the recently identified magnesium channel TRPM6 in the apical membrane, and a putative Na/Mg exchanger in the basolateral membrane.

Diagnosis, diagnostic methods and differential diagnosis

The diagnosis of Gitelman syndrome is based on the clinical symptoms and biochemical abnormalities. The most typical biochemical abnormalities in GS are hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria. Serum potassium concentration is comparably low (2.7 ± 0.4 mmol/L) to Bartter syndrome. Serum magnesium concentration is low (less than 0.65 mmol/l). In a few GS patients magnesium concentration is easily maintained in the normal range early on, which may lead to a false diagnosis of Bartter syndrome, and only drops below normal with time (personal observation). Urinary calcium concentration is usually less than 0.2 mmol/mmol creatinine and rarely exceeds 0.5 mg/kg/day. Hypomagnesemia and hypocalciuria have always been considered obligate features for GS. This assumption has recently been disputed by Lin et al. [10]. They reported two families with molecularly proven GS, in which male patients had severe hypokalemia, and were symptomatic with episodes of paralysis, impaired urinary concentration ability, but with normal serum magnesium and urinary calcium excretion. Remarkably, female GS patients within these families, carrying the same causative mutations as the male patients, were asymptomatic, had less severe hypokalemia, intact urine concentration ability, but did have hypomagnesemia and hypocalciuria [10]. Although this was a small study, the authors concluded that gender may affect phenotypic expression in GS and that hypomagnesemia and hypocalciuria may not be invariant features of the disorder.

Prostaglandin excretion is normal and plasma renin activity and plasma aldosterone concentration are only slightly elevated compared to Bartter syndrome. Renal functional studies have demonstrated normal or slightly decreased urinary concentrating mechanism, but clearly reduced distal fractional chloride reabsorption during hypotonic saline infusion. GS patients have a blunted natriuretic response to hydrochlorothiazide administration but a prompt natriuresis after administration of furosemide, indicating that the defect in GS is located at the level of the distal tubule. DNA mutation analysis of the gene responsible for GS may confirm the diagnosis.

Bartter syndrome is the most important genetic disorder to consider in the differential diagnosis of GS. Especially type III Bartter syndrome, which is caused by mutations in the CLCNKB gene, is clinically and biochemically overlapping with Gitelman syndrome. The other types of Bartter syndrome usually have an earlier onset and a more severe phenotype.

Primary forms of renal hypomagnesemia can be distinguished from GS by the absence of hypokalemia. Important acquired conditions which should be differentiated from GS are diuretic and laxative abuse and chronic vomiting. The two latter conditions can be confirmed by measuring of low urinary excretion of Cl-.

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