**4.4 "Pseudo" Gitelman's syndrome and reverse phenotypes**

The molecular basis for the syndrome of autosomal dominant hypomagnesemia has recently been made (Glaudemans, et al., 2009). This syndrome presents in childhood with recurrent muscle cramps, tetanic episodes, tremor, and muscle weakness. Patients have low serum Mg2+ levels, while serum K+ and Ca2+ levels and urinary Ca2+ excretion are not affected. This condition is therefore biochemically different from both Gitelman's syndrome and other forms of inherited hypomagnesemia. Mutations were identified in the *KCNA1* gene, encoding the Kv1.1 potassium channel, expressed in the apical membrane of the DCT and connecting tubule (Glaudemans, et al., 2009). This potassium channel is thought to work to stabilize the apical membrane, in the context of TRPM6 mediated magnesium reabsportion in these nephron segments. Loss of function mutations leads to a depolarisation of the membrane and defective magnesium reabsorption, resulting in hypermagnesuria and hypomagnesemia.

In contrast to Gitelman's, the biochemical phenotype of patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis secondary to mutations in the genes encoding claudin 16 and claudin 19 includes hypercalciuria rather than hypocalciuria. Isolated dominant hypomagnesemia caused by mutations in FXYD2 leads to hypocalciuria, and can resemble Gitelman's syndrome. Patient may be relatively symptom free as magneseium levels are mildly low, and may also have chondrocalcinosis (Geven, et al., 1987,Meij, et al., 2000). Recently a complex syndrome including epilepsy, ataxia, sensorineural deafness and a tubulopathy resulting in Gitelman's like biochemical derangement has been described (Bockenhauer, et al., 2009, Scholl, et al., 2009). The syndrome has been named both EAST syndrome (Bockenhauer, et al., 2009) and SeSAME syndrome (Scholl, et al., 2009). The biochemical defects are hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria. Mutations have been identified in the *KCJN10* gene encoding the renal Kir4.1 potassium channel, located on the basolateral membrane of the DCT. Loss of function mutations therefore disrupt DCT tubular handling of salts in a similar manner to NCCT defects, leading to secondary activation of the renin-

angiotensin-aldosterone axis. Recent molecular genetic studies have identified the basis of Gordon syndrome, also known as pseudohypoaldosteronism type II or chloride shunt syndrome, an autosomal dominant form of hypertension. It is noteworthy and mentioned here given that the diagnostic features resemble a mirror image of Gitelman's syndrome. This includes hyperkalemia, hypertension and hyperchloraemic metabolic acidosis. It can present in early neonatal period with hyperkalemic acidosis or later in life with hypertension. Additional clinical features include short stature, muscle weakness, intellectual impairment and dental abnormalities. Laboratory findings include low fractional excretion of sodium, low renin and aldosterone levels and normal renal function. This syndrome is caused by mutations in the gene encoding WNK4 (Lalioti, et al., 2006), which is a member of serine-threonine protein kinases. In humans, WNK4 is present exclusively in kidney. WNK4 acts as an inhibitor of thiazide-sensitive sodium-chloride co-transporter (NCCT). Mutations in WNK4 relieve this inhibition causing excess sodium retention and subsequent hypertension. Hyperkalemia is explained by inhibition of potassium ROMK channels. Treatment of Gordon syndrome is with low potassium diet and use of thiazide diuretics. Sodium loading should be avoided as it may worsen hypertension.

#### **4.5 Liddle's syndrome**

96 Basic Nephrology and Acute Kidney Injury

may occur, mimicking Bartter's syndrome in terms of severity. Early replacement of electrolytes is important and in common with Bartter's syndrome, NSAIDs have been used to good effect to promote growth in these children (Liaw, et al., 1999). Patients with Gitelman's syndrome have very good long term prognosis, however sudden cardiac deaths associated with prolonged QT intervals and cardiac arrhythmias have been reported (Cortesi, et al., 2010). In keeping with this less than benign phenotype, Gitelman's patients may have severe symptoms which are debilitating. For example, weakness, tetany and cramps are often so severe that emergency admissions to hospitals are required for intravenous potassium and magnesium replacement. Indeed, following quality of life questionnaires, Gitelman's patients' scores were comparable to patients with congestive heart failure (Cruz, et al., 2001). As discussed previously, mutations in *CLCNKB* encoding the basolateral chloride channel can also cause a Gitelman's phenotype. CLC-KB is expressed in the DCT as well as the TAL, accounting for this phenotypic overlap. Indeed, patients within the same family with identical *CLCNKB* mutation may present with a spectrum of phenotypes including both Bartter's and Gitelman's syndrome (Zelikovic, et al., 2003). In a recent large cohort of 448 Gitelman's patients, *CLCNKB* mutations accounted for just 3% of cases (Vargas-Poussou, et al., 2011).

The molecular basis for the syndrome of autosomal dominant hypomagnesemia has recently been made (Glaudemans, et al., 2009). This syndrome presents in childhood with recurrent muscle cramps, tetanic episodes, tremor, and muscle weakness. Patients have low serum Mg2+ levels, while serum K+ and Ca2+ levels and urinary Ca2+ excretion are not affected. This condition is therefore biochemically different from both Gitelman's syndrome and other forms of inherited hypomagnesemia. Mutations were identified in the *KCNA1* gene, encoding the Kv1.1 potassium channel, expressed in the apical membrane of the DCT and connecting tubule (Glaudemans, et al., 2009). This potassium channel is thought to work to stabilize the apical membrane, in the context of TRPM6 mediated magnesium reabsportion in these nephron segments. Loss of function mutations leads to a depolarisation of the membrane and defective magnesium reabsorption, resulting in hypermagnesuria and

In contrast to Gitelman's, the biochemical phenotype of patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis secondary to mutations in the genes encoding claudin 16 and claudin 19 includes hypercalciuria rather than hypocalciuria. Isolated dominant hypomagnesemia caused by mutations in FXYD2 leads to hypocalciuria, and can resemble Gitelman's syndrome. Patient may be relatively symptom free as magneseium levels are mildly low, and may also have chondrocalcinosis (Geven, et al., 1987,Meij, et al., 2000). Recently a complex syndrome including epilepsy, ataxia, sensorineural deafness and a tubulopathy resulting in Gitelman's like biochemical derangement has been described (Bockenhauer, et al., 2009, Scholl, et al., 2009). The syndrome has been named both EAST syndrome (Bockenhauer, et al., 2009) and SeSAME syndrome (Scholl, et al., 2009). The biochemical defects are hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria. Mutations have been identified in the *KCJN10* gene encoding the renal Kir4.1 potassium channel, located on the basolateral membrane of the DCT. Loss of function mutations therefore disrupt DCT tubular handling

**4.4 "Pseudo" Gitelman's syndrome and reverse phenotypes** 

hypomagnesemia.

Liddle's syndrome, also called pseudoaldosteronism, is an autosomal dominant disorder which is characterized by early onset severe hypertension, suppressed renin and aldosterone levels and hypokalaemic metabolic alkalosis (Liddle, et al., 1963). This syndrome is a familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion and is caused by up regulation of epithelial Na channel (ENaC) located in the collecting duct. Up regulation leaves the ENaC in 'open' state which enhances sodium reabsorption and causes hypertension. ENaC is a heterotrimeric protein, its three subunits named alpha, beta and gamma. Mutations in the beta and gamma subunits can cause constitutive channel opening (Hansson, et al., 1995a, Hansson, et al., 1995b). The beta and gamma subunits of ENaC are encoded by *SCNN1B* and *SCNN1G* genes, respectively. A key regulator of ENaC is NEDD4L, which is able to ubiquitinate ENaC leading to its removal from the luminal cell membrane in the renal collecting ducts. It has been postulated that loss of function defects in NEDD4L or alternative splicing of NEDD4L may also lead to hypertension (Dunn, et al., 2002). Patients with Liddle's syndrome are often asymptomatic and they are usually investigated after incidental finding of hypertension. Affected children may have symptomatic polyuria and polydipsia and faltering growth. A strong family history of premature stroke may prompt investigations. Liddle's syndrome should be suspected in a young person with high blood pressure, a family history of hypertension and low serum potassium together with a metabolic alkalosis. However, Liddle's syndrome may mimic essential hypertension as hypokalemia may not always be present (Rossi, et al., 2011). Indeed, genetic variants in ENaC genes may be found in patients with presumed essential hypertension (Hannila-Handelberg, et al., 2005). In Liddle's syndrome, there is a high variability of penetration which appears to be dependent on environmental factors such as dietary salt intake. Because serum and urine aldosterone levels are low, differential diagnosis should include certain forms of congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid

Renal Potassium Handling and Associated Inherited Tubulopathies Leading to Hypokalemia 99

The ability to provide a definitive molecular genetic diagnosis to a patient with an inherited tubulopathy allows a confidence in the diagnosis, despite phenotypic variabilities (which may be intrafamilial). A molecular genetic diagnosis also allows the targeted pharmacology to be employed to achieve normalization / improvement in symptoms, serum biochemistry and blood pressure. The discovery of renal tubular transporters and channels has allowed significant gains in our understanding of this group of renal diseases, with families with inherited tubulopathies providing the ultimate "animal model". Although perhaps uncommon, the discovery of the molecular players of salt and water handling within the nephron has allowed applications to be made to

It is certainly true that a patient with hypokalemia / metabolic alkalosis, no matter how

JAS is a GlaxoSmithKline clinician scientist and is also supported by Kidney Research UK

Ariceta, G. & Rodriguez-Soriano, J. (2006) Inherited renal tubulopathies associated with

Bartter, F.C., Pronove, P., Gill, J.R., Jr. & Maccardle, R.C. (1962) Hyperplasia of the

Bockenhauer, D., Feather, S., Stanescu, H.C., Bandulik, S., Zdebik, A.A., Reichold, M., Tobin,

Cappola, T.P., Matkovich, S.J., Wang, W., van Booven, D., Li, M., Wang, X., Qu, L., Sweitzer,

Cobeta-Garcia, J.C., Gascon, A., Iglesias, E. & Estopinan, V. (1998) Chondrocalcinosis and

metabolic alkalosis: Effects on blood pressure. *Semin Nephrol*, Vol. 26, No. 6, (Nov),

juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. *Am J Med*, Vol. 33, No. (Dec), pp. (811-828), 0002-9343 (Print) 0002-

J., Lieberer, E., Sterner, C., Landoure, G., Arora, R., Sirimanna, T., Thompson, D., Cross, J.H., van't Hoff, W., Al Masri, O., Tullus, K., Yeung, S., Anikster, Y., Klootwijk, E., Hubank, M., Dillon, M.J., Heitzmann, D., Arcos-Burgos, M., Knepper, M.A., Dobbie, A., Gahl, W.A., Warth, R., Sheridan, E. & Kleta, R. (2009) Epilepsy, ataxia, sensorineural deafness, tubulopathy, and kcnj10 mutations. *N Engl J Med*, Vol. 360, No. 19, (May 7), pp. (1960-1970), 1533-4406 (Electronic) 0028-4793

N.K., Fang, J.C., Reilly, M.P., Hakonarson, H., Nerbonne, J.M. & Dorn, G.W. (2011), 2nd. Loss-of-function DNA sequence variant in the clcnka chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation. *Proc Natl Acad Sci U S A*, Vol. 108, No. 6, (Feb 8), pp. (2456-2461), 1091-6490 (Electronic)

gitelman's syndrome. A new association? *Ann Rheum Dis*, Vol. 57, No. 12, (Dec), pp.

mild, warrants further evaluation to determine the underlying cause.

pp. (422-433), 0270-9295 (Print) 0270-9295 (Linking).

(748-749), 0003-4967 (Print) 0003-4967 (Linking).

**5. Conclusions** 

sufferers of "essential hypertension".

and the Northern Counties Kidney Research Fund.

**6. Acknowledgements** 

9343 (Linking).

(Linking).

0027-8424 (Linking).

**7. References** 

excess, chronic liquorice ingestion and carbenoxolone therapy. Treatment of Liddle's syndrome consists of sodium restriction and potassium-sparing diuretics, like amiloride and triamterene, which directly inhibit the ENaC. There is no benefit of using mineralocorticoid antagonists, such as spironololactone, as in this syndrome the up regulation of ENaC is not mediated by aldosterone.
