**2. Liddle Syndrome**

## *2.1. Historical Description*

The first family affected by a new clinical syndrome that mimicked primary aldosteronism was reported by Liddle et al. [4,5] in 1963 (pseudoaldosteronism, subsequently named Liddle syndrome, OMIM #177200). The index case was a 16-year-old Caucasian girl, who presented with low renin resistant hypertension (180/110 mmHg), severe hypokalemia (2.8 mmol/L) and metabolic alkalosis. These features could resemble those of primary aldosteronism, but this disease was ruled out on the basis of suppressed plasma aldosterone. At the time, Liddle et al. conducted many clinical and biochemical analyses in order to further characterize this peculiar disorder. Under the condition of low sodium intake, aldosterone secretion did not increase and urinary sodium excretion rate decreased, but not to the level that would have been expected in a normal subject. Instead, the urinary sodium levels fell maximally after the administration of exogenous aldosterone. These pieces of evidence suggested an inadequate level of plasma aldosterone rather than an intrinsic renal defect in sodium reabsorption as a cause of the incapability to maximally retain sodium. Compared with patients affected by Addison's disease, subjects with LS presented a lower urinary Na+ excretion, indicating a greater renal reabsorption due to a mechanism different from mineralocorticoid activity. Urinary mineralocorticoid and glucocorticoid metabolites resulted within the physiologic range. Notably, spironolactone administration neither modified urinary electrolytes excretion nor corrected hypokalemia, hence an intrinsic renal defect was hypothesized. Instead, the index case responded to the administration of triamterene, an inhibitor of the epithelial Na+ channel, that induced an increase in urinary sodium and a reduction in urinary potassium excretion [4,5]. Moreover, the association of triamterene (100 mg every 8 h) and a low sodium diet normalized blood pressure (diastolic blood pressure dropped to 80 mmHg) and hypokalemia (serum K+ rose to 5 mmol/L) [4,6]. Considering the biochemical profile and the response to triamterene, Liddle et al. hypothesized that the distal nephron could be the site of sodium retention. The index case developed chronic renal failure due to hypertensive nephrosclerosis and she underwent renal transplantation in 1989. This intervention corrected the disorder, normalizing blood pressure (140/79 mmHg) and the kalemia (4.2 mmol/L). After the transplantation, a regimen of low salt intake resulted in a normal increase in plasma renin activity and in plasma aldosterone concentration [6]. In 1994, Botero-Velez et al. described the extended pedigree of the family reported by Liddle et al., thus, demonstrating the autosomal dominant inheritance of the disorder [6]. Indeed, in the original manuscript, Liddle et al. described the index case and her two siblings while Botero-Velez et al. studied the index case again at the age of 49 (20 months after kidney transplantation), in addition to 43 family members. They considered as affected 18 relatives presenting with arterial hypertension, as unaffected 15 normotensive subjects with an affected parent and ten not-at-risk subjects (partners and offspring of unaffected parents) [6]. A great variability in clinical features (hypertension severity, age at onset, plasma potassium concentration, urinary aldosterone excretion levels) suggested a variable penetrance of the disease [7]. Considering the clinical response to epithelial sodium channel inhibitor triamterene and the lack of improvement using mineralocorticoid receptor antagonist and a low sodium diet, it was hypothesized that the candidate gene could be involved in the pathway of sodium handling in the distal nephron. Thus, in 1994, a complete linkage of LS to the *SCNN1B* gene (encoding the β subunit of epithelial sodium channel, ENaC) was demonstrated and the first causative mutation was identified in Liddle's original kindred as a premature stop codon, p.Arg566\* (originally referred as p.Arg564\* according to the homologous rat sequence) [7]. In the following years, several different germinal mutations in the *SCNN1A*, *SCNN1B* and *SCNN1G* genes, encoding, respectively, for the α, β and γ subunits of ENaC were identified, as described below.
