Liddle Syndrome

Question 1

Liddle Syndrome

Answer 1

Autosomal dominant, gain of function mutation in either the β- or γ-subunits of ENaC in the collecting tubules

Question 2

Liddle Syndrome

Answer 2

The mutations affect the PY motif of ENaC, which is the peptide segment necessary for Nedd4-2 to recognize ENaC for ubiquitination for internalization and degradation. This results in an increased number of functioning apical ENaC on the apical membranes and increased Na+ reabsorption.

Question 3

Liddle Syndrome

Answer 3

Affected patients present with HTN due to increased Na+ retention, hyporenin/hypoaldosteronism due to volume expansion, but hypokalemia and metabolic alkalosis due to facilitated renal K+ and H+ secretion in the collecting tubules via the favorable electrochemical gradient generated by the enhanced Na+ reabsorption through ENaC.

Question 4

Liddle Syndrome

Answer 4

Treatment: low-sodium diet and direct ENaC inhibitors such as amiloride and triamterene.

Question 5

Liddle Syndrome

Answer 5

Treatment cont’d: Spironolactone is ineffective since Liddle syndrome is not due to aldosterone-induced upregulation of ENaC. The increased ENaC activity is due to reduced internalization and degradation of apical ENaC.