Liddle's syndrome mechanisms, diagnosis and management

Abstract

Liddle's syndrome is a genetic disorder characterized by hypertension with hypokalemic metabolic alkalosis, hyporeninemia and suppressed aldosterone secretion that often appears early in life. It results from inappropriately elevated sodium reabsorption in the distal nephron. Liddle's syndrome is caused by mutations to subunits of the Epithelial Sodium Channel (ENaC). Among other mechanisms, such mutations typically prevent ubiquitination of these subunits, slowing the rate at which they are internalized from the membrane, resulting in an elevation of channel activity. A minority of Liddle's syndrome mutations, though, result in a complementary effect that also elevates activity by increasing the probability that ENaC channels within the membrane are open. Potassium-sparing diuretics such as amiloride and triamterene reduce ENaC activity, and in combination with a reduced sodium diet can restore normotension and electrolyte imbalance in Liddle's syndrome patients and animal models. Liddle's syndrome can be diagnosed clinically by phenotype and confirmed through genetic testing. This review examines the clinical features of Liddle's syndrome, the differential diagnosis of Liddle's syndrome and differentiation from other genetic diseases with similar phenotype, and what is currently known about the population-level prevalence of Liddle's syndrome. This review gives special focus to the molecular mechanisms of Liddle's syndrome.

Keywords: ENaC; Liddle’s syndrome; blood pressure; distal nephron; hypertension.

Figure 1

Each ENaC subunit has intracellular amino and carboxy termini, two transmembrane domains, and an extracellular loop. When an intact PY motif is present the E-3 ubiquitin ligase NEDD4-2 can bind to ENaC carboxy termini, and ubiquitinate amino termini. In typical Liddle’s syndrome this mechanism is disrupted.

Figure 2

Model of a principal cell of the distal nephron. In normal conditions aldosterone activates mineralocorticoid receptor (MR), which can increase transcription of ENaC subunits, or an inhibitor of NEDD4-2, SGK. The Na+/K+ ATPase creates the electrochemical gradient for the reabsorption of sodium, and potassium efflux in these cells. In Liddle’s syndrome, additional sodium reabsorption in these cells can result in additional potassium efflux through ROMK, and BK channels.