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.

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Keywords:

• ENaC
• Liddle’s syndrome
• hypertension
• blood pressure
• distal nephron

Glossary of terms

Liddle’s-like Phenotype– Used here to mean the constellation of symptoms: Elevated blood pressure, low plasma aldosterone, low plasma renin, and sometimes hypokalemia, and metabolic alkalosis.

Liddle’s Mutation– Used here to mean any gain of function mutation to an Epithelial Sodium Channel subunit that results in Liddle’s syndrome, usually through changes to membrane density or open probability.

Liddle’s syndrome– Used here to mean Liddle’s Phenotype secondary to a Liddle’s Mutation.

Disclosure

The authors report no conflicts of interest in this work.