<p>Liddle’s syndrome mechanisms, diagnosis and management</p>

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.

Genotype–phenotype correlation in Gordon’s syndrome: report of two cases carrying novel heterozygous mutations

“…The SCNN1G gene encodes for the γ subunit of ENaC, whose dominant mutations may cause another form of monogenic hypertension, Liddle syndrome (MIM#618114), which is characterized by hypokalemia and metabolic acidosis due to ENaC activation [12]. Most of the described mutations remove a proline rich segment in the carboxyl cytoplasmic tail of the γ subunit, which is engaged in negative regulation of the channel and its over-activation [13].…”

COVID-19 and late-onset hypertension with hyporeninaemic hypoaldosteronism

“…This results in intravascular volume expansion and hypokalaemic metabolic alkalosis. This hypothesis is supported by reversibility of electrolyte abnormalities and hypertension with the diuretic amiloride which inhibits Na+ reabsorption by selectively blocking this channel [1,2].…”

Covid-19 and hypokalaemia – A potential mechanism

“…We postulate that transient hyporeninaemic hypoaldosteronism may be related to dysregulated sodium channel (ENaC) pathophysiology similar to that seen in Liddle’s syndrome. Effective correction of electrolyte abnormalities and hypertension with the diuretic amiloride, which inhibits sodium reabsorption by selectively blocking this channel, 3,4 supports this reasoning. The disease entity appears to be self-limiting and contained within the period of acute infection.…”