Description

• Autosomal dominant (AD) disorder characterized by early-onset hypertension associated with hypokalemia, metabolic alkalosis, suppressed plasma renin activity, and aldosterone levels
• Mutation of β- or γ-subunit of epithelial sodium channel (ENaC) located in the distal nephron results in gain of function mutation of ENaC and the following:
  • Excess sodium reabsorption
  • Increased urinary potassium excretion
  • Suppressed renin and aldosterone levels
  • Secondary hypertension
• Resistant to conventional treatment including mineralocorticoid receptor antagonist (spironolactone, eplerenone) but responsive to ENaC inhibitor (amiloride, triamterene)

Epidemiology

Incidence
Unknown

Prevalence

• Unknown, rare
• May be underrecognized due to variable expressivity
• Described in populations worldwide

Etiology and Pathophysiology

• The ENaC is a cell membrane–bound ion channel that is permeable to sodium (Na⁺) ion. In the kidney, it is expressed in the apical membrane of principal cells and controls sodium reabsorption at the cortical collecting duct (CCD) and is regulated by aldosterone.
• ENaC is composed of three subunits: α, β, and γ.
• Under normal condition, ENaC is degraded by ubiquitin proteasome or NEDD4.
• Mutations in β- or γ-subunit make ENaC unrecognizable by NEDD4 and result in decreased degradation and removal of ENaC from the cell membrane, causing an overactivity of ENaC (gain of function mutation).
• Net result: excessive reabsorption of sodium, which leads to volume expanded hypertension and suppression of renin and aldosterone
• Mineralocorticoid antagonists are therefore ineffective.
• Hypokalemia and metabolic alkalosis develop in response to reabsorption of sodium in exchange for potassium and hydrogen ions secretion. These findings are, however, variable.

Genetics

• Monogenic AD inheritance with high penetrance but variable expressivity
• Children of affected parents have a 50% chance of inheriting disease allele.
• Mutation in SCNN1B or SCNN1G genes encoding for β- or γ-subunit of ENaC located on chromosome 16p12

Risk Factors

Family history of first-degree relative with onset of hypertension at young age. Sporadic cases have also been reported.