Liddle Syndrome

Extremely rare but described in a variety of populations

True incidence and prevalence unknown

Chronically untreated Htn

Undiagnosed cerebrovascular, CV, and/or renal disease secondary to chronic Htn

Worsening of hypokalemia with hyperventilation and nasogastric suctioning

Hypokalemia-induced dysrhythmias and potentiation of NMB

Monogenic AD gain-of-function mutation in the ENaC resulting in early onset Htn, hypokalemia, and metabolic alkalosis with suppressed plasma renin activity; resembles primary aldosteronism but aldosterone excretion is markedly suppressed (also known as “pseudoaldosteronism”).

Htn results from volume expansion due to increased Na ⁺ reabsorption via the constitutively active ENaC; urinary secretion of K ⁺ and H ⁺ occurs to balance out movement of electrical charges, resulting in a hypokalemic metabolic alkalosis.

Presentation is variable.

• Htn may not be early in onset or severe.

• Hypokalemia may be absent.

• Family history is not reliable, as spontaneous mutations have been reported.

ENaC is a membrane-bound ion channel located on the apical membrane of the principal cell in the distal tubule, which is selectively permeable to sodium ions; their activity is normally regulated by aldosterone.

ENaC is composed of three subunits: α, β, and γ.

NEDD4, a ubiquitin ligase enzyme, negatively modulates ENaC via ubiquitination.

Gene mutations resulting in deletions or alterations of the carboxy-terminus of the β or γ subunits (located on chromosome 16p) make NEDD4 binding impossible; this prevents channel degradation and removal, resulting in the constitutive activity of ENaC.