Liddle syndrome

Vignettes says a 16 year old male presents to the cardiology clinic with persistent high blood pressure noted during a school health check-up; He has no significant past medical history and no family history of hypertension; He reports occasional muscle cramps and weakness; Vital signs show blood pressure of 160/100 mm of Hg, pulse rate of 78 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 97.9 F; Laboratory studies show serum sodium of 135mEq/L, serum potassium of 2.8 mEq/L, low plasma aldosterone, low plasma renin activity; Genetic testing reveals a mutation in the β-subunit of the epithelial sodium channel (ENaC); USG (A+P) is normal; Diagnosis?

Diagnosis is Liddle syndrome. 

Liddle syndrome is an autosomal dominant disorder due to mutation of epithelial Na+ channels (i.e. ENaC); causes increased absorption of sodium in collecting tubules (due to increased activity of ENaC).

Pathogenesis:- Normally, ENaC are degraded by ubiquitin proteasome pathway; Nedd4-2 (i.e. ubiquitin-protein ligase) binds with ENaC and facilitates its degradation. ENaC is activated by aldosterone via the RAAS pathway (i.e. Aldosterone activates serum and glucocorticoid-regulated kinase (SGK)-1; SGK-1 phosphorylates and inactivates Nedd4-2 that cannot bind with ENaC preventing its degradation). However, in Liddle syndrome mutated epithelial Na+ channels cannot bind with Nedd4-2 preventing its degradation and causing its increased activation.

Presents with hypertension, hypokalemia, and metabolic alkalosis; Laboratory parameters show low plasma aldosterone and low renin activity.

Management:- Epithelial Na+ channel blockers i.e. ENaC blockers (e.g. Amiloride); Amiloride also is useful for lithium-induced nephrogenic diabetes insipidus as it blocks Li+ transport into collecting tubule cells.