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Liddle syndrome is a rare inherited form of hypertension characterized by severe early-onset hypertension associated with decreased plasmatic levels of potassium, renin and aldosterone.
ORPHA:526Classification level: Disorder
Prevalence is unknown. About 80 cases have been reported to date.
Severe hypertension is found in young patients, from infancy to young adulthood (<35 years of age). Children are usually asymptomatic. Adults can present with symptoms of hypokalemia such as weakness, fatigue, myalgia, constipation or palpitations. A family history of hypertension across several generations suggesting autosomal dominant inheritance is often present.
Liddle syndrome is due to gain-of-function mutations in the genes encoding the epithelial sodium channel (ENaC), involved in sodium reabsorption of the distal renal tubules. The channel comprises three subunits (alpha, beta, gamma) and the mutations occur on the C-terminus of the beta and gamma subunits, encoded by the SCNN1B and SCNN1G genes (16p13-p12) respectively, in proline-rich region called the PY motif. These mutations impair ENaC interaction with the Nedd4 (E3 ligase) protein and its subsequent degradation by the ubiquitin proteasome system. This results in constitutive expression of ENaC channels in the membrane inducing sodium reabsorption, secondary potassium secretion and ultimately, hypertension.
Diagnosis is suspected by the fortuitous detection of early-onset hypertension, especially in the presence of family history. It is then confirmed by blood and urinary electrolyte tests which show hypokalemia, decreased or normal plasma levels of renin and aldosterone, metabolic alkalosis with high sodium plasma levels, and low rates of urinary excretion of sodium and aldosterone with high rates of urinary potassium excretion. The diagnosis is confirmed by genetic testing.
The clinical picture resembles that of primary hyperaldosteronism (see this term) but the hormonal profile resembles that of hyporeninism-hypoaldosteronism (see this term).
Transmission is autosomal dominant.
Management and treatment
Treatment is based on administration of potassium-sparing diuretics, such as amiloride or triamterene, which act by blocking ENaC activity. This results in reduction of blood pressure and correction of hypokalemia and metabolic alkalosis. Conventional antihypertensive therapies are not effective. Patients must also follow a low sodium diet.
With treatment, prognosis is good. Without treatment, cardiovascular and renal complications usually occur.