Liddle Syndrome 1

A number sign (#) is used with this entry because Liddle syndrome-1 (LIDLS1) is caused by heterozygous mutation in the SCNN1B gene (600760), encoding the beta subunit of the renal epithelial sodium channel (ENaC), on chromosome 16p12.

Description

Liddle syndrome is an autosomal dominant disorder characterized by early-onset salt-sensitive hypertension, hypokalemia, metabolic alkalosis, and suppression of plasma renin activity and aldosterone secretion (summary by Yang et al., 2014).

Genetic Heterogeneity of Liddle Syndrome

Liddle syndrome-2 (618114) is caused by mutation in the SCNN1G gene (600761), which encodes the ENaC gamma subunit. Liddle syndrome-3 (618126) is caused by mutation in the SCNN1A gene (600228), which encodes the ENaC alpha subunit.

Hanukoglu and Hanukoglu (2016) provided a detailed review of the ENaC gene family, including structure, function, tissue distribution, and associated inherited diseases.

Clinical Features

Liddle et al. (1963) described hypertension associated with hypokalemic alkalosis that was not due to hyperaldosteronism but rather to a renal tubular peculiarity. Three generations were affected, with no known male-to-male transmission. Botero-Velez et al. (1994) provided a follow-up of the index case. She was 16 years old in 1960 when she was studied by Liddle et al. (1963) and found to have hypertension and hypokalemic metabolic alkalosis. A brother and sister, aged 14 and 19 years, respectively, had the same abnormalities. The fact that their urinary aldosterone excretion was low, even while they were on a low-sodium diet, excluded primary aldosteronism. Ingestion or hypersecretion of other mineralocorticoids was excluded by the finding of high ratios of sodium to potassium in saliva and sweat, a lack of effect of spironolactone on electrolyte excretion and hypertension, and normal urinary excretion of glucocorticoid metabolites. Renal failure eventually developed in the proposita, who received a cadaveric renal transplant in 1989, following which her disorder resolved with normalization of the aldosterone and renin responses to salt restriction.

Studies by Rodriguez et al. (1981), Wang et al. (1981), Nakada et al. (1987), and others confirmed the original description of Liddle et al. (1963) and demonstrated that amiloride and triamterene, but not spironolactone, were effective treatments for hypertension and hypokalemia in patients with this syndrome as long as dietary sodium intake was restricted. Gardner et al. (1971) and Wang et al. (1981) found an enhanced influx of sodium into red cells in patients with Liddle syndrome, but there was no generalized increase in the permeability of the cell membrane to sodium.

Hansson et al. (1995) described an African American kindred (K242) with Liddle syndrome in which the proband was an 11-year-old girl who had elevated blood pressure from 18 months of age. She also exhibited hypokalemia and suppressed plasma renin activity and aldosterone concentration. Her hypertension was resistant to treatment but ultimately improved on triamterene in conjunction with a low sodium diet. Her similarly affected 13-year-old brother was also successfully treated with triamterene and low-salt diet. Their mother, who had been diagnosed with severe hypertension and hypokalemia at age 15, experienced a stroke at age 21, which left her with mild residual right-sided weakness.

Tamura et al. (1996) restudied 2 Japanese brothers with Liddle syndrome who were originally reported by Matsui et al. (1976) at ages 17 and 21 years. One brother had chronic renal failure due to nephrosclerosis and was on hemodialysis at age 37. The other brother was on antihypertensive medications at age 41, and had a 17-year-old affected son. The brothers' mother had a history of hypertension and was on hemodialysis for chronic renal failure before her death at age 72. In addition, 2 sisters also had hypertension with low plasma aldosterone concentration, although they were not hypokalemic. Tamura et al. (1996) noted that hypokalemia is not a universal finding among affected individuals, as had been observed in the original Liddle pedigree (Botero-Velez et al., 1994).

Findling et al. (1997) reported a large kindred (K176) in which 8 living and 2 deceased family members had Liddle syndrome. The proband was a 16-year-old girl who was diagnosed with hypertension at preschool age, with blood pressures ranging from 136/114 to 142/100 mmHg. Examination revealed intermittent mild hypertension and hypokalemia, as well as low plasma renin activity and aldosterone levels. There was a family history of early-onset hypertension in her mother and 2 maternal aunts, 1 of whom had a myocardial infarction at age 44; 2 more maternal aunts had pregnancy-related hypertension. The proband's maternal grandfather died of complications of hypertensive cardiovascular disease in his 70s, and his mother had a long history of hypertension and died of a stroke at age 90. The youngest affected family member was 2 years old and had blood pressures above the 90th percentile for age and gender; his plasma renin activity and aldosterone level were below the limits of detection. The authors noted variability in the severity of hypertension and hypokalemia in this kindred, and suggested that Liddle syndrome may be underdiagnosed among patients with mild essential hypertension.

Jeunemaitre et al. (1997) reported a family in which a mother and her 3 sons had Liddle syndrome and a heterozygous mutation in the SCNN1B gene. All 4 patients had early-onset moderate to severe hypertension, as well as mild hypokalemia and suppressed levels of plasma renin and aldosterone. Administration of 10 mg/day amiloride for 2 months normalized the blood pressure and plasma potassium levels of all 4 patients, whereas plasma and urinary aldosterone levels remained low. A similar pattern was observed after 11 years of follow-up. Many of the mother's relatives had had stroke or sudden death before age 60 years.

Reviews

Scheinman et al. (1999) provided a comprehensive review of genetic disorders of renal electrolyte transport. Each of the syndromes reviewed demonstrated the power of molecular and genetic techniques in defining the underlying pathophysiology of human disease. The candidate gene approach was directly applied in the example of Liddle syndrome and type I pseudohypoaldosteronism (264350).

Pathogenesis

The clinical abnormalities in persons with Liddle syndrome can be corrected by a low salt diet plus antagonists of the epithelial sodium channel of the distal nephron, but are not improved by antagonists of the mineralocorticoid receptor. These features suggested that the hypertension in these patients results from excessive sodium reabsorption in the kidney. Botero-Velez et al. (1994) suggested that constitutive activation of any component of the epithelial sodium channel complex or constitutive activation of the mineralocorticoid receptor, specifically in the collecting tubule, could explain the syndrome.

Snyder et al. (1995) investigated the mechanism by which truncation of the C terminus of the beta and gamma subunits alter the function of the renal epithelial sodium channel. They identified a conserved motif in the C terminus of all 3 subunits of the sodium channel that, when mutated, reproduced the effect of Liddle truncations. Further, both truncation of the C terminus and mutation of the conserved C-terminal motif increased surface expression of chimeric proteins containing the C terminus of the beta subunit. Thus, by deleting a conserved motif, mutations in the Liddle syndrome increased the number of sodium channels in the apical membrane, which increases renal sodium absorption and creates a predisposition to hypertension.

In Xenopus oocyte studies, Abriel et al. (1999) demonstrated that overexpression of wildtype NEDD4 (602278) together with the epithelial sodium channel (ENaC) inhibited activity of the channel. These effects were dependent on the presence of C-terminal PY motifs of ENaC, and changes in channel activity were due entirely to alterations in ENaC numbers at the plasma membrane. Abriel et al. (1999) concluded that NEDD4 is a negative regulator of ENaC and suggested that loss of NEDD4 binding sites in ENaC observed in Liddle syndrome might explain the increase in channel number at the cell surface, increased sodium resorption by the distal nephron, and hence hypertension.

Baker et al. (1998) measured transnasal potential difference in 3 brothers with genetically proven Liddle syndrome, their unaffected sister, and 40 normotensive controls. Increase in epithelial sodium channel activity with increase in sodium reabsorption in the renal distal tubule is the basis for hypertension in Liddle syndrome. The measurements in the patients represented the first in vivo demonstration of increased sodium channel activity in Liddle syndrome. Nasal potential difference measurements should provide a simple clinical test for Liddle syndrome.

Inheritance

In studies of the extended pedigree of the family originally reported by Liddle et al. (1963), Botero-Velez et al. (1994) demonstrated autosomal dominant inheritance with several instances of male-to-male transmission.

Mapping

In studies of the kindred originally described by Liddle et al. (1963), Shimkets et al. (1994) demonstrated complete linkage of the disorder to the gene encoding the beta subunit of the epithelial sodium channel on chromosome 16.

Molecular Genetics

In affected members of the kindred originally described by Liddle et al. (1963), Shimkets et al. (1994) identified a premature stop codon (R564X; 600760.0001) in the beta subunit of the renal epithelial sodium channel that truncated the cytoplasmic C terminus of the protein. Analysis of subjects with the disorder from 4 additional kindreds demonstrated either premature termination or frameshift mutations in the same C-terminal domain. (Clinical evaluation of 1 of these kindreds had previously been reported by Gardner et al. (1971).)

In an African American mother and 2 children (kindred K242) with Liddle syndrome, Hansson et al. (1995) screened the last coding exon of both the SCNN1B and SCNN1G genes by SSCP and identified heterozygosity for a missense mutation in SCNN1B (P616L; 600760.0002) that segregated fully with disease in the family and was not found in 1,000 controls. Because haplotype analysis revealed that the mutation arose de novo in the mother, the authors concluded that absence of family history should not be used to exclude the diagnosis of Liddle syndrome in apparently sporadic patients.

In 4 affected sibs and the son of 1 of the sibs from a Japanese family with Liddle syndrome, Tamura et al. (1996) sequenced the carboxyl terminus of the SCNN1B and SCNN1G genes and identified heterozygosity for a missense mutation in SCNN1B (Y618H; 600760.0004) that segregated with disease.

In a large kindred (K176) with Liddle syndrome, Findling et al. (1997) screened subunits of the renal amiloride-sensitive epithelial sodium channel and identified a 1-bp insertion in the SCNN1B gene (600760.0005) that segregated fully with disease and was not found in more than 750 controls. Noting the clinical variability exhibited in this family, the authors concluded that sustained hypertension and hypokalemia are not obligatory among patients carrying mutations causing Liddle syndrome. In addition, low 24-hour urinary aldosterone and/or a blunted response of plasma aldosterone to cosyntropin allowed complete and accurate separation of affected and unaffected family members, suggesting that these would be useful tests for excluding the diagnosis.

In a mother and 3 sons with Liddle syndrome, Jeunemaitre et al. (1997) identified heterozygosity for a 32-bp deletion in the SCNN1B gene (600760.0006).

In affected members of a 3-generation Japanese family with Liddle syndrome, Inoue et al. (1998) identified heterozygosity for a missense mutation in the SCNN1B gene (P615S; 600760.0007).

In a Japanese mother and daughter with Liddle syndrome, Furuhashi et al. (2005) identified heterozygosity for a missense mutation in SCNN1B (P616R; 600760.0008).