Hypokalemic Alkalosis, Familial, With Specific Renal Tubulopathy

Clinical Features

Potter et al. (1974) described a 'new' form of familial hypokalemia in 2 brothers. (Two sisters and a third brother had elevated plasma renin levels and/or decreased plasma potassium levels.) The older brother had fatigue and muscle cramps, nausea, and intermittent vomiting. He could not conserve sodium on a low sodium diet. On a high sodium diet and triamterene, his potassium returned to normal. The younger brother was asymptomatic and could retain sodium when dietary intake of sodium was restricted. The findings differed from those of Bartter syndrome (see 241200) in which hyperaldosteronism and juxtaglomerular hyperplasia are important features and sodium conservation occurs.

Gullner et al. (1980, 1983) studied 3 black sibs (2 girls, 1 boy) with hypokalemia. Their disorder resembled Bartter syndrome in the presence of hyperreninemia, high urinary prostaglandin E2, normal blood pressure, and resistance of BP to the pressor effect of angiotensin II. In contrast to Bartter syndrome, the juxtaglomerular apparatus was histologically normal and changes were observed in the proximal tubules: intense staining of the cells, extreme hypertrophy of the basement membranes, and, by electron microscopy, dense cytoplasm, compact mitochondria, and pyknotic nuclei. Glomerular distal tubular and loop of Henle functions were normal. The 3 affected sibs had identical HLA-A and HLA-B types whereas a single unaffected sib had the complementary haplotype. A lod score of 1.322 (21:1 odds; P less than 0.05) for linkage was calculated. Gullner et al. (1981) found that the hypokalemia was corrected by magnesium repletion. They reviewed the impressive body of evidence for an interrelationship of magnesium and potassium metabolism and suggested that abnormal magnesium metabolism may be responsible for the hypokalemia in this syndrome. Serum magnesium concentrations were within normal limits before treatment in the 3 sibs they studied (then aged 12, 13, and 14 years). Magnesium treatment did not affect renin levels, but caused an increase in plasma aldosterone concentration in both the supine and upright positions. Gullner et al. (1983) reported definitively on their family. (Liddle syndrome (177200), another disorder with hypokalemia, is differentiated from this and Bartter syndrome by the presence of hypertension.)

Molecular Genetics

In 2 Chinese patients with hypokalemia of unknown cause, metabolic alkalosis, and normal to low blood pressure, both of whom were heterozygous for known mutations in the SLC12A3 gene (600968) that had previously been found in patients with Gitelman syndrome (263800), Zhang et al. (2013) identified heterozygosity for missense mutations in the WNK1 gene (605232.0012 and 605232.0013) and suggested that inactivating mutations in WNK1 may cause salt-losing renal tubulopathy.