Identification of compound mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome exhibiting Bartter syndrome-liked phenotypes.

BACKGROUND: Gitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity. METHODS: In this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome. RESULTS: The proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C > T (p.Arg145Cys), c.1077C > G (p.Asn359Lys), and c.1666C > T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges. CONCLUSIONS: In this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.

Rare mutation in the SLC26A3 transporter causes life-long diarrhoea with metabolic alkalosis.

SLC26A3, a chloride/bicarbonate transporter mainly expressed in the intestines, plays a pivotal role in chloride absorption. We present a 23-year-old woman with a history of congenital chloride diarrhoea (CCD) and renal transplant who was admitted for rehydration and treatment of acute kidney injury after she presented with an acute diarrhoeal episode. Laboratory investigations confirmed metabolic alkalosis and severe hypochloraemia, consistent with her underlying CCD. This contrasts with most other forms of diarrhoea, which are normally associated with metabolic acidosis. Genetic testing was offered and revealed a homozygous non-sense mutation in SLC26A3 (Gly-187-Stop). This loss-of-function mutation results in bicarbonate retention in the blood and chloride loss into the intestinal lumen. Symptomatic management with daily NaCl and KCl oral syrups was supplemented with omeprazole therapy. The loss of her own kidneys is most likely due to crystal-induced nephropathy secondary to chronic volume contraction and chloride depletion. This case summarises the pathophysiology and management of CCD.

[An asymptomatic chronic hypokalaemia]. / Une hypokaliémie chronique asymptomatique.

We report the case of an asymptomatic patient presenting a severe chronic renal hypokalaemia. Once being sure of no diuretics use, two hypothesis can be mentioned for a normotensive patient presenting an hypokalaemia associated with a metabolic alcalosis: Bartter syndrome or Gitelman syndrome. The highlighting of low magnesaemia and hypocalciuria strongly concentrates the diagnosis on Gitelman syndrome. First, this has been strengthened by the results of renal function tests and later it has confirmed by molecular diagnosis with the identification of a known homozygous mutation on SLC12A3 gene. In the patient family, the same chromosomal abnormality has been found in the young sister. For these two patients the treatment ordered is an antikaliuretic diuretic, magnesium and potassium supplements. This case shows the difficulty to diagnose Gitelman syndrome: it is frequently mistaken for Bartter syndrome. The main differences between these two syndromes are magnesaemia and calciuria. Furthemore , patients with Gitelman syndrome are often asymptomatic, this explains why prevalence of this illness is probably underestimated.

A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension.

We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS.

Hypokalemic metabolic alkalosis--three case reports.

The two most common forms of inherited normotensive hypokalemic metabolic alkalosis are Bartter's and Gitelman's syndromes. Bartter's syndrome typically present with normal or increased calcium excretion. Hypomagnesemia occurs in only one third of affected individuals. In contrast, hypomagnesemia and hypocalciuria are considered hallmarks of Gitelman's syndrome. In most patients, the symptom of muscle weakness and polyuria occur early in life, which may be attributed to potassium depletion. Despite hyperaldosteronism, the patients tend to be normotensive, which is at least explained by vascular hyperresponsiveness to prostaglandins. Therapeutic approaches to Bartter's and Gitelman's syndromes include potassium supplementation, prostaglandin synthesis inhibitors (nonsteroid anti-inflammatory agents), aldosterone antagonists and converting enzyme inhibitors. Three patients with hypokalemia, normal blood pressure, metabolic alkalosis, hyperreninemia and hyperaldosteronism are described. Two patients had Bartter's syndrome and one patients had Gitelman's syndrome.

[Chronic metabolic alkalosis in a newborn infant caused by congenital chloride diarrhea]. / Chronische, metabolische Alkalose bei einem Neugeborenen durch eine kongenitale Chloriddiarrhö.

The case of a female preterm infant (gestational age 36 weeks) is described, who presented with abdominal distension, diarrhoea, dehydration and metabolic alkalosis at the fifth day of life. After different diagnostic tests had been performed, congenital chloride diarrhoea was suspected and chloride supplementation was started. However, this diagnosis could not be confirmed, until the measurement of electrolytes in faeces had been improved. Then, we found the typically elevated fecal chloride concentration (130-153 mmol/l) which exceeded the sum of the fecal concentration of sodium (64-90 mmol/l) and potassium (28-35 mmol/l). The chloride supplementation was increased to 6 mmol/kg/d NaCl and 2 mmol/kg/d KCl. The most recent examination at the age of 1 year revealed the girl to be in good clinical condition, with normal growth and psychomotor-development and with no evidence of renal impairment.

Correction of hypokalemia by magnesium repletion in familial hypokalemic alkalosis with tubulopathy.

The effect of magnesium treatment on serum potassium and potassium balance was examined in three siblings with a recently described syndrome of hypokalemic alkalosis with renal tubulopathy. Oral magnesium supplementation for 11 days in the three siblings increased mean serum potassium from 2.7 +/- 0.1 meq/liter to 3.3 +/- 0.2 meq/liter (p less than 0.05). In addition, urinary and fecal potassium excretion decreased by about 11 meq/day. Magnesium chloride did not affect plasma renin activity while the patients were supine or upright. In contrast, mean supine plasma aldosterone concentration increased from 5.3 +/- 1.5 ng/dl to 13.2 +/- 4.1 ng/dl (p greater than 0.1) and mean upright plasma aldosterone concentration increased from 17.4 +/- 3.8 ng/dl to 66.1 +/- 7.3 ng/dl (p less than 0.01). These findings suggest that hypokalemia and potassium loss in this disorder may be caused by abnormal magnesium metabolism. The increase in plasma aldosterone concentration may have been caused by the positive potassium balance or a direct effect of magnesium on aldosterone secretion from the adrenal gland.