Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome

BACKGROUND: Mutations in the renal K+ channel ROMK (Kir 1.1) cause hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a severe tubular disorder leading to renal salt and water wasting. Several studies confirmed the predominance of alterations of current properties in ROMK mutants. However, in most of these studies, analysis was restricted to nonmammalian cells and electrophysiologic methods. Therefore, for the majority of ROMK mutations, disturbances in protein trafficking remained unclear. The aim of the present study was the evaluation of different pathogenic mechanisms of 20 naturally occurring ROMK mutations with consecutive classification into mutational classes and identification of distinct rescue mechanisms according to the underlying defect. METHODS: Mutated ROMK potassium channels were expressed in Xenopus oocytes and a human kidney cell line and analyzed by two electrode voltage clamp analysis, immunofluorescence, and Western blot analysis. RESULTS: We identified 14 out of 20 ROMK mutations that did not reach the cell surface, indicating defective membrane trafficking. High expression levels rescued six out of 14 ROMK mutants, leading to significant K+ currents. In addition, two early inframe stop mutations could be rescued by aminoglycosides, resulting in full-length ROMK and correct trafficking to the plasma membrane in a subset of transfected cells. CONCLUSION: In contrast to previous reports, most of the investigated ROMK mutations displayed a trafficking defect that might be rescued by pharmacologic agents acting as molecular chaperones. The evaluation of different disease-causing mechanisms will be essential for establishing new and more specific therapeutic strategies for HPS/aBS patients.     

Antenatal Bartter syndrome with sensorineural deafness: refinement of the locus on chromosome 1p31.

BACKGROUND: Recently a locus for antenatal Bartter syndrome associated with sensorineural deafness was mapped to human chromosome 1p31 in a single consanguineous Bedouin family (Brennan et al. Am J Hum Genet 1998; 62: 355-361). METHODS: By haplotype analysis we demonstrate linkage to this locus in nine consanguineous families with antenatal Bartter syndrome associated with sensorineural deafness. RESULTS: The critical interval compatible with linkage was refined to 4.0 cM by two novel recombinational events with markers D1S2661 and D1S475. CONCLUSION: We thereby confirmed this gene locus and distinguished this clinical subtype from other variants of Bartter syndrome as a new disease entity.     

Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome

BACKGROUND: Hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS) is a congenital salt-losing tubulopathy with an induced expression of cyclooxygenase-2 (COX-2) in the macula densa probably leading to hyperreninemia. Inhibition of stimulated prostaglandin E2 (PGE2) formation with indomethacin results in a significant improvement of clinical symptoms and is therefore standard therapy. Using the COX-2 selective inhibitor rofecoxib, we investigated the role of COX-2 in the pathophysiology of HPS/aBS. METHODS: Six clinically well-characterized patients with HPS/aBS (3 girls) were enrolled into the study. Four patients had mutations in the renal potassium channel ROMK, one patient in the furosemide-sensitive cotransporter NKCC2, whereas in one patient no molecular abnormality could be detected. Median age was 15.8 years (range: 9.1 to 19.0 years). Patients were evaluated on indomethacin treatment, 3 days after indomethacin withdrawal, and after 4 days of treatment with rofecoxib. Therapeutic drug monitoring was performed. RESULTS: COX-2-selectivity of rofecoxib was confirmed in vivo and ex vivo. Both indomethacin and rofecoxib ameliorated clinical symptoms, the typical laboratory findings, and significantly suppressed PGE2 and PGE-M excretion to normal values while it was elevated under withdrawal conditions. Rofecoxib suppressed hyperreninemia to a similar extent as indomethacin. CONCLUSION: In patients with HPS/aBS, excessive PGE2 synthesis and hyperreninemia is dependent on COX-2 activity. This observation proves the stimulatory role of COX-2 on renin-secretion in salt-depletion in humans. Clinical long-term efficacy and potential side effects of rofecoxib need to be evaluated in a larger cohort of HPS/aBS-patients.     

Unilateral sensorineural deafness in children

Heredity, viral infection, and head or acoustic trauma are considered the common etiologies for a unilateral sensorineural deafness in children. The incidence of perilymphatic fistula in a unilateral hearing loss is still unknown. Inner ear-related symptoms in children are scarce, and little diagnostic laboratory testing is available. A definite diagnosis of a perilymphatic fistula can therefore be made only by an exploratory tympanotomy. Four children, ages 5 to 15 years, with a history of a recent and rapidly progressive unilateral sensorineural hearing loss, were explored. Preoperative laboratory data, which included a fistula test, ENG, CT scan of the temporal bones, and an ABR, were all within normal limits. An overt fistula was found in only one of the patients. Only an exploratory tympanotomy can arrest and possibly reverse a unilateral hearing loss or discontinue a middle ear-cranial cavity communication. It is therefore our feeling that, in patients with an appropriate history, the potential benefit outweighs the risk and morbidity of an exploratory tympanotomy.     

Mutation G47R in the BSND gene causes Bartter syndrome with deafness in two Spanish families

Bartter syndrome (BS) is a heterogeneous group of autosomal recessive hypokalaemic salt-losing tubulopathies. Five types of BS caused by different genetic defects have been identified, and one of them is associated with sensorineural deafness (BSND). Mutations in the recently described BSND gene, mapped in chromosome 1p31, have been reported to be associated with BSND. This gene encodes barttin, an essential β-subunit subunit for ClC-Ka and ClC-Kb channels. Both subunits are co-expressed in basolateral membranes of renal tubules, in the ascending limb of the loop of Henle, and in the stria vascularis of the inner ear. We studied two apparently unrelated Spanish families from the Canary Islands, with five members showing this pathology. Sequence analysis of the BSND gene showed that the affected members were homozygous for a C-to-T transition in exon 1, while their parents were heterozygous. This alteration results in a missense mutation, G47R, which has been previously shown to abolish the stimulatory effect on the subunit barttin of the ClC-Kb channel. Our results indicate that families with the G47R mutation indeed present polyhydramnios, premature birth and salt loss. Nevertheless, glomerular filtration rate was normal in all patients. Clinical manifestations are moderate in patients with the G47R mutation compared to other published data form patients with BSND. This constitutes the first report of BSND cases in Spain.     

Neonatal Bartter syndrome

A pre-term baby girl was born following a pregnancy complicated by severe polyhydramnios at a gestational age of 36 weeks. She was initially suffering from respiratory distress consistent with idiopathic respiratory distress syndrome, and altered electrolyte imbalance with hyponatremia, hypokalemia and hypochloremic metabolic alkalosis. However, during the third week of life when she had dehydration along with significant electrolyte imbalance, Bartter's syndrome was considered which was supported by findings of high renin and aldosterone levels. Treatment was done by correction of electrolytes and dehydration along with indomethacin. The drug was well tolerated. The infant showed correction of electrolyte imbalance. The features of this case suggest an extreme form of Bartter's syndrome presenting from the early days of life. The syndrome is reported because of it's rarity and alerts pediatricians to the antenatal and neonatal variant of Bartter's syndrome.     

Long-term follow-up in distal renal tubular acidosis with sensorineural deafness

A 20-year-old man presented with failure to thrive and bilateral genu valgum. On the basis of growth failure, skeletal deformity, hyperchloremic metabolic acidosis with alkaline urine and hypokalemia, nephrocalcinosis, and hearing loss, a diagnosis of distal renal tubular acidosis (DRTA) with sensorineural deafness was made. The genu valgum was treated by corrective osteotomy. Skeletal deformity was corrected and impaired growth improved after sustained therapy of metabolic acidosis with alkali supplementation. During an 8-year follow-up period the patient’s glomerular filtration rate remained stable, the nephrocalcinosis did not progress, and his height increased 10 cm. Although nephrolithiasis led to atrophy of the right kidney, at last follow-up, when the patient was 44 years old, his creatinine clearance was 50 ml/min per 1.73 m² body surface. Received: 17 December 1999 / Revised: 26 April 2000 / Accepted: 2 May 2000     

Familial IgA nephropathy associated with bilateral sensorineural deafness.

Alport's syndrome is the most frequent disorder with familial nephritis and deafness, but other types of nephropathy have been occasionally associated with hereditary hearing loss. The familial occurrence of IgA nephropathy has been well documented. We report a family with hereditary, bilateral, sensorineural deafness spanning four generations. Three of five members with deafness had microscopic hematuria. Renal histology of the two deaf members undergoing biopsy showed mesangial glomerulonephritis with mesangial IgA deposits, without ultrastructural abnormalities of the glomerular basement membranes. Familial nephritis with deafness should not be equated with the diagnosis of Alport's syndrome.     

Two brothers with idiopathic membranous nephropathy and familial sensorineural deafness

Genetic factors could play an important role in the pathogenesis of idiopathic membranous nephropathy, and a few cases of familial membranous nephropathy have been described: an increased incidence of some HLA antigens as DR3 and others has been reported. We present two brothers with idiopathic membranous nephropathy and sensorineural deafness. HLA typing was performed in the two patients and in the members of the family, and it showed the absence of linkage of an HLA antigen with the renal disease in the family.     

Autosomal dominant polycystic kidney disease associated with familial sensorineural deafness

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by both renal and non-renal disorders. Extrarenal involvement includes noncystic manifestations such as cardiovascular abnormalities, colonic diverticula and intracranial aneurysms. Familial sensorineural hearing loss (SNHL) has been included in the definition of Alport's syndrome. However, other types of nephropathy have been occasionally associated with hereditary deafness. The association of ADPKD with hereditary SNHL has not been previously documented. We report a family with ADPKD associated with bilateral sensorineural deafness in a pedigree of four affected members in four generations.     

Remote tentorium meningioma causing sudden sensorineural deafness

BACKGROUND: Sudden sensorineural deafness is a well-known symptom mostly of unknown etiology. CASE DESCRIPTION: A case of sudden sensorineural deafness is reported to be caused by a small, remote, ipsilateral tentorial meningioma not compressing the vestibulocochlear nerve or auditory tract. Surgical resection of the meningioma immediately restored the patient's hearing. CONCLUSION: The authors hypothesize that the sudden sensorineural deafness resulted from a growing meningioma inducing a neurovascular compression of the vestibulocochlear nerve, the vertebral artery already being in close relationship with the vestibulocochlear nerve in the premorbid phase. Resection of the meningioma allows for an autodecompression of this vascular conflict resulting in hearing restoration.     

Adrenomedullin and nitrite levels in children with Bartter syndrome

Children with Bartter syndrome have lower than normal vascular reactivity with normotension in spite of biochemical and hormonal abnormalities which are typical of hypertension. Nitric oxide (NO) is a potent endogenous vasodilator, and plays an important role in the control of vascular tone. Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from human pheochromocytoma. The possible role of NO and AM in maintaining this reduced vascular reactivity was examined by studying plasma and urinary nitrite, a stable metabolite of NO, and AM levels in ten children with Bartter syndrome, ten healthy controls, and five children with hypokalemia of causes other than Bartter syndrome (pseudo-Bartter). Urinary excretion of nitrite (μmol/mg urinary creatinine) was 8.9.±1.2 in children with Bartter syndrome, 4.7.±0.9 in healthy controls, and 2.9.±0.8 in pseudo-Bartter (P<0.05). Plasma nitrite levels (μmol/l) were 101.9±23.4, 59.9±14.7, and 65.0±29.7, respectively (P>0.05), in the three groups. Urinary excretion of AM (pmol/mg urinary creatinine) was 187±40, 65±10, and 160±50, respectively (P<0.05), in the three groups. Plasma AM levels were 47.4±1.8, 39.9±5.9, and 42.4±3.9, respectively (P>0.05), in the three groups. The same parameters were repeated in the two groups of controls and in the Bartter patients in the 6th month of therapy. Urinary nitrite and AM levels were still higher in the Bartter patients than in the other groups. We conclude that in Bartter syndrome the increased NO production may be responsible for the reduced vascular response of the disease. Initially, increased levels of AM in Bartter syndrome and pseudo-Bartter may be a compensatory response to acute hypokalemia; however, continuation of a high level of urinary excretion of AM in children with Bartter syndrome may suggest also the possible role of AM in the reduced vascular response of the disease. Received: 2 December 1999 / Revised: 24 July 2000 / Accepted: 27 July 2000     

巴特综合征研究进展

巴特综合征表现为低钾血症、代谢性碱中毒、肾素-血管紧张素-醛固酮系统激活，而血压正常或偏低，是一种常染色体遗传病。现已证实6种基因突变可导致不同的亚型：新生儿型巴特综合征是由于Na—K-2C1协同转运体NKCC2或K^＋通道ROMK缺陷所致；经典型巴特综合征，是由于Cl^-通道CIC—Kb缺陷所致；新生儿型巴特综合征伴神经性耳聋，缘于barttin蛋白异常；巴特综合征并常染色体显性遗传，是由于钙敏受体基因突变导致；巴特综合征变异型则是由于Na—Cl同向转运体NCCT缺陷所致。     

Two novel mutations of the gene for Kir 1.1 (ROMK) in neonatal Bartter syndrome

Bartter syndrome, an autosomal recessive renal tubular disorder, is associated with hypokalemic metabolic alkalosis with high renin and aldosterone plasma concentrations with low or normal blood pressure and renal salt loss. Two genes, the gene encoding the furosemide-sensitive apical Na-K-2Cl cotransporter (NKCC2) and the gene encoding the luminal inwardly-rectifying potassium channel K_ir 1.1 (ROMK), have been reported to cause the neonatal subtype of Bartter syndrome. In a patient with neonatal Bartter syndrome, we report two novel mutations resulting in amino acid exchanges Ala156Val and Leu220Phe in the gene for K_ir 1.1 that have been identified by single-strand conformation polymorphism analysis and subsequent direct sequencing. Both mutations occur in functional relevant domains of the channel protein and are therefore highly suggestive of altering channel properties. Received October 29, 1997; accepted November 6, 1997     

Phenotypic variability in Bartter syndrome type I

Limited phenotypic variability has been reported in patients with Bartter syndrome type I, with mutations in the Na-K-2Cl cotransporter gene (BSC). The diagnosis of this hereditary renal tubular disorder is usually made in the antenatal-neonatal period, due to the presence of polyhydramnios, premature delivery, hypokalemia, metabolic alkalosis, hypercalciuria, and nephrocalcinosis. Among nine children with hypercalciuria and nephrocalcinosis, we identified new mutations consistent with a loss of function of the mutant allele of the BSC gene in five. Three of the five cases with BSC gene mutations were unusual due to the absence of hypokalemia and metabolic alkalosis in the first years of life. The diagnosis of incomplete distal renal tubular acidosis was considered before molecular evaluation. Three additional patients with hypokalemia and hypercalciuria, but without nephrocalcinosis in the first two and with metabolic acidosis instead of alkalosis in the third, were studied. Two demonstrated the same missense mutation A555T in the BSC gene as one patient of the previous group, suggesting a single common ancestor. The third patient presented with severe hypernatremia and hyperchloremia for about 2 months, and a diagnosis of nephrogenic diabetes insipidus was hypothesized until the diagnosis of Bartter syndrome type I was established by molecular evaluation. We conclude that in some patients with Bartter syndrome type I, hypokalemia and/or metabolic alkalosis may be absent in the first years of life and persistent metabolic acidosis or hypernatremia and hyperchloremia may also be present. Molecular evaluation can definitely establish the diagnosis of atypical cases of this complex hereditary tubular disorder, which, in our experience, may exhibit phenotypic variability.     

Bartter syndrome in a neonate: early treatment with indomethacin

The neonatal form of Bartter syndrome is characterized by intrauterine onset of polyuria leading to severe polyhydramnios. We report a patient with the early onset of the syndrome and a similar history in a previous sibling who died in early neonatal life. The patient is a female product of 33 weeks of gestation complicated by severe polyhydramnios. Her birth weight was 2,100 g. Polyuria led to severe dehydration on the 3rd day of life. Laboratory studies showed hypokalemia, hyponatremia, and elevated plasma levels of renin and aldosterone. Hypercalciuria was associated with echographic evidence of nephrocalcinosis. Indomethacin therapy resulted in a significant reduction in urine volume and correction of biochemical abnormalities. Growth and development are satisfactory after 4 years of indomethacin therapy, but nephrocalcinosis remains unchanged. Received: 22 December 1998 / Revised: 13 May 1999 / Accepted: 1 June 1999     

Baroreflex function in a patient with Bartter’s syndrome

Canadian Journal of Anesthesia/Journal canadien d'anesthésie - There is little information regarding circulatory responses in Bartter’s syndrome, with the exception of marked...     

Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome

Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient mortality and morbidity. However, the pathogenic role of PGE2 in HPS/aBS awaits clarification. Chronic blockade of the Na-K-2Cl co-transporter NKCC2 by diuretics causes symptoms similar to HPS/aBS and provides a useful animal model. In wild-type (WT) mice and in mice lacking distinct PGE2 receptors (EP1-/-, EP2-/-, EP3-/-, and EP4-/-), the effect of chronic furosemide administration (7 d) on urine output, sodium and potassium excretion, and renin secretion was determined. Furthermore, furosemide-induced diuresis and renin activity were analyzed in mice with defective PGI2 receptors (IP-/-). In all animals studied, furosemide stimulated a rise in diuresis and electrolyte excretion. However, this effect was blunted in EP1-/-, EP3-/-, and EP4-/- mice. Compared with WT mice, no difference was observed in EP2-/- and IP-/- mice. The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4-/- mice. The GFR in EP4-/- mice was not changed compared with that in WT mice, which indicated that blunted diuresis and salt loss seen in EP4-/- mice were not a consequence of lower GFR. In summary, these findings demonstrate that the EP4 receptor mediates PGE2-induced renin secretion and that EP1, EP3, and EP4 receptors all contribute to enhanced PGE2-mediated salt and water excretion in the HPS/aBS model.