NDT Advance Access originally published online on August 25, 2006
Nephrology Dialysis Transplantation 2007 22(1):288-289; doi:10.1093/ndt/gfl493
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Unusual adult-onset manifestation of an attenuated Bartter's syndrome type IV renal phenotype caused by a mutation in BSND
Email: jcalado.gene{at}fcm.unl.ptSir,
Bartter's syndrome (BS) comprises a range of overlapping autosomal recessive renal salt-losing phenotypes, characterized by hypocalaemic metabolic alkalosis. The antenatal BS variant associated with sensorineural deafness (BS type IV) is caused by mutations in BSND [1]. This gene encodes barttin, an essential ß-subunit for ClC-Ka and ClC-Kb chloride channels in basolateral membranes of renal tubular epithelia and inner ear [2]. BS type IV presents with life-threatening neonatal volume depletion accompanied by hypocalaemia [3,4]. Chronic renal failure frequently develops during infancy [1,3], although this finding is not uniformly reported [4], but persistent hypercalciuria and nephrocalcinosis are unusual findings.
Herein we report a deaf daughter of consanguineous parents, who was referred to our nephrology unit for the first time at the age of 20, because of refractory hypocalaemia. The patient was born by vaginal delivery, and although the mother had a large amount of amniotic fluid on ultrasound examination during pregnancy, the post-natal period was unremarkable until the 2nd year of life, when parents reported hearing loss and she was diagnosed with congenital bilateral sensorineural deafness. Thereafter the clinical history was unexceptional apart from poly dipsia and polyuria. The patient's height and weight reached, respectively, 165 cm (percentile range of 25–50) and 70 kg (percentile range of 50–75). Serum and urine biochemical data at admission are summarized in Table 1. The association of hypocalaemic metabolic alkalosis and hearing impairment led us to consider the diagnosis of BS type IV. Plasma renin and aldosterone were abnormally high and subsequent evaluation detected hypercalciuria and nephrocalcinosis (Figure 1A). The patient was found to be homozygous for the BSND c.139G>A allele (Figure 1B), resulting in Gly to Arg at position 47 (p.G47R). The patient was prescribed 40 mEq/day of chloride potassium and 25 mg/day of spironolactone. Three months after diagnosis, serum potassium and creatinine were 3.5 mmol/l and 61.9 µmol/l, respectively. However, hypercalciuria persisted.
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A late-onset presentation of a renal phenotype in BS type IV has been previously published [5]. Similar to our case, the patient was homozygous for the p.G47R allele, but a decreased glomerular filtration rate (GFR) and unexplained bilateral nephrocalcinosis, given the absence of hypercalciuria, were reported. The same mutation was also described, in homozygosity, in two additional Spanish kindreds, with affected individuals presenting polyhydramnios, premature birth and salt loss, although not as severe as usually reported for BS type IV [6]. Since the co-expression of p.G47R barttin and ClC-Ka resulted in a Cl– current reduction to the same extent as those observed for other missense mutations [2], we can hypothesize that this allele enables barttin to retain some residual function with ClC-Kb, therefore conditioning a milder phenotype. In addition, the better long-term GFR preservation possibly allows for the filtered calcium to be over-excreted leading to more persistent hypercalciuria, as demonstrated for the first time in our patient.
Conflict of interest statement. None declared.
1Department of Nephrology
Hospital Curry Cabral 2Department of Genetics
Faculty of Medical Sciences
New University of Lisbon
Portugal
References
- Birkenhager R, Otto E, Schurmann MJ, et al. (2001) Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29:310–314.[CrossRef][Web of Science][Medline]
- Estévez R, Boettger T, Stein V, et al. (2001) Barttin is a Cl- channel ß-subunit crucial for renal Cl– reabsorption and inner ear K+ secretion. Nature 414:558–561.[CrossRef][Medline]
- Jeck N, Reinalter SC, Henne T, et al. (2001) Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108:E5.
- Shalev H, Ohali M, Kachko L, Landau D. (2003) The neonatal variant of Bartter syndrome and deafness: preservation of renal function. Pediatrics 112:628–633.
[Abstract/Free Full Text] - Miyamura N, Matsumoto K, Taguchi T, et al. (2003) Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the beta-subunit for ClC-Ka and ClC-Kb chloride channels, barttin. J Clin Endocrinol Metab 88:781–786.
[Abstract/Free Full Text] - García-Nieto V, Flores C, Luis-Yanes MI, Gallego E, Villar J, Claverie-Martín F. (2006) Mutation G47R in the BSND gene causes Bartter syndrome with deafness in two Spanish families. Pediatr Nephrol 21:643–648.[CrossRef][Web of Science][Medline]
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