Threading through the mizmaze of Bartter syndrome

Pediatric Nephrology, University of Leuven, 3000, Leuven, Belgium.
Pediatric Nephrology (Impact Factor: 2.86). 08/2006; 21(7):896-902. DOI: 10.1007/s00467-006-0113-7
Source: PubMed


The story, described here in detail, started in 1962 with the publication of a seminal paper by Frederic Bartter et al. in the December issue of the American Journal of Medicine. The authors reported two pediatric patients with hitherto undescribed features, namely growth and developmental delay associated with hypokalemic alkalosis and normal blood pressure despite high aldosterone production. It soon became clear that this condition was not so exceptional. The syndrome named after Bartter was actually identified in children as well as in adults, females as well as males and in all five continents. It took almost four decades to clarify the exact nature of the disease. Bartter disease is an autosomal recessive disorder with four genotypes and mainly two phenotypes. Moreover, there are acquired secondary forms of Bartter syndrome as well as pseudo-Bartter syndromes. The history demonstrates the power of genetics but also illustrates the fundamental and irreplaceable contributions from nephrologists and renal physiologists.

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    • "Additional clinical features may include short stature (Buyukcelik et al. 2012), failure to thrive, and developmental delay. Mutations in genesencoding thick ascending limb of Henle (TALH) transporters NKCC2, ROMK, CLC-Ka, CLC-Kb, and the subunit Barttin may all result in a BS phenotype (Proesmans 2006). "
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    ABSTRACT: A multiplex family was identified with biochemical and clinical features suggestive of Bartter's syndrome (BS). The eldest sibling presented with developmental delay and rickets at 4 years of age with evidence of hypercalciuria and hypokalemia. The second sibling presented at 1 year of age with urinary tract infections, polyuria, and polydipsia. The third child was born after a premature delivery with a history of polyhydramnios and neonatal hypocalcemia. Following corrective treatment she also developed hypercalciuria and a hypokalemic metabolic alkalosis. There was evidence of secondary hyperreninemia and hyperaldosteronism in all three siblings consistent with BS. Known BS genes were screened and functional assays of ROMK (alias KCNJ1, Kir1.1) were carried out in Xenopus oocytes. We detected compound heterozygous missense changes in KCNJ1, encoding the potassium channel ROMK. The S219R/L220F mutation was segregated from father and mother, respectively. In silico modeling of the missense mutations suggested deleterious changes. Studies in Xenopus oocytes revealed that both S219R and L220F had a deleterious effect on ROMK-mediated potassium currents. Coinjection to mimic the compound heterozygosity produced a synergistic decrease in channel function and revealed a loss of PKA-dependent stabilization of PIP2 binding. In conclusion, in a multiplex family with BS, we identified compound heterozygous mutations in KCNJ1. Functional studies of ROMK confirmed the pathogenicity of these mutations and defined the mechanism of channel dysfunction.
    Full-text · Article · Nov 2013
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    ABSTRACT: Le syndrome de pseudo-Bartter, caractérisé par une alcalose hypochlorémique-hypokaliémique, mime les anomalies biochimiques du syndrome de Bartter sans atteinte rénale primaire. Il peut survenir suite à des vomissements chroniques au cours de la grossesse liés à des désordres psychiatriques. Il peut affecter aussi le foetus. L’absence de symptômes maternels due à l’installation lente des anomalies biochimiques au cours de la grossesse pourrait faire sousestimer de sérieux désordres électrolytiques présents chez la mère et son enfant à la naissance. Deux situations de cet ordre sont décrites où le diagnostic a été posé chez le nouveau-né et, a posteriori, chez sa mère. Les obstétriciens doivent rester attentifs aux signes de désordre alimentaire de leur patiente qui les minimise souvent.
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