Rare but Relevant Kidney Disorders

Abstract

These two groups of investigators identified simultaneously the same disease, named SeSame and EAST syndrome, respectively, acronyms based on the clinical abnormalities found in this disease (seizures or epilepsy, sensorineural deafness, ataxia, mental retardation and tubulopathy). This new autosomal recessive disorder was described from the study of six kindreds. In four of them, parental consanguinity was documented. All affected patients initially presented with generalized seizures in infancy. Later, they developed speech and motor delay and marked ataxia. Brain magnetic resonance imaging did not show significant lesions, except volume loss of cerebellum in rare patients. Sensorineural hearing loss was noted from the ages of 1 to 18 yr. All affected patients had hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. Renin-angiotensin-aldosterone system was stimulated. BP was normal. By ultrasonography, kidneys were normal. Electrolyte imbalance mimics Gitelman syndrome; however, neurologic involvement makes the difference. Genome-wide linkage analysis was performed on four informative families and identified a single significant locus on chromosome 1q23.2 with a logarithm of odds score of 3.00 and 4.98, respectively. The linked interval contains 70 well-defined and at least six hypothetical genes. Attention was focused on KCNJ10, which encodes the inwardly rectifying K+ channel Kir4.1, which consists of two transmembrane segments and one pore. KCNJ10 had been shown to be expressed in the central nervous system, cochlea, and distal nephron. A mouse knockout has a neurologic phenotype similar to that seen in the patients. Various homozygous or compound heterozygous mutations were identified in KCNJ10 in affected patients. Heterologous expression of wild-type KCJN10 in Xenopus oocytes resulted in robust currents. In contrast, currents from KCNJ10 mutants were reduced in the study by Bockenhauer et al. In normal mice, the presence of Kcnj10 was demonstrated on the basolateral membrane of the distal convoluted tubule, the connecting tubule, and the early cortical collecting duct. No signal was detected in Kcnj10 knockout mice. These mice die very early as a consequence of central nervous system symptoms. They also had diminished growth, renal salt wasting, and decreased calcium urinary excretion. Conditional knockout in glial cells resulted in death later in life, suggesting that renal salt loss is an aggravating factor in the mice with complete knockout. Kir4.1/5.1 heteromultimers are located in the basolateral membrane of the distal nephron (more specific, in the distal convoluted tubule, the only tubular site at which inhibition of NaCl reabsorption produces hypomagnesemia and reduced calcium excretion). These multimers recycle potassium that enters the cell via the Na+-K+-ATPase back into the interstitial space and contribute to the negative membrane potential that promotes basolateral Cl exit. Loss of Kir4.1 activity inhibits the function of Na+-K+-ATPase via loss of K recycling, reduces basolateral Cl reabsorption by rendering the membrane potential less negative, and thereby inhibits both apical sodium and Cl reabsorption by NCCT and Mg2+ reabsorption by TRPM6 because of a less negative membrane potential. The resulting renal salt loss activates the renin-angiotensin-aldosterone system. In the brain, KCNJ10 seems to be primarily expressed in glial cells. Some Mendelian seizure disorders have already been described, involving K+ or Na+ channels. Kir4.1 is expressed in intermediate cells of the stria vascularis, where it is believed to contribute to the generation of the endocochlear potential. As emphasized by Claude Amiel several decades ago, there are many analogies between cochlear and renal physiology and pathology. Single-gene mutations may produce effects on both systems. For example, loss-of-function mutations in ATP6B1, which encodes a subunit of the H+-ATPase, result in distal tubular acidosis and sensorineural hearing loss. Similarly, mutations in Barttin, which encodes a subunit of some Cl channels, result in both Bartter syndrome and deafness. Not surprising, inherited channel or transporter disorders bridge the gap between medical disciplines and open new avenues for further research (1).