Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance

A number sign (#) is used with this entry because this disorder, which comprises seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), is caused by homozygous or compound heterozygous mutation in the KCNJ10 gene (602208) on chromosome 1q23.

Clinical Features

Scholl et al. (2009) reported 5 patients from 4 families with a complex disorder characterized by onset of generalized seizures in infancy, delayed psychomotor development, ataxia, and sensorineural hearing loss. One patient was reported in detail. She developed seizures at age 3 months and was unable to walk or speak at age 5 years and 7 months. She had markedly reduced muscle strength in the lower limbs, severe ataxia, and progressive axonal neuropathy with hypomyelination confirmed by sural nerve biopsy. Sensorineural hearing loss became apparent at age 18. She had 2 presumably affected sibs: 1 had seizures, was never able to walk, and died at age from a diarrheal illness, and the other presented with seizures and vomiting at age 5 months, was unable to walk until 16 months, and died at 18 months from an infection. The other 4 patients had a similar disorder, with intention tremor and cerebellar atrophy in some of them. Laboratory studies in all patients showed persistent hypokalemia, metabolic alkalosis, and hypomagnesemia. Plasma renin and aldosterone were increased in the absence of hypertension. Urinary studies showed potassium, magnesium, and sodium wasting. Salt craving, enuresis, and polydipsia/polyuria were reported, consistent with renal salt wasting. Scholl et al. (2009) termed this disorder 'SeSAME syndrome.'

Bockenhauer et al. (2009) reported a consanguineous family of Pakistani origin in which 4 children presented in infancy with generalized tonic-clonic seizures. Another child from an unrelated consanguineous Arabic family had a similar disorder. All 5 patients had speech and motor delay as well as pronounced gait ataxia, intention tremor, and dysdiadochokinesis, consistent with cerebellar dysfunction. Two patients were unable to walk at age 9 and 3 years, respectively. Brain MRI, electromyographic studies, and nerve conduction velocities were all normal in those patients studied. Four patients developed sensorineural hearing impairment; the fifth patient was not tested. Laboratory studies showed hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. There was no proteinuria or glycosuria, and kidney ultrasound was normal. Blood pressure was at the low end of the normal range. All patients were receiving potassium and magnesium supplements. Bockenhauer et al. (2009) referred to the disorder as 'EAST syndrome' for epilepsy, ataxia, sensorineural deafness, and tubulopathy.

Freudenthal et al. (2011) reported 6 patients with genetically confirmed EAST syndrome characterized by epilepsy from infancy, debilitating ataxia from an early age with difficulties in walking, sensorineural deafness, and hypokalemic metabolic acidosis with variable hypomagnesemia. One patient was born of consanguineous Algerian parents, 2 sibs were born of consanguineous Indian parents, 2 sibs were born of unrelated Afro-Caribbean parents, and 1 boy was born of unrelated Iranian parents.

Pathogenesis

Bockenhauer et al. (2009) noted that the KCNJ10 inwardly rectifying potassium channel is on the basolateral side of distal renal tubule cells and functions to recycle potassium, which is necessary for the function of the primary sodium/potassium ATPase and establishment of a cell-negative transmembrane potential. Alterations in membrane voltage resulting from loss of KCNJ10 secondarily affects other transport processes, such as those for chloride and magnesium. KCNJ10 activity thus provides a mechanism for indirectly regulating reabsorption of renal tubular sodium, which modulates volume homeostasis and maintains blood pressure (145500). Loss of KCNJ10 function results in a compensated state of salt loss, resulting in stimulation of the renin/angiotensin/aldosterone system. A concomitant proximal tubular increase in bicarbonate causes metabolic alkalosis and calcium absorption. In addition, KCNJ10 is expressed in glial cells in the brain, and it is believed to establish the resting membrane potential of the neuron through a process called potassium 'spatial buffering.' Accumulation of potassium extracellularly in the brain decreases the membrane potential and lowers the seizure threshold.

Mapping

By linkage analysis of 3 informative kindreds, Scholl et al. (2009) mapped the SESAME disease locus to a 2.5-Mb region on chromosome 1q23.2-q23.3 (lod score of 3.0).

By linkage analysis of a consanguineous Pakistani family with seizures, ataxia, hearing loss, and electrolyte abnormalities, Bockenhauer et al. (2009) identified a 1.9-cM region on chromosome 1 between rs726640 and rs1268524 (lod score of 4.98). Haplotype analysis indicated that the affected patients were homozygous by descent for the alleles in the critical region.

Molecular Genetics

In 5 patients from 4 families with a complex syndrome comprising seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance, Scholl et al. (2009) identified 6 different homozygous or compound heterozygous mutations in the KCNJ10 gene (602208.0001-602208.0006).

In affected members of a Pakistani family with EAST syndrome, Bockenhauer et al. (2009) identified a homozygous mutation in the KCNJ10 gene (602208.0001).

In 6 patients from 4 families with EAST syndrome, Freudenthal et al. (2011) identified 4 different homozygous mutations in the KCNJ10 gene (602208.0006, 602208.0010-602208.0012). In vitro physiologic studies in Xenopus oocytes showed that the mutant proteins caused significantly reduced inwardly rectifying potassium conductance compared to control.

Animal Model

Studies of Kcnj10-null mice showed motor disability with ataxia (Neusch et al., 2001), profound deafness (Rozengurt et al., 2003), and renal tubular dysfunction (Bockenhauer et al., 2009), similar to the features identified in patients with mutations in the KCNJ10 gene.