A case series of adult patients affected by EAST/SeSAME syndrome suggests more severe disease in subjects bearing <i>KCNJ10</i> truncating mutations

Abstract

Kir4.1, potassium channel, tubulopathy EAST/SeSAME syndrome is a rare disease affecting the Central Nervous System (CNS), inner ear, and kidney. The syndrome is due to loss-of-function mutations in the KCNJ10 gene encoding the inward-rectifying potassium channel Kir4.1. EAST/SeSAME syndrome is mainly diagnosed during childhood with a tonic-clonic seizure being the usual first symptom. Due to a limited number of patients and recent identification of the disease, few data are available on the clinical progress of this disease in adulthood. In particular, neurologic and nephrological outcomes have not been reported. We present a case series of 4 adult patients harbouring homozygous missense mutation p.Ala167Val and homozygous frameshift mutations p.Asn232Glnfs * 14 and p.Gly275Valfs * 7. Effects of these mutations were predicted by in silico modelling and bioinformatic tools. Patients with truncating mutations were associated with more severe outcomes, both in tubulopathy severity and neurological symptomatology. Conversely, either missense or truncating mutations were correlated with similar severity of epilepsy, with a long free-of-event period up to 20 years old. No eGFR decline was documented. Modelling predicted that truncating mutations lead to complete Kir4.1 dysfunction. Finally, all patients had a mild increase in urinary protein excretion. Our study indicates that the prognosis of patients suffering from EAST/SeSAME syndrome is related to the severity of the mutation causing the disease. As predicted by in silico modelling, truncating mutations of KCNJ10 are associated with more severe disease, with recurrence of symptomatic hypokalemia and more severe neurological phenotype. The type of mutation should be considered for the therapy tailored to patients' phenotype.

Role of Kir4.1 Channel in Auditory Function: Impact on Endocochlear Potential and Hearing Loss

“…Suzumoto et al described four adult patients with EAST/SeSAME syndrome with homozygous missense mutation p.Ala167Val (identified in two siblings) and homozygous frameshift mutations p.Asn232Glnfs*14 and p.Gly275Valfs*7 (both born from consanguineous parents, first cousins). These mutation predictions were made using in silico modeling and bioinformatics, which indicated that patients who had truncated mutations had more serious consequences: tubulopathy and neurological symptoms associated with severe epilepsy [62].…”

Envisioning the role of inwardly rectifying potassium (Kir) channel in epilepsy

“…Expression of KCNJ10 mutations in CHO and HEK293 cells showed low Kir4.1 currents due to decreased channel open time and shift of pH sensitivity to alkaline range (Reichold et al, 2010). A case series of adult patients with EAST/SeSAME syndrome revealed that truncating mutations of KCNJ10 cause more severe symptoms (Suzumoto et al, 2021).…”

“…Expression of KCNJ10 mutations in CHO and HEK293 cells showed low Kir4.1 currents due to decreased channel open time and shift of pH sensitivity to alkaline range (Reichold et al, 2010). A case series of adult patients with EAST/SeSAME syndrome revealed that truncating mutations of KCNJ10 cause more severe symptoms (Suzumoto et al., 2021). Interestingly, it has been reported that T262S and R271C mutations in the KCNJ10 gene do not significantly affect the structure and function of the Kir4.1 channel (Shang et al., 2005).…”