Abstract
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.