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Pendred Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
There is tangible evidence that mutations in the FOXI1 gene on chromosome 5q35.1 encoding forkhead box protein I1 and the KCNJ10 gene on chromosome 1q23.2 encoding the ATP-sensitive inward rectifier potassium channel 10 may be implicated in about 2% of non-classic Pendred syndrome (also known as nonsyndromic enlarged vestibular aqueduct [NSEVA]), but not classic Pendred syndrome. Further, biallelic KCNJ10 pathogenic variants are involved in SeSAME syndrome (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) and EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) [17,18].
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Mutations of inward rectifying channels are relatively rare in epileptic patients and mostly involve astrocytic Kir4.1. Kir4.1 channels are expressed primarily in astrocytes and support the spatial buffering of potassium. The missense variations in Kir4.1 lead to disruption of astrocyte-dependent spatial buffering of potassium and its pathological accumulation, suggesting a potential mechanism of seizure susceptibility [104]. Loss-of-function mutations in KCNJ10 gene encoding Kir4.1 channel was linked to EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) syndrome [105]. Brain abnormalities in EAST syndrome include mild cerebellar atrophy and intramyelinic edema, which may be important diagnostic clues for suspecting this condition in MRI [106]. Single nucleotide polymorphisms of genes encoding Kir4.1 subunits were found in patients with focal and generalized epilepsies including TLE [104,107]. Reduction in glial Kir4.1 function without alterations in activity of Kv channels was found in the tissue of patients with intractable epilepsy and hippocampal sclerosis [108,109]. Mutations of Kir4.1 channels have been detected in patients with the autism-epilepsy phenotype [110], suggesting that dysfunction of the channels may be a common mechanism contributing to seizures and behavioral features of Autism Spectrum Disorders. Mutations in Kir6.2 (KATP) channels are associated with DEND syndrome (infantile diabetes, developmental delay and epilepsy) [111–113].
The utility of whole exome sequencing in diagnosing neurological disorders in adults from a highly consanguineous population
Published in Journal of Neurogenetics, 2019
Weiyi Mu, Nicoline Schiess, Jennifer L. Orthmann-Murphy, Ayman W. El-Hattab
Another notable finding from this cohort of adults with neurological disorders is the high rate of novel variants (38%) and variants with a low minor allele frequency among genetically diagnosed cases. In particular, the c.179T > C (p.I60T) variant, in KCNJ10, previously reported but with a minor allele frequency of 0.00001, was identified in two unrelated families, raising the possibility that I60T is a founder mutation for EAST syndrome in this population. Similar studies in Middle Eastern populations have also identified novel variants in a large proportion of cases (Monies et al., 2017). This propensity of detecting novel and rare pathogenic variants is likely due to the unique genetic diversity of this population, which is underrepresented in known genetic variation databases. Conglomerations of exome data such as the Exome Aggregation Consortium (ExAC) and the Genome Aggregation Database (gnomAD) are enriched for European groups, especially individuals of Northern European descent (Lek et al., 2016), causing difficulty in interpretation of variants of unknown significance for patients of non-European background (Manrai et al., 2016). Population initiatives such as carrier screening depends on knowledge of common mutations specific to an individual’s ethnic background; our findings may help contribute to knowledge of genetic variation in the Arabian Peninsula with this important future goal in mind.
Novel mutation in the KCNJ10 gene in three siblings with seizures, ataxia and no electrolyte abnormalities
Published in Journal of Neurogenetics, 2018
Muna A. Al Dhaibani, Ayman W. El-Hattab, Kathryn B. Holroyd, Jennifer Orthmann-Murphy, Valerie A. Larson, Khurram A. Siddiqui, Miklos Szolics, Nicoline Schiess
The KCNJ genes code for a potassium channel family (Kir channels) facilitating the flow of potassium into cells. KCNJ10 is expressed mainly in central nervous system (CNS) glial cells, inner ear cells and renal epithelial cells. Biallelic mutations in this gene present with a combination of features generally known as EAST (or SeSAME) syndrome (Bockenhauer et al., 2009; Scholl et al., 2009). Both syndromes were reported simultaneously in 2009 and describe an autosomal recessive disorder characterized by Epilepsy, Ataxia, Sensorineural deafness, and electrolyte abnormalities from a renal Tubulopathy (EAST syndrome). The name SeSAME (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) also included the characteristic of intellectual disability, which is not consistent across most patients (Cross et al., 2013). Since these first reports, several other phenotypic descriptions have been published (see Table 1). In this paper, we present three siblings with EAST syndrome and a novel KCNJ10 mutation who presented with seizures, ataxia and no electrolyte abnormalities.