Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype

Morín, Matías; Forst, A. W.; Pérez-Torre, Paula; Jiménez‐Escrig, Adriano; Barca-Tierno, Verónica; García-Galloway, Eva; Warth, Richard; Moreno, José Luis López-Sendón; Moreno-Pelayo, Miguel A.

doi:10.1007/s10048-020-00605-6

Cited by 10 publications

(7 citation statements)

References 20 publications

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“…They showed pronounced gait ataxia, intention tremor, and dysdiadochokinesis ( Bockenhauer et al, 2009 ), with some affected individuals being unable to walk. Meanwhile, disruptive mutations have been identified in older atactic patients ( Morin et al, 2020 ), and cerebellar imaging has revealed progressive cerebellar vermis degeneration in some of these individuals, while more discrete changes in MRI seem to prevail at younger age ( Scholl et al, 2009 ), which were not appreciated in our early study ( Bockenhauer et al, 2009 ), nor in a clinical update on the initial study ( Abdelhadi et al, 2016 ). The reported signs and symptoms in children clearly indicate cerebellar dysfunction.…”

Section: East/sesame Syndrome: a Pleiotropic Monogenetic Disease Caus...mentioning

confidence: 83%

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

Forst

Warth

et al. 2022

Front. Physiol.

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In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin–angiotensin–aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.

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Section: East/sesame Syndrome: a Pleiotropic Monogenetic Disease Caus...mentioning

confidence: 83%

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

Forst

Warth

et al. 2022

Front. Physiol.

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“…Two new missense variants G163D and R171Q were identified by next-generation sequencing in patients with EAST/SeSAME syndrome. Functional analysis in the Chinese hamster ovary cell (CHO) showed that Kir4.1 currents were significantly decreased in these variants (Morin et al, 2020).…”

Section: K Ir41 and Its Role In Epilepsymentioning

confidence: 99%

“…Two new missense variants G163D and R171Q were identified by next‐generation sequencing in patients with EAST/SeSAME syndrome. Functional analysis in the Chinese hamster ovary cell (CHO) showed that Kir4.1 currents were significantly decreased in these variants (Morin et al., 2020). Customized targeted‐exome sequencing showed two novel missense mutations (A201T and I209T) in siblings presenting with seizures and motor delays.…”

Section: Kir41 and Its Role In Epilepsymentioning

confidence: 99%

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

Akyüz

Köklü

Uner

et al. 2021

J of Neuroscience Research

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Epilepsy is a neurological disease characterized by two spontaneous seizures occurring within 24 hr, or two spontaneous seizures within 10 years after an unprovoked seizure (Fisher et al., 2014). The disease occurs by an increased tendency to generate seizures attributed to abnormal brain activity, caused by the disruption of the dynamic excitatory and inhibitory neuronal balance in the central nervous system (CNS) (Navidhamidi et al., 2017). Aberrant connectivity between neuronal networks may result in pathologically synchronized discharges and subsequently recurrent seizures (Aronica & Muhlebner, 2017). Epilepsy not only poses a significant burden on the patients and their families, but is also associated with significant social, behavioral, and economic effects (Tatum et al., 2009).Epilepsy affects people of all ages and has emerged as a global health concern affecting more than 70 million patients worldwide.Despite the recent advances in pre-clinical and clinical research, the

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“…EAST/SeSAME syndrome is usually diagnosed during infancy and consequently the data on this disease are mainly from childhood. Indeed, among the 54 cases reported on PubMed database identified as "EAST syndrome" or "EAST/SeSAME syndrome", none was centered on adult patients prognosis and clinical progress (2,(6)(7)(8). Thus, several questions on the prognosis and evolution of renal and neurologic phenotype are still open.…”

Section: Introductionmentioning

confidence: 99%

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

Suzumoto

Columbano

Gervasi

et al. 2021

IRDR

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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.

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Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype

Cited by 10 publications

References 20 publications

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

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

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

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