KCNMA1 mutation in children with paroxysmal dyskinesia and epilepsy: Case report and literature review

Wang, Jiaping; Yu, Shujie; Zhang, Qingping; Chen, Yan; Bao, Xinhua; Wu, Xiru

doi:10.3233/trd-170018

Cited by 15 publications

(35 citation statements)

References 9 publications

(33 reference statements)

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“…A second GOF mutation is reported in the literature using three different reference sequence numbering schemes but constitutes the same residue substitution ( Fig. 1 and Table 1; Zhang et al, 2015;Wang et al, 2017;Li et al, 2018;Heim et al, 2019;Plante et al, 2019). In this review, this mutation will be referred to by the numbering scheme in the original publication for the data being discussed.…”

Section: N995s/n999s/n1053smentioning

confidence: 92%

KCNMA1-linked channelopathy

Bailey

Moldenhauer

Park

et al. 2019

Journal of General Physiology

108

118

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KCNMA1 encodes the pore-forming α subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1−/−) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as “KCNMA1-linked channelopathy.” These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

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Section: N995s/n999s/n1053smentioning

confidence: 92%

KCNMA1-linked channelopathy

Bailey

Moldenhauer

Park

et al. 2019

Journal of General Physiology

108

118

View full text Add to dashboard Cite

show abstract

“…The N1053S mutation (also called N995S or N999S) has been identified in 7 unrelated patients from around the world Wang et al, 2017;Li et al, 2018;Heim et al, 2019) who share similar symptoms with the D434G patients. Of these patients, 4 developed early-onset PNKD, 2 developed epileptic seizures, and 1 patient developed both symptoms.…”

Section: Kcnma1-linked Channelopathy and The Spectrum Of Patient Phenmentioning

confidence: 99%

“…Patients with both GOF and LOF KCNMA1 alleles showed developmental delay and intellectual disability (Figure 4). Of the 37 patients reported in the literature, 21 were described as having developmental delay Carvalho-de-Souza et al, 2016;Wang et al, 2017;Li et al, 2018;Yesil et al, 2018;Heim et al, 2019;Liang et al, 2019) and 12 were noted to have intellectual disability Carvalho-de-Souza et al, 2016;Wang et al, 2017;Heim et al, 2019;Liang et al, 2019). The developmental delays ranged from mild to severe and included psychomotor symptoms such as delayed/unstable sitting, inability to support head or walk unassisted, speech delay, and global developmental delay Tabarki et al, 2016;Heim et al, 2019;Liang et al, 2019).…”

Section: Neurodevelopmental and Cognitive Phenotypesmentioning

confidence: 99%

“…The majority of the pathogenic KCNMA1 mutations reported in the literature occurred de novo, however few mutations exhibit autosomal recessive or autosomal dominant inheritance patterns (Figure 1). To date, the literature reports a total of 16 mutations identified in 37 symptomatic patients (Du et al, 2005;Zhang et al, 2015;Carvalho-de-Souza et al, 2016;Tabarki et al, 2016;Wang et al, 2017;Li et al, 2018;Yesil et al, 2018;Heim et al, 2019;Liang et al, 2019). Seventeen patients have de novo mutations, which constitute 9/16 KCNMA1 mutations.…”

Section: Inheritance and Prevalence Of Kcnma-linked Channelopathymentioning

confidence: 99%

“…Of note, the genes included with each panel are frequently updated as additional genetic mutations are associated with specific medical conditions. Three of the 37 patients with KCNMA1 mutations were identified using epilepsy-and paroxysmal dyskinesiaspecific gene panels Wang et al, 2017).…”

Section: Diagnosis and Treatment Of Kcnma1-linked Channelopathymentioning

confidence: 99%

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KCNMA1-linked channelopathy

Bailey

Moldenhauer

Park

et al. 2019

Preprint

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KCNMA1 encodes the pore-forming α subunit of the 'Big K + ' (BK) large conductance calcium and voltage-activated K + channel. BK channels are widely distributed across tissues, including both excitable and non-excitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1 -/-) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well-characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as 'KCNMA1-linked channelopathy.'These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction.Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date, and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability.Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.27876v3 | CC BY 4.0 Open Access | rec

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Potassium channel‐related epilepsy: Pathogenesis and clinical features

Zhao,

Wang,

Chen

2024

Epilepsia Open

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Variants in potassium channel‐related genes are one of the most important mechanisms underlying abnormal neuronal excitation and disturbances in the cellular resting membrane potential. These variants can cause different forms of epilepsy, which can seriously affect the physical and mental health of patients, especially those with refractory epilepsy or status epilepticus, which are common among pediatric patients and are potentially life‐threatening. Variants in potassium ion channel‐related genes have been reported in few studies; however, to our knowledge, no systematic review has been published. This study aimed to summarize the epilepsy phenotypes, functional studies, and pharmacological advances associated with different potassium channel gene variants to assist clinical practitioners and drug development teams to develop evidence‐based medicine and guide research strategies. PubMed and Google Scholar were searched for relevant literature on potassium channel‐related epilepsy reported in the past 5–10 years. Various common potassium ion channel gene variants can lead to heterogeneous epilepsy phenotypes, and functional effects can result from gene deletions and compound effects. Administration of select anti‐seizure medications is the primary treatment for this type of epilepsy. Most patients are refractory to anti‐seizure medications, and some novel anti‐seizure medications have been found to improve seizures. Use of targeted drugs to correct aberrant channel function based on the type of potassium channel gene variant can be used as an evidence‐based pathway to achieve precise and individualized treatment for children with epilepsy.Plain Language SummaryIn this article, the pathogenesis and clinical characteristics of epilepsy caused by different types of potassium channel gene variants are reviewed in the light of the latest research literature at home and abroad, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of children with this type of disease.

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KCNMA1 mutation in children with paroxysmal dyskinesia and epilepsy: Case report and literature review

Cited by 15 publications

References 9 publications

KCNMA1-linked channelopathy

KCNMA1-linked channelopathy

KCNMA1-linked channelopathy

Potassium channel‐related epilepsy: Pathogenesis and clinical features

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