Intellectual Disability and Potassium Channelopathies: A Systematic Review

Abstract

Intellectual disability (ID) manifests prior to adulthood as severe limitations to intellectual function and adaptive behavior. The role of potassium channelopathies in ID is poorly understood. Therefore, we aimed to evaluate the relationship between ID and potassium channelopathies. We hypothesized that potassium channelopathies are strongly associated with ID initiation, and that both gain-and loss-of-function mutations lead to ID. This systematic review explores the burden of potassium channelopathies, possible mechanisms, advancements using animal models, therapies, and existing gaps. The literature search encompassed both PubMed and Embase up to October 2019. A total of 75 articles describing 338 cases were included in this review. Nineteen channelopathies were identified, affecting the following genes: KCNMA1,

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3—a subgroup of K+ channelopathies

“…Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the function of the central nervous system, heart, kidney, and other organs [ 5 – 8 ]. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels has been greatly appreciated [ 2 , 5 , 6 ], GOF missense variants in K + channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized [ 9 ]. One of these syndromic phenotypes is Zimmermann–Laband syndrome (ZLS) (MIM: 135500), a rare disorder characterized by distinct facial dysmorphism with a bulbous nose and thick ears, gingival enlargement, ID with or without epilepsy, hypo- or aplasia of terminal phalanges and nails, and hypertrichosis [ 10 – 13 ].…”

Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

“…K + channels can be categorized by the stimulus to which they are activated and include voltage‐gated (K V ), calcium‐activated (K Ca ), inwardly rectifying (K IR ), ATP‐sensitive (K ATP ), and sodium‐activated (K Na ) channels. A recent systematic review identified 19 potassium channelopathies implicated in a variety of neurodevelopmental disorders (Kessi et al, 2020).…”

Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

“…Similarly, Ambrosino et al identified a gain-of-function mutation in the KCNT2 gene in a patient with EIMFS-like DEE. It suggested that pathogenic variants in KCNT1 and KCNT2 therefore might contribute to a similar and overlapping spectrum of DEEs (Ambrosino et al, 2018 ; Kessi et al, 2020 ). Meantime, Mao et al also reported EIMFS in patients carrying loss-of-function mutations in the KCNT2 gene (Mao et al, 2020 ), which indicated that EIMFS might be caused not only by an increase but also by a decrease in the function of K Na .…”

“…Increasing number of genes identified as the cause of DEEs and channelopathies represent an important and broad class (Kumar et al, 2016 ). A systematic review of neurological disorders and potassium channelopathies revealed pathogenic variants in 19 potassium channel genes, including KCNMA1, KCNN3, KCNT1, KCNT2, KCNB1, KCNJ6, KCNJ10, KCNJ11, KCNA2, KCNA4, KCND3, KCNH1, KCNQ2, KCNAB1, KCNQ3, KCNQ5, KCNC1, KCNC3 , and KCTD3 (Kessi et al, 2020 ). There is a large phenotypic and genetic heterogeneity and the majority of genetic defects are still unknown.…”