An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy
JournalChannels (Austin, Tex.)
PublisherTaylor and Francis Inc.
MetadataShow full item record
AbstractKCNMA1-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 encodes the BK K+ channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations. In this review, we summarize 37 KCNMA1 alleles from 69 patients currently defining the channelopathy and assess key diagnostic and clinical hallmarks. At present, 3 variants are classified as gain-of-function with respect to BK channel activity, 14 loss-of-function, 15 variants of uncertain significance, and putative benign/VUS. Symptoms associated with these variants were curated from patient-provided information and prior publications to define the spectrum of clinical phenotypes. In this newly expanded cohort, seizures showed no differential distribution between patients harboring GOF and LOF variants, while movement disorders segregated by mutation type. Paroxysmal non-kinesigenic dyskinesia was predominantly observed among patients with GOF alleles of the BK channel, although not exclusively so, while additional movement disorders were observed in patients with LOF variants. Neurodevelopmental and structural brain abnormalities were prevalent in patients with LOF mutations. In contrast to mutations, disease-associated KCNMA1 single nucleotide polymorphisms were not predominantly related to neurological phenotypes but covered a wider set of peripheral physiological functions. Together, this review provides additional evidence exploring the genetic and biochemical basis for KCNMA1-linked channelopathy and summarizes the clinical repository of patient symptoms across multiple types of KCNMA1 gene variants.
calcium-activated potassium channel
paroxysmal non-kinesigenic dyskinesia
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/16172
- <i>KCNMA1</i>-linked channelopathy.
- Authors: Bailey CS, Moldenhauer HJ, Park SM, Keros S, Meredith AL
- Issue date: 2019 Oct 7
- Comparative gain-of-function effects of the <i>KCNMA1</i>-N999S mutation on human BK channel properties.
- Authors: Moldenhauer HJ, Matychak KK, Meredith AL
- Issue date: 2020 Feb 1
- De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes.
- Authors: Liang L, Li X, Moutton S, Schrier Vergano SA, Cogné B, Saint-Martin A, Hurst ACE, Hu Y, Bodamer O, Thevenon J, Hung CY, Isidor B, Gerard B, Rega A, Nambot S, Lehalle D, Duffourd Y, Thauvin-Robinet C, Faivre L, Bézieau S, Dure LS, Helbling DC, Bick D, Xu C, Chen Q, Mancini GMS, Vitobello A, Wang QK
- Issue date: 2019 Sep 1
- Expanding the Phenotype of Homozygous <i>KCNMA1</i> Mutations; Dyskinesia, Epilepsy, Intellectual Disability, Cerebellar and Corticospinal Tract Atrophy
- Authors: Yeşil G, Aralaşmak A, Akyüz E, İçağasıoğlu D, Uygur Şahin T, Bayram Y
- Issue date: 2018 Jul 24
- Impaired Pre-Motor Circuit Activity and Movement in a Drosophila Model of KCNMA1-Linked Dyskinesia.
- Authors: Kratschmer P, Lowe SA, Buhl E, Chen KF, Kullmann DM, Pittman A, Hodge JJL, Jepson JEC
- Issue date: 2021 May