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dc.contributor.authorMiller, Jacob P
dc.contributor.authorMoldenhauer, Hans J
dc.contributor.authorKeros, Sotirios
dc.contributor.authorMeredith, Andrea L
dc.date.accessioned2021-07-12T14:13:19Z
dc.date.available2021-07-12T14:13:19Z
dc.date.issued2021-07-05en_US
dc.identifier.urihttp://hdl.handle.net/10713/16172
dc.description.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.en_US
dc.description.urihttps://doi.org/10.1080/19336950.2021.1938852en_US
dc.language.isoenen_US
dc.publisherTaylor and Francis Inc.en_US
dc.relation.ispartofChannels (Austin, Tex.)en_US
dc.subjectBK channelen_US
dc.subjectGEPDen_US
dc.subjectKCNMA1en_US
dc.subjectKCa1.1en_US
dc.subjectMaxiKen_US
dc.subjectPNKD3en_US
dc.subjectSloen_US
dc.subjectcalcium-activated potassium channelen_US
dc.subjectchannelopathyen_US
dc.subjectdevelopmental delayen_US
dc.subjectepilepsyen_US
dc.subjectintellectual disabilityen_US
dc.subjectmovement disorderen_US
dc.subjectparoxysmal non-kinesigenic dyskinesiaen_US
dc.subjectpotassium channelen_US
dc.subjectseizureen_US
dc.subjectslowpokeen_US
dc.titleAn emerging spectrum of variants and clinical features in KCNMA1-linked channelopathyen_US
dc.typeArticleen_US
dc.identifier.doi10.1080/19336950.2021.1938852
dc.identifier.pmid34224328
dc.source.volume15
dc.source.issue1
dc.source.beginpage447
dc.source.endpage464
dc.source.countryUnited States


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