TY - JOUR
T1 - KCNT2-Related Disorders
T2 - Phenotypes, Functional, and Pharmacological Properties
AU - Cioclu, Maria Cristina
AU - Mosca, Ilaria
AU - Ambrosino, Paolo
AU - Puzo, Deborah
AU - Bayat, Allan
AU - Wortmann, Saskia B
AU - Koch, Johannes
AU - Strehlow, Vincent
AU - Shirai, Kentaro
AU - Matsumoto, Naomichi
AU - Sanders, Stephan J
AU - Michaud, Vincent
AU - Legendre, Marine
AU - Riva, Antonella
AU - Striano, Pasquale
AU - Muhle, Hiltrud
AU - Pendziwiat, Manuela
AU - Lesca, Gaetan
AU - Mangano, Giuseppe Donato
AU - Nardello, Rosaria
AU - Lemke, Johannes R
AU - Møller, Rikke S
AU - Soldovieri, Maria Virginia
AU - Rubboli, Guido
AU - Taglialatela, Maurizio
N1 - Wortmann, Koch: University Children's Hospital, Paracelsus Medical University, Salzburg, Austria
PY - 2023/8
Y1 - 2023/8
N2 - OBJECTIVE: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants.METHODS: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells.RESULTS: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others.INTERPRETATION: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.
AB - OBJECTIVE: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants.METHODS: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells.RESULTS: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others.INTERPRETATION: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.
KW - MIGRATING PARTIAL SEIZURES
KW - EPILEPTIC ENCEPHALOPATHY
KW - MUTATIONS
KW - CHANNELS
KW - SLACK
KW - DRUG
U2 - 10.1002/ana.26662
DO - 10.1002/ana.26662
M3 - Original Article
C2 - 37062836
SN - 0364-5134
VL - 94
SP - 332
EP - 349
JO - ANNALS OF NEUROLOGY
JF - ANNALS OF NEUROLOGY
IS - 2
ER -