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Drug
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Compound
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Target Concepts:
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Query: UMLS:C0036572 (
seizures
)
80,221
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Sodium-activated potassium (K
Na
) channels contribute to firing frequency adaptation and slow after hyperpolarization. The KCNT1 gene (also known as
SLACK
) encodes a K
Na
subunit that is expressed throughout the central and peripheral nervous systems. Missense mutations of the
SLACK
C-terminus have been reported in several patients with rare forms of early onset epilepsy and in some cases severely delayed myelination. To date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal
seizures
(EIMFS) and Ohtahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016). An exome sequencing study identified a p.Phe932Ile KCNT1 mutation as the disease-causing change in a child with severe early infantile epileptic encephalopathy and abnormal myelination (Vanderver et al., 2014). We characterized an analogous mutation in the rat Slack channel and unexpectedly found this mutation to produce a loss-of-function phenotype. In an effort to restore current, we tested the known Slack channel opener loxapine. Loxapine exhibited no effect, indicating that this mutation either caused the channel to be insensitive to this established opener or proper translation and trafficking to the membrane was disrupted. Protein analysis confirmed that while total mutant protein did not differ from wild type, membrane expression of the mutant channel was substantially reduced. Although gain-of-function mutations to the Slack channel are linked to epileptic phenotypes, this is the first reported loss-of-function mutation linked to severe epilepsy and delayed myelination.
...
PMID:The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype. 2836 65
A 2-yr-old boy presented profound developmental delay, failure to thrive, ataxia, hypotonia, and tonic-clonic
seizures
that caused the death of the patient. Targeted and whole exome sequencing revealed two heterozygous missense variants: a novel mutation in the
KCNJ10
gene that encodes for the inward-rectifying K
+
channel Kir4.1 and another previously characterized mutation in
KCNT1
that encodes for the Na
+
-activated K
+
channel known as Slo2.2 or
SLACK
. The objectives of this study were to perform the clinical and genetic characterization of the proband and his family and to examine the functional consequence of the Kir4.1 mutation. The mutant and wild-type
KCNJ10
constructs were generated and heterologously expressed in
Xenopus laevis
oocytes, and whole cell K
+
currents were measured using the two-electrode voltage-clamp technique. The
KCNJ10
mutation c.652C>T resulted in a p.L218F substitution at a highly conserved residue site. Wild-type
KCNJ10
expression yielded robust Kir current, whereas currents from oocytes expressing the mutation were reduced, remarkably. Western Blot analysis revealed reduced protein expression by the mutation. Kir5.1 subunits display selective heteromultimerization with Kir4.1 constituting channels with unique kinetics. The effect of the mutation on Kir4.1/5.1 channel activity was twofold: a reduction in current amplitudes and an increase in the pH-dependent inhibition. We thus report a novel loss-of-function mutation in Kir4.1 found in a patient with a coexisting mutation in
SLACK
channels that results in a fatal disease.
NEW & NOTEWORTHY
We present and characterize a novel mutation in
KCNJ10
Unlike previously reported EAST/SeSAME patients, our patient was heterozygous, and contrary to previous studies, mimicking the heterozygous state by coexpression resulted in loss of channel function. We report in the same patient co-occurrence of a
KCNT1
mutation resulting in a more severe phenotype. This study provides new insights into the phenotypic spectrum and to the genotype-phenotype correlations associated with EAST/SeSAME and MMFSI.
...
PMID:Lethal digenic mutations in the K
+
channels Kir4.1 (
KCNJ10
) and SLACK (
KCNT1
) associated with severe-disabling seizures and neurodevelopmental delay. 2874 64
Mutations in the
Potassium channel subfamily T member 1
(
KCNT1
) gene have been reported in a range of epileptic encephalopathies. Here we report the case of a 12-year-old male suffering from multiple types of epileptic
seizures
and cognitive decline from the age of 10. The patient had four types of epileptic
seizures
, including tonic
seizures
, atypical absence
seizures
, myoclonic
seizures
, and generalized tonic-clonic
seizures
. The electroencephalogram showed generalized slow spike-and-slow-waves, mutiple-spike-and-slow-waves, as well as short-term fast rhythms bursts. Thus, he was diagnosed with Lennox-Gastaut syndrome. The patient had failed to control
seizures
after using five first-line antiepileptic drugs. Whole exome sequencing revealed a missense
KCNT1
mutation (c.625 C>T). Previous studies revealed that quinidine could block the
KCNT1
channel. Therefore, we assumed that quinidine might be effective for him. Add-on treatment with quinidine was started when the patient was 12 years old. After an 8-month treatment, the frequency of
seizures
and epileptiform discharges were significantly reduced. In conclusion, quinidine therapy may offer a new choice for the treatment of Lennox-Gastaut syndrome with
KCNT1
mutations.
...
PMID:Quinidine Therapy for Lennox-Gastaut Syndrome With
KCNT1
Mutation. A Case Report and Literature Review. 3080 80
