View in EDS HTML Full Text PDF Full Text

Lack of response to quinidine in KCNT1‐related neonatal epilepsy.

Saved in:
Bibliographic Details
Title: Lack of response to quinidine in KCNT1‐related neonatal epilepsy.
Authors: Oldham, Michael S., Numis, Adam L., Cilio, Maria Roberta, Patel, Akash, Nair, Umesh, Li, Melody, Gazina, Elena, Petrou, Steven, Datta, Anita N., Sands, Tristan T.
Source: Epilepsia (Series 4). Oct2018, Vol. 59 Issue 10, p1889-1898. 10p.
Subjects: Quinidine, Partial epilepsy, Brain imaging, Xenopus, Electroencephalography
Abstract: Summary: Objective: To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1‐related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro. Methods: We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings. Results: Three of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)–confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain‐of‐function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain‐of‐function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine. Significance: Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single‐dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade. [ABSTRACT FROM AUTHOR]
Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
Full text is not displayed to guests.
FullText Links:
  – Type: pdflink
Text:
  Availability: 1
Header DbId: pbh
DbLabel: Psychology and Behavioral Sciences Collection
An: 132655910
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Lack of response to quinidine in KCNT1‐related neonatal epilepsy.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Oldham%2C+Michael+S%2E%22">Oldham, Michael S.</searchLink><br /><searchLink fieldCode="AR" term="%22Numis%2C+Adam+L%2E%22">Numis, Adam L.</searchLink><br /><searchLink fieldCode="AR" term="%22Cilio%2C+Maria+Roberta%22">Cilio, Maria Roberta</searchLink><br /><searchLink fieldCode="AR" term="%22Patel%2C+Akash%22">Patel, Akash</searchLink><br /><searchLink fieldCode="AR" term="%22Nair%2C+Umesh%22">Nair, Umesh</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+Melody%22">Li, Melody</searchLink><br /><searchLink fieldCode="AR" term="%22Gazina%2C+Elena%22">Gazina, Elena</searchLink><br /><searchLink fieldCode="AR" term="%22Petrou%2C+Steven%22">Petrou, Steven</searchLink><br /><searchLink fieldCode="AR" term="%22Datta%2C+Anita+N%2E%22">Datta, Anita N.</searchLink><br /><searchLink fieldCode="AR" term="%22Sands%2C+Tristan+T%2E%22">Sands, Tristan T.</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22Epilepsia+%28Series+4%29%22">Epilepsia (Series 4)</searchLink>. Oct2018, Vol. 59 Issue 10, p1889-1898. 10p.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Quinidine%22">Quinidine</searchLink><br /><searchLink fieldCode="DE" term="%22Partial+epilepsy%22">Partial epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Brain+imaging%22">Brain imaging</searchLink><br /><searchLink fieldCode="DE" term="%22Xenopus%22">Xenopus</searchLink><br /><searchLink fieldCode="DE" term="%22Electroencephalography%22">Electroencephalography</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Summary: Objective: To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1‐related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro. Methods: We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings. Results: Three of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)–confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain‐of‐function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain‐of‐function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine. Significance: Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single‐dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Epilepsia (Series 4) is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=132655910
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1111/epi.14551
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 10
        StartPage: 1889
    Subjects:
      – SubjectFull: Quinidine
        Type: general
      – SubjectFull: Partial epilepsy
        Type: general
      – SubjectFull: Brain imaging
        Type: general
      – SubjectFull: Xenopus
        Type: general
      – SubjectFull: Electroencephalography
        Type: general
    Titles:
      – TitleFull: Lack of response to quinidine in KCNT1‐related neonatal epilepsy.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Oldham, Michael S.
      – PersonEntity:
          Name:
            NameFull: Numis, Adam L.
      – PersonEntity:
          Name:
            NameFull: Cilio, Maria Roberta
      – PersonEntity:
          Name:
            NameFull: Patel, Akash
      – PersonEntity:
          Name:
            NameFull: Nair, Umesh
      – PersonEntity:
          Name:
            NameFull: Li, Melody
      – PersonEntity:
          Name:
            NameFull: Gazina, Elena
      – PersonEntity:
          Name:
            NameFull: Petrou, Steven
      – PersonEntity:
          Name:
            NameFull: Datta, Anita N.
      – PersonEntity:
          Name:
            NameFull: Sands, Tristan T.
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 10
              Text: Oct2018
              Type: published
              Y: 2018
          Identifiers:
            – Type: issn-print
              Value: 00139580
          Numbering:
            – Type: volume
              Value: 59
            – Type: issue
              Value: 10
          Titles:
            – TitleFull: Epilepsia (Series 4)
              Type: main
ResultId 1