Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

DOI

  1. cyCombine allows for robust integration of single-cell cytometry datasets within and across technologies

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  2. Serum metabolome associated with severity of acute traumatic brain injury

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  3. Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  1. Genetikken fremmer individualiseret behandling af epilepsi

    Publikation: Bidrag til tidsskriftReviewpeer review

  2. PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  3. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  4. Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  • Nathan L Absalom
  • Vivian W Y Liao
  • Katrine M H Johannesen
  • Elena Gardella
  • Julia Jacobs
  • Gaetan Lesca
  • Zeynep Gokce-Samar
  • Alexis Arzimanoglou
  • Shimriet Zeidler
  • Pasquale Striano
  • Pierre Meyer
  • Ira Benkel-Herrenbrueck
  • Inger-Lise Mero
  • Jutta Rummel
  • Mary Chebib
  • Rikke S Møller
  • Philip K Ahring
Vis graf over relationer

Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.

OriginalsprogEngelsk
Artikelnummer1822
TidsskriftNature Communications
Vol/bind13
Udgave nummer1
Antal sider15
ISSN2041-1722
DOI
StatusUdgivet - 5 apr. 2022
Eksternt udgivetJa

Bibliografisk note

© 2022. The Author(s).

ID: 76235240