TY - JOUR
T1 - Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies
AU - Absalom, Nathan L.
AU - Liao, Vivian W.Y.
AU - Johannesen, Katrine M.H.
AU - Gardella, Elena
AU - Jacobs, Julia
AU - Lesca, Gaetan
AU - Gokce-Samar, Zeynep
AU - Arzimanoglou, Alexis
AU - Zeidler, Shimriet
AU - Striano, Pasquale
AU - Meyer, Pierre
AU - Benkel-Herrenbrueck, Ira
AU - Mero, Inger Lise
AU - Rummel, Jutta
AU - Chebib, Mary
AU - Møller, Rikke S.
AU - Ahring, Philip K.
N1 - Funding Information:
The authors thank the affecomcted individuals and their families for participating in this study. The Australian National Health & Medical Research Council grants APP1185122 and APP1081733 (N.A., P.K.A., M.C.). The Novo Nordisk Foundation (NNF19OC0058749 to R.S.M.) and The Lundbeck Foundation (R324-2019-1083 to R.S.M.).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4/5
Y1 - 2022/4/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127704108&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29280-x
DO - 10.1038/s41467-022-29280-x
M3 - Article
C2 - 35383156
AN - SCOPUS:85127704108
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1822
ER -