Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/25620
Title: Contribution of rare genetic variants to drug response in absence epilepsy.
Austin Authors: Myers, Kenneth A;Bennett, Mark F ;Grinton, Bronwyn E;Dabscheck, Gabriel;Chan, Eunice K;Bello-Espinosa, Luis E;Sadleir, Lynette G;D'Alfonso, Sabrina;Schneider, Amy L ;Damiano, John A;Hildebrand, Michael S ;Bahlo, Melanie;Berkovic, Samuel F ;Buchhalter, Jeffrey;Scheffer, Ingrid E 
Affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G, Royal Parade, Parkville, VIC, 3052, Australia
Department of Medical Biology, The University of Melbourne, 1G, Royal Parade, Parkville, VIC, 3052, Australia
Epilepsy Research Centre
Research Institute of the McGill University Health Center, 1001 Décarie Blvd, Montreal, PQ, H4A 3J1, Canada
Department of Neurology & Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, 1001 Décarie Blvd, Montreal, PQ, H4A 3J1, Canada
Department of Pediatrics, Division of Child Neurology, Montreal Children's Hospital, McGill University Health Centre, 1001 Décarie Blvd, Montreal, PQ, H4A 3J1, Canada
Department of Neurology, Royal Children's Hospital, The University of Melbourne, 50 Flemington Rd, Parkville, VIC, 3052, Australia
Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville, VIC, 3052, Australia
Florey Institute of Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC, 3052, Australia
Division of Pediatric Neurology, Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, 28 Oki Dr NW, Calgary, AB, T3B 6A8, Canada
Department of Paediatrics and Child Health, University of Otago, Wellington, 23 Mein Street, Newtown, Wellington, 6021, New Zealand
Division of Pediatric Neurology, Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, 28 Oki Dr NW, Calgary, AB, T3B 6A8, Canada
Issue Date: 4-Jan-2021
metadata.dc.date: 2021-01-04
Publication information: Epilepsy Research 2021; 170: 106537
Abstract: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. Sixty-two patients were included; 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43; 0.43-27.65; p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82; 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups; these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger sample is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.
URI: https://ahro.austin.org.au/austinjspui/handle/1/25620
DOI: 10.1016/j.eplepsyres.2020.106537
PubMed URL: 33421703
Type: Journal Article
Subjects: Absence epilepsy
CACNA1H
Ethosuximide
Pharmacogenomics
T-type calcium channels
Valproic acid
Appears in Collections:Journal articles

Show full item record

Page view(s)

30
checked on Jan 27, 2021

Google ScholarTM

Check


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.