GATOR1-related focal cortical dysplasia in epilepsy surgery patients and their families: A possible gradient in severity?

Abstract

BACKGROUND:

Variants of GATOR1-genes represent a recognised cause of focal cortical dysplasia (FCD), the most common structural aetiology in paediatric drug-resistant focal epilepsy. Reports on familial cases of GATOR1-associated FCD are limited, especially with respect to epilepsy surgery outcomes.

METHODS:

We present phenotypical manifestations of four unrelated patients with drug-resistant focal epilepsy, FCD and a first-degree relative with epilepsy. All patients underwent targeted gene panel sequencing as a part of the presurgical work up. Literature search was performed to compare our findings to previously published cases.

RESULTS:

The children (probands) had a more severe phenotype than their parents, including drug-resistant epilepsy and developmental delay, and they failed to achieve seizure freedom post-surgically. All patients had histopathologically confirmed FCD (types IIa, IIb, Ia). In Patient 1 and her affected father, we detected a known pathogenic NPRL2 variant. In patients 2 and 3 and their affected parents, we found novel likely pathogenic germline DEPDC5 variants. In family 4, we detected a novel variant in NPRL3. We identified 15 additional cases who underwent epilepsy surgery for GATOR1-associated FCD, with a positive family history of epilepsy in the literature; in 8/13 tested, the variant was inherited from an asymptomatic parent.

CONCLUSION:

The presented cases displayed a severity gradient in phenotype with children more severely affected than the parents. Although patients with GATOR1-associated FCD are considered good surgical candidates, post-surgical seizure outcome was poor in our familial cases, suggesting that accurate identification of the epileptogenic zone may be more challenging in this subgroup of patients.

• Authors: Barbora Benova, Maurits W C B Sanders, Anna Uhrova-Meszarosova, Anezka Belohlavkova, Barbora Hermanovska, Vilem Novak, David Stanek, Marketa Vlckova, Josef Zamecnik, Eleonora Aronica, Kees P J Braun, Bobby P C Koeleman, Floor E Jansen, Pavel Krsek
• Journal: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society (Eur J Paediatr Neurol) Vol. 30 Pg. 88-96 (Jan 2021) ISSN: 1532-2130 [Electronic] England
• PMID: 33461085 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Chemical References

• DEPDC5 protein, human
• GTPase-Activating Proteins
• NPRL2 protein, human
• NPRL3 protein, human
• Tumor Suppressor Proteins

Topics

• Adolescent
• Child
• Drug Resistant Epilepsy (genetics)
• Female
• GTPase-Activating Proteins (genetics)
• Germ-Line Mutation
• Humans
• Magnetic Resonance Imaging
• Male
• Malformations of Cortical Development (genetics, surgery)
• Phenotype
• Retrospective Studies
• Tumor Suppressor Proteins (genetics)