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

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

Research output: Contribution to JournalArticleAcademicpeer-review

5 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)88-96
Number of pages9
JournalEuropean journal of paediatric neurology : EJPN
Volume30
DOIs
Publication statusPublished - 1 Jan 2021

Keywords

  • Epilepsy surgery
  • Focal cortical dysplasia
  • Focal epilepsy
  • GATOR1
  • Malformations of cortical development
  • Targeted gene panel sequencing

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