Genetic Landscape of Early Infantile Developmental and Epileptic Encephalopathy with Suppression-Burst in a Cohort of 121 Patients
Abstract number :
2.113
Submission category :
4. Clinical Epilepsy / 4A. Classification and Syndromes
Year :
2023
Submission ID :
721
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Mathieu MILH, MD, PhD – Aix-Marseille Univ
Béatrice Desnous, MD, PhD – APHM; EIDEE French Study Group, MD – APHM; Caroline LACOSTE, PhD – APHM; Florence Molinari, PhD – AMU; Florence Riccardi, MD, PhD – AMU; Laurent VILLARD, PhD – AMU; Nathalie Villeneuve, MD – APHM
Rationale: Early infantile developmental and Epileptic Encephalopathy have been recognized as an heterogeneous condition in which epilepsy begin before three months of age. The initial clinical examination and interictal EEG may be normal or abnormal, but in all cases, development is profoundly impaired. The most severe situation is represented by EIDEE with suppression-burst, as the EEG is highly recognizable, even between seizures. The rationale of this study is to describe the place of SB-IDEA, within DEA, in particular its frequency, and its etiology.
Methods: We report clinical and genetic results of a large cohort of 402 EIDEE patients, of which 121 were classified as having an EIDEE-SB. Different genetic techniques (CGH-array, epilepsy gene panel, and/or whole exome sequencing) have been employed over time to determine the diagnosis. We obtained and reviewed comprehensive clinical data of 121 patients with confirmed burst-suppression EEG, without structural brain MRI anomalies nor treatable inborn errors of metabolism.
Results: This cohort had a strong and heterogeneous genetic component. We identified pathogenic or likely pathogenic single nucleotide variants in 23 genes and two copy number variations, resulting in a diagnosis rate of 62.7%. KCNQ2, STXBP1 and SCN2A were the most frequently mutated genes (21.8%, 14.5% and 2.7% respectively). We described novel associations between a burst-suppression EEG and known genes (DPM1, GRIN2A, KCNT2, PIGO, PURA, and WWOX), newly identified genes (KMT2E, SNAP25, and SYT1) and candidate genes. We provided an overview of the molecular pathways involved in developmental and epileptic encephalopathies with burst-suppression EEG. Genetic anomalies were mainly de novo heterozygous variants (83%). There was a significant proportion of ultra-rare diseases with autosomal recessive inheritance (11.6%), which warrants cautious genetic counseling. A correlation between genotype and phenotype cannot be established based only on seizures semiology. However, in-depth analysis and monitoring of EEG can provide key elements while waiting for the genetic result. Three patterns were identified according to the duration of bursts and suppressions. KCNQ2 and STXBP1 diagnoses can be ruled out when suppression lasts longer than burst. We observed an increased delay between seizures onset and burst-suppression EEG recording in STXBP1 patients which can distinguish them from KCNQ2 patients. In this cohort, 28.2% of patients were older than five years and 20% were older than ten years, allowing a detailed assessment of the prognosis. Despite significant homogeneity of the initial phenotype, prognosis varied significantly from premature death (23.6%) to mild-moderate intellectual disability (16.2%). Seizures persisted in 73,9% of patients, but half of them were controlled.
Conclusions: This study provides phenotype-genotype correlations, electro-clinical phenotyping at the onset of disease, and long-term follow-up data to improve the diagnosis and management of patients with developmental and epileptic encephalopathies with burst-suppression EEG.
Funding: INSERM
Clinical Epilepsy