# Epilepsy with myoclonic-atonic seizures: genetic aetiologies, outcomes and prognostic indicators

## TL;DR

This study explores the genetic causes and outcomes of epilepsy with myoclonic-atonic seizures, finding diverse genetic factors and emphasizing the importance of early developmental assessments for prognosis.

## Contribution

The study identifies novel genetic variants and highlights the effectiveness of older antiseizure drugs and the value of whole exome sequencing for diagnosis.

## Key findings

- Pathogenic variants were found in 38.5% of patients, including four novel genes (KMT2E, POGZ, SHANK3, YWHAG).
- Older antiseizure drugs like valproate and ethosuximide were more effective than newer drugs.
- Global developmental delay at epilepsy onset predicted drug resistance and intellectual disability.

## Abstract

Epilepsy with myoclonic-atonic seizures, formerly myoclonic-astatic epilepsy or Doose syndrome, accounts for 1–2.2% of childhood-onset epilepsies. We investigated genetic determinants, long-term clinical outcomes and prognostic indicators in a large cohort using homogeneous inclusion criteria. We studied 60 patients (26.7% female), mean age 14.5 years (±9.1, range 3.2–41), followed between 1986 and 2024 at two paediatric neurology centres. Average follow-up was 11.7 years. Inclusion criteria were seizure onset between 6 months and 8 years, generalized 2–6 Hz spike-wave discharges and video-EEG documented myoclonic-atonic, myoclonic seizures or both. We analysed clinical, EEG, neuroimaging, neuropsychological and genetic data obtained with next-generation sequencing. We used χ² test, t-test, Log-rank test, Cox regression, population-averaged logistic models and Benjamini–Yekutieli procedure to identify predictors of seizure outcome, intellectual disability and other neurodevelopmental comorbidities. We observed myoclonic-atonic seizures in 55/60 (91.7%), tonic-vibratory seizures in 44/60 (73.4%), absence seizures in 30/60 (50%), myoclonic seizures without post-myoclonic atonia in 25/60 (42%) and non-convulsive status epilepticus in 13/60 (21.7%). A ‘stormy’ onset occurred in 26/60 patients (43.3%). The most effective drugs were valproate, ethosuximide, benzodiazepines and phenobarbital, used in different combinations, whereas the newer drugs offered no benefit. Long-term outcomes were variable. Thirty-seven patients (61.7%) achieved seizure freedom after 5.1 years on average. We observed drug resistance in 23/60 patients (38.3%) and intellectual disability in 35/60 (58.3%). One adult patient died (mortality rate 1.80/1000-person-years). Attention deficit hyperactivity disorder was the most common comorbidity (24/60, 40%). ‘Stormy’ onset did not predict a worse prognosis. Global developmental delay at epilepsy onset was associated with drug resistance (P = 0.004, Q = 0.064) and with intellectual disability (P = 0.003, Q = 0.048). We found pathogenic variants in 15/39 (38.5%) patients undergoing next-generation sequencing, including four genes novel for this syndrome (KMT2E; POGZ; SHANK3; YWHAG), with exome sequencing yielding higher diagnostic rates than gene panels. Epilepsy with myoclonic-atonic seizures is a complex syndrome with diverse genetic causes and variable seizure severity and outcomes. Our findings expand its genetic landscape and highlight the prognostic value of prompt overall neurodevelopmental assessment at clinical onset. Whole exome sequencing should be prioritized for early diagnosis and counselling.

Pellacani et al. report that epilepsy with myoclonic-atonic seizures has diverse genetic causes, variable severity and outcomes. Early motor and language delays are strong predictors of poor long-term prognosis. Older antiseizure drugs are more effective than newer ones. Whole exome sequencing is recommended for early diagnosis and targeted counselling.

Graphical Abstract