Genetics of neonatal-onset epilepsies
Marie-Coralie Cornet1, Maria Roberta Cilio2
1Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States.
Insights
Genetic epilepsy in newborns, often caused by specific gene mutations, requires early recognition. Understanding the genetic cause is crucial for targeted treatments and improving outcomes for neonatal-onset epilepsy.
Area of Science:
- Neuroscience
- Genetics
- Pediatric Neurology
Background:
- Neonatal seizures are often linked to acute brain injury, but a significant portion stem from genetic causes.
- Historically, neonatal seizures were treated as a single entity, overlooking the impact of etiology on outcomes.
- Recent advances identify monogenic disorders as a key cause of neonatal-onset epilepsy, previously misclassified.
Purpose of the Study:
- To define and classify genetic epilepsy in neonates.
- To review key monogenic neonatal-onset epilepsies, their mechanisms, and phenotypes.
- To emphasize the importance of early diagnosis for precision medicine and improved outcomes.
Main Methods:
- Literature review of genetic epilepsy classifications and monogenic neonatal-onset epilepsies.
- Analysis of pathophysiologic mechanisms and electroclinical phenotypes.
- Highlighting diagnostic and therapeutic implications of specific genetic mutations.
Main Results:
- Genetic factors explain up to one-third of neonatal-onset epilepsy syndromes.
- Specific genes (e.g., KCNQ2, KCNT1) are associated with distinct epilepsy phenotypes.
- Early identification of genetic causes enables targeted diagnostic testing.
Conclusions:
- Etiology is a critical determinant of outcome in neonatal seizures.
- Recognizing genetic epilepsy allows for precision medicine approaches.
- Early diagnosis and targeted treatment can significantly improve outcomes for affected neonates.
Abstract:
Although the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy often linked to a pathogenic genetic variant. Historically, studies on neonatal seizures including treatment response and long-term consequences have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. In the past few years, an increasing number of monogenic disorders have been described and might explain up to a third of neonatal-onset epilepsy syndromes previously included under the umbrella of Ohtahara syndrome and early myoclonic encephalopathy. In this chapter, we define the concept of genetic epilepsy and review the classification. Then, we review the most relevant monogenic neonatal-onset epilepsies, detail their underlying pathophysiologic mechanisms, and present their electroclinical phenotypes. We highlight that, in some cases, such as neonates with KCNQ2 or KCNT1 gene mutations, the early recognition of the electroclinical phenotype can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
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