Abstract
The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and enabled precision medicine approaches. These have been instrumental in providing insights into the pathophysiology of both early-onset benign and self-limited syndromes and devastating developmental and epileptic encephalopathies (DEEs). Genetic heterogeneity is seen in many epilepsy syndromes such as West syndrome and epilepsy of infancy with migrating focal seizures (EIMFS), indicating that two or more genetic loci produce the same or similar phenotypes. At the same time, some genes such as SCN2A can be associated with a wide range of epilepsy syndromes ranging from self-limited familial neonatal epilepsy at the mild end to Ohtahara syndrome, EIFMS, West syndrome, Lennox–Gastaut syndrome, or unclassifiable DEEs at the severe end of the spectrum. The aim of this study was to review the clinical and genetic heterogeneity associated with epilepsy syndromes starting in the first year of life including: Self-limited familial neonatal, neonatal-infantile or infantile epilepsies, genetic epilepsy with febrile seizures plus spectrum, myoclonic epilepsy in infancy, Ohtahara syndrome, early myoclonic encephalopathy, West syndrome, Dravet syndrome, EIMFS, and unclassifiable DEEs. We also elaborate on the advantages and pitfalls of genetic testing in such conditions. Finally, we describe how a genetic diagnosis can potentially enable precision therapy in monogenic epilepsies and emphasize that early genetic testing is a cornerstone for such therapeutic strategies.
Highlights
Epilepsy can result from factors such as stroke, asphyxia, infections, autoimmune disorders, trauma, and tumors, a significant number of subjects with epilepsy are thought to have an underlying genetic factor [1]
Before describing the electroclinical syndromes that start during the first year of life, we must emphasize that most developmental and epileptic encephalopathies (DEEs) do not fit well within any of these electroclinical syndromes and can at best only be categorized as unclassified DEEs
While protein-truncating variants in KCNQ2 tend to cause benign familial epilepsy syndromes of infancy, missense variants may present with a distinct phenotype characterized by neonatal seizures that evolve to drug-resistant DEE and intellectual disability—KCNQ2related neonatal epileptic encephalopathy (KCNQ2-NEE) (Table 2) [10,45]— this entity does not always fulfill the clinical criteria for Ohtahara syndrome
Summary
Epilepsy can result from factors such as stroke, asphyxia, infections, autoimmune disorders, trauma, and tumors, a significant number of subjects with epilepsy are thought to have an underlying genetic factor [1]. BFNE is a genetically heterogeneous disorder due to loss-of-function variants in the KCNQ2 or KCNQ3 genes These two genes encode voltage-gated potassium channel subunits Kv7.2 and Kv7.3.7 [10,11]. SCN1A (encoding the voltage-gated sodium channel subunits Nav1.1) accounts for the largest fraction, with disease-causing variants detected in approximately 10–20% of families [28,29]. Other genes such as GABRA1, GABRB3, GABRG2, SCN1B, and STX1B have been linked to the syndrome [28,29,30,31,32]. Factors underlying the mechanism of pleiotropy are not fully understood but may involve variable expressivity of a single disease-causing gene, genetic modifiers, or epigenetic factors
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