Early infantile epileptic encephalopathy

Early infantile epileptic encephalopathy is recognised under the ILAE 2022 classification within the broader category of developmental and epileptic encephalopathies (DEEs). Clinical presentation is dominated by multiple seizure types emerging in the neonatal period or first months of life, drug-resistant epilepsy, and developmental delay or regression attributable in part to the ongoing epileptic activity. Onset clusters within narrow windows for several monogenic forms: neonatal onset for KCNQ2-related disease; within the first six months for CDKL5 deficiency; and during the first year for Dravet syndrome. Electroclinical patterns differ across the spectrum and include burst-suppression on the interictal EEG, hypsarrhythmia, and migrating focal seizures; individual genes such as SCN2A may underlie a broad range of phenotypes from self-limited familial neonatal epilepsy to severe unclassifiable DEEs.

Although precise European prevalence data are limited, EIEE is estimated to occur in approximately 1 in 50,000 births in the UK. Broader European population-based research has shown that epilepsies with onset during the first three years of life affect approximately 239 per 100,000 live births, highlighting the rarity of EIEE within this group of early childhood epilepsies.

A large number of genes have been associated with EIEE, and submicroscopic microdeletions and microduplications represent a further important mechanistic class. The genetic forms group into ion channelopathies, synaptic-vesicle and neurotransmitter-release disorders, and X-linked or chromatin disorders. The most common cause is Dravet syndrome (SCN1A, severe myoclonic epilepsy of infancy); further examples include STXBP1 encephalopathy (infantile-onset encephalopathy with intractable seizures) and CDKL5 deficiency disorder (early-onset encephalopathy with severe developmental delay).

The genetic conditions associated with EIEE follow heterogeneous inheritance patterns. Across large genome sequencing cohorts, autosomal dominant de novo variants account for the majority of identified germline pathogenic variants (45.9%), followed by autosomal dominant inherited (14.6%) and autosomal recessive (11.4%) variants; a small proportion (2.1%) are inherited from a mosaic parent, and X-linked forms also occur.

• Where Early Infantile Epileptic Encephalopathy is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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• Symonds JD, Elliott KS, Shetty J, Armstrong M, Brunklaus A, Cutcutache I, et al. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants. Brain. 2021;144(9):2879–2891. doi:10.1093/brain/awab162. [2] PMID: PMCID: PMC8557326 ()
• Henry OJ, Ygberg S, Barbaro M, Lesko N, Karlsson L, Peña-Pérez L, et al. Clinical whole genome sequencing in pediatric epilepsy: Genetic and phenotypic spectrum of 733 individuals. Epilepsia. 2025;66(8):2966-2979. doi: 10.1111/epi.18403. PMID: . PMCID: PMC12371643.
• Orphanet. Early infantile epileptic encephalopathy (ORPHA:1934). Orphanet Rare Disease Database. Available at: .