Table 3

Electroclinical syndromes

SyndromeElectroclinical featuresGene
Angelman’s syndromeRare 1/15 000 children. Developmental delay, intellectual disability, happy demeanour, absence of speech, ataxic gait, microcephaly and epilepsy. Seizures: myoclonic, atonic, astatic, tonic, absences, generalised tonic-clonic seizures, focal; infantile spasms rare. Non-convulsive status epilepticus may occur. EEG: very high-amplitude 2–3 Hz delta, anterior spike–slow wave; centrotemporal rhythmic theta; posterior theta facilitated by eye closure.UBE3A
(deletion or mutation maternal gene, sporadic)
Rett’s syndromeRare 1/12 000 girls. Arrested development 6–18 months age, regression acquired skills, loss of speech, stereotypic hand movements, microcephaly, seizures and intellectual disability. Rarely affected males (somatic mosaicism or extra X chromosome). Seizures: generalised tonic-clonic seizures, absences, myoclonic, tonic, focal, infantile spasms. EEG: rhythmical slowing (3–5 Hz), focal and generalised discharges.MECP2 (XLD)
SCN1A related syndromesRare, prevalence unknown. Spectrum with variable severity. (1) Febrile seizures alone onset 6 months to 4 years age, remits by age 6 years. (2) GEFS+ febrile and afebrile seizures continue with generalised (absence, myoclonic, atonic) or focal seizures; majority have normal intelligence. (3) Dravet syndrome (severe myoclonic epilepsy of infancy) most severe phenotype (70% have SCN1A mutation), onset first year of life typically with prolonged febrile hemiclonic seizures or generalised tonic-clonic seizures. Between 1 and 4 years age myoclonic, absence, partial-onset and atonic seizures develop, with developmental delay and regression. Seizures reduce in adulthood, and there is mild to severe intellectual disability. EEG can be normal initially, generalised, polyspike, focal discharges.SCN1A (AD)
SCN2A related epilepsyRare, prevalence unknown. Associated with (1) autism spectrum disorders, (2) benign familial infantile epilepsy (clusters afebrile seizures in first year of life without neurological sequelae), (3) early infantile epileptic encephalopathy (neonatal or infantile onset refractory seizures; may progress to West syndrome with tonic spasms, arrest psychomotor development, hypsarrhythmia on EEG.SCN2A (AD)
SCN8A related epilepsy with encephalopathyRare, 1% early onset epileptic encephalopathy. Onset before 18 months age. Epilepsy, developmental regression, mild to severe intellectual disability, movement disorders, high incidence of SUDEP. Seizures: generalised tonic-clonic seizures (common), absence, atonic, myoclonic, focal. Febrile seizures rare, distinguishing it from Dravet syndrome. EEG: can be normal at onset, multifocal sharp waves/spikes, generalised discharges, hypsarrhythmia rare.SCN8A (AD)
GLUT1 deficiency syndromeRare 1/90 000. Epilepsy, paroxysmal exertional dystonia, ataxia and intellectual disability (see text). Seizures: generalised tonic-clonic seizures, absences, focal, myoclonic seizures, early onset absence status epilepticus. EEG: Anterior predominant generalised discharges, increase during fasting.SLC2A1 (AD)
Ring Chromosome 20
Rare, prevalence unknown. Development normal or mildly delayed, cognitive and behavioural decline after typically explosive seizure onset (can occur paediatric or adult age). Seizures: focal, atypical absences, generalised tonic-clonic seizures, focal motor seizures. Frequently non-convulsive status epilepticus. EEG: Frontal or fronto-temporal slow waves.De novo mosaicism r(20) chromosome
Fragile X syndromeRare, 1/4000 males, 1/8000 females. second the most common cause of intellectual disability after trisomy 21. Males more severely affected with moderate to severe intellectual disability, seizures (15%), macro-orchidism, distinct facial features. 50% females have mild intellectual disability.
Seizures: commonly focal, improve with age. EEG: normal, centrotemporal discharges.
X linked epilepsy in females with mental retardationRare, prevalence unknown. Clinical spectrum similar to GEFS+; consider in females with epileptic encephalopathy and negative SCN1A mutation; men are carriers; females are affected; sporadic cases can occur. Intellectual disability, autistic, obsessive, aggressive behaviour.Seizures: febrile, afebrile, focal, generalised. EEG: Focal and generalised discharges.PCDH19 (XL)
SYNGAP1 related intellectual disability1%–2% intellectual disability cases. Mild to severe intellectual disability, epilepsy, developmental delay, hypotonia, gait ataxia and autism. Seizures: typical or atypical absences, atonic, myoclonic, eyelid myoclonia, myoclonic-astatic; focal clonic or tonic seizures rare. Photosensitivity triggering seizures common, sensitivity to sunlight/artificial light diagnostic clue. EEG: bursts generalised spikes, spike and slow waves, generalised with occipital predominance.SYNGAP1 (AD)
GRIN2A related epilepsiesRare, accounts for 20% LKS or ECSWS; part of epilepsy-aphasia spectrum. Speech disorder, aphasia, focal or focal/motor seizures onset age three to six, with developmental regression. In LKS, seizures improve by adolescence; 80% have language and intellectual disability in adult life. EEG: temporal and parietal spike wave, continuous spike wave in sleep or centrotemporal discharges.GRIN2A (AD)
Some copy number variants associated with epilepsy
 15q13.3 recurrent microdeletionRare, 1/40 000. Most common microdeletion associated with epilepsy (1% IGE). Variable phenotype. Intellectual disability, autism, schizophrenia and epilepsy. Comorbidity absence seizures and intellectual disability should prompt consideration. EEG: Generalised spike wave discharges.Copy number variant (AD)
 16p13.11 recurrent microdeletionRare, prevalence unknown. Variable phenotype. Mild to moderate developmental delay, mild intellectual disability, speech defects; generalised, focal seizures. EEG: Focal, generalised discharges.Copy number variant (AD)
 15q11.2 recurrent microdeletionRare, prevalence unknown. Variable phenotype. Autism, intellectual disability, ataxia, generalised epilepsy, developmental delay and behavioural problems. EEG: Generalised spike wave discharges.Copy number variant (AD)
  • GEFS+: genetic epilepsy with febrile seizures plus; IGE: Idiopathic generalised epilepsy; UBE3A: ubiquitin protein ligase E3A; MECP2: methyl-CpG binding protein 2; SCN: voltage-gated sodium channel; GLUT1: glucose transporter protein type 1; SLC2A1: solute carrier family 2 member 1; FMR1: fragile X mental retardation 1; PCDH19: Protocadherin 19; SYNGAP1: synaptic Ras GTPase activating protein 1; GRIN2A: glutamate ionotropic receptor NMDA type subunit 2A

  • ECSWS, epileptic encephalopathy with continuous spike wave during sleep; FMR1, fragile X mental retardation 1; GEFS+, genetic epilepsy with febrile seizures plus; GLUT1, glucose transporter protein type 1; GRIN2A, glutamate ionotropic receptor NMDA type subunit 2A; IGE, Idiopathic generalised epilepsy; LKS, Landau–Kleffner syndrome; MECP2, methyl-CpG binding protein 2; PCDH19, Protocadherin 19; SCN, voltage-gated sodium channel; SLC2A1, solute carrier family 2 member 1; SUDEP, sudden unexpected death in epilepsy; SYNGAP1, synaptic Ras GTPase activating protein 1; UBE3A, ubiquitin protein ligase E3A.