Epileptic Encephalopathy, Early Infantile, 11
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-11 (EIEE11) is caused by heterozygous mutation in the SCN2A gene (182390) on chromosome 2q24.
Mutation in the SCN2A gene can also cause benign familial infantile seizures-3 (BFIS3; 607745).
DescriptionEarly infantile epileptic encephalopathy-11 is an autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities (Ogiwara et al., 2009).
For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Clinical FeaturesKamiya et al. (2004) reported a 29-year-old Japanese woman with delayed onset of early infantile epileptic encephalopathy-11. She had onset of seizures at age 1 year, 7 months, and thereafter became hyperkinetic and autistic. The EEG was reported to show only slow waves initially, but after 3 years, there was clear focal onset and spike activity appeared and increased. Convulsive and atonic seizures continued throughout childhood and were difficult to treat. She had severe intellectual and psychomotor retardation but no paralysis. Brain MRI showed moderate diffuse brain atrophy.
Ogiwara et al. (2009) reported 2 unrelated patients with early infantile epileptic encephalopathy. The first patient had onset of infantile spasms at age 11 months, which evolved to frequent occurrence of refractory tonic-clonic seizures at age 2 to 3 years. He also showed marked developmental delay and severe intellectual disability in infancy and childhood. Febrile seizures occurred after age 10 years. After an episode of status epilepticus at age 17 years, he became quadriplegic and speechless. EEG showed background activity lacking alpha waves but containing abundant slow waves and right hemisphere dominant diffuse sharp waves or polyspikes; ictal EEG showed diffuse recruiting fast spike activity preceded by diffuse flattening. MRI showed mild cerebral atrophy with wider left lateral ventricle. The second patient developed tonic or tonic-clonic seizures from age 1 month. She also had early infantile status epilepticus with a highly suppressed EEG with ictal burst activities, hyponatremia, and megalencephaly. The seizures were responsive to lidocaine treatment. She died at age 7 years and 8 months from unknown causes. The reports of these patients significantly expanded the phenotype resulting from SCN2A mutations, and indicated that SCN2A is a candidate gene underlying intractable childhood epilepsies. In vitro functional expression studies showed that both E1211K and I1473M altered the channel properties of SCN2A to a greater extent than the BFIS3 mutations, suggesting a molecular mechanism for the more severe epileptic phenotypes.
Hackenberg et al. (2014) reported a girl, born of a Japanese mother and European father, with EIEE11 associated with a de novo heterozygous missense mutation in the SCN2A gene. She had feeding problems, rare smiling, and lack of visual contact in early infancy, consistent with marked developmental delay. At age 5 months, she developed abnormal eye movements and tonic seizures; EEG showed hypsarrhythmia and multifocal sharp wave activity. She also had severe hypotonia, choreoathetotic movements, and excessive daytime sleepiness. Over the following years, she developed multiple types of treatment-resistant seizures as well as progressive microcephaly (-4.0 SD) associated with lack of visual contact and rare spontaneous movements. Brain MRI showed progressive cortical and subcortical atrophy with minor cerebellar atrophy.
Baasch et al. (2014) reported a 5-year-old girl with severe EIEE11. She had neonatal hypotonia and developed focal and generalized tonic-clonic seizures on the first day of life. EEG showed generalized and irregular spike wave and polyspike wave activity. The seizure type changed constantly during the newborn period; seizures were refractive to therapy. Brain imaging at age 11 months showed supratentorial atrophy, hypoplastic corpus callosum, and intracranial calcifications. She had global motor, intellectual, and language impairment with no speech or purposeful movements. Other features included bilateral optic atrophy, microcephaly (-3.4 SD), and temperature regulation problems. Exome sequencing identified a de novo heterozygous missense mutation in the SCN2A gene.
Clinical Variability
Liao et al. (2010) reported an 11-year-old boy with neonatal onset of seizures followed by unusually long persistence of seizures as well as residual neurologic signs. The phenotype was considered to be more severe than that of BFIS3. He presented from the first day of life with hypomotor seizures followed by tonic-clonic movements on alternating sides. Hypomotor, focal, and bilateral motor seizures continued weekly to monthly until 1.3 years. Beginning at this time, he developed episodes with poor balance, ataxia, slurred speech, intermittent myoclonic jerks, and severe distress with headache, back pain, hypermotor activity, hyperventilation, and retching or vomiting. Mild motor dyspraxia, but no ataxia, was present between the episodes. After numerous medications that were ineffective, he became seizure-free on acetazolamide. Neuropsychologic testing showed normal intelligence, but specific problems in visual processing, fine motor function, and tactile sensation. MRI showed mild cerebellar atrophy at age 5 years. Genetic analysis identified a de novo heterozygous mutation in the SCN2A gene (A263V; 182390.0011).
Touma et al. (2013) reported a pair of monozygotic twin boys who carried the same de novo heterozygous A263V mutation identified in the patient reported by Liao et al. (2010). Both developed refractory seizures (up to 60 per day) on the first day of life. One twin died on day 19 from iatrogenic cardiopulmonary arrest. The other twin became seizure-free on medication at age 8 months, and seizure-free without medication at age 2 years. The surviving twin showed global developmental delay; he could say short sentences but had head lag, axial hypotonia, and inability to crawl. EEG at age 2 weeks in both twins showed a suppression-burst pattern. Serial EEGs of the surviving twin showed improvement of the abnormalities to occasional multifocal spikes in parietal regions with a symmetric background. Brain imaging of the surviving twin showed diffuse signal abnormalities in the basal ganglia and brainstem suggestive of cytotoxic edema; these abnormalities improved with age. Neuropathologic examination of the deceased twin showed hyperconvolution in the cerebellar dentate nucleus and medulla, consistent with a dentate-olivary dysplasia. The white matter was intensely gliotic.
Clinical ManagementTarailo-Graovac et al. (2016) reported an 8-year-old boy with EIEE11 confirmed by genetic analysis who had persistently abnormal neurotransmitter profiles in cerebrospinal fluid. Treatment with 5-hydroxytryptophan, levodopa, carbidopa, and a dopa agonist normalized the neurotransmitter levels and was associated with improvements in attention, communication, and seizure control.
Molecular GeneticsIn a 29-year-old Japanese woman with delayed onset of early infantile epileptic encephalopathy-11, Kamiya et al. (2004) identified a de novo heterozygous truncating mutation in the SCN2A gene (R102X; 182390.0008). Electrophysiologic studies in HEK293 cells showed that the R102X mutant protein was nonfunctional when expressed in isolation, and shifted the voltage dependence of inactivation of wildtype channels in the hyperpolarizing direction, consistent with a dominant-negative effect.
In 2 unrelated patients with early infantile epileptic encephalopathy-11, Ogiwara et al. (2009) identified 2 different de novo heterozygous missense mutations in the SCN2A gene (E1211K; 182390.0009 and I1473M; 182390.0010, respectively).
In an 11-year-old boy with early-onset seizures and persistent neurologic impairment, Liao et al. (2010) identified a de novo heterozygous mutation in the SCN2A gene (A263V; 182390.0011).