Epileptic Encephalopathy, Early Infantile, 52

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-52 (EIEE52) is caused by homozygous mutation in the SCN1B gene (600235) on chromosome 19q13.

Description

EIEE52 is an autosomal recessive seizure disorder characterized by infantile onset of refractory seizures with resultant delayed global neurologic development that causes intellectual disability and other persistent neurologic abnormalities (summary by Patino et al., 2009).

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Patino et al. (2009) reported a dizygotic twin boy, born of consanguineous Moroccan parents, with EIEE52. At age 3 months, the patient developed generalized tonic-clonic seizures after vaccination. He subsequently had multiple recurrent seizures, including febrile seizures and myoclonic seizures, associated with rolandic discharges on EEG. The seizures were refractory to treatment, and he showed deterioration of psychomotor abilities, global hypotonia, and a tetrapyramidal syndrome. He died around age 14 months from aspiration pneumonia. His twin brother was unaffected.

Ogiwara et al. (2012) reported a 24-year-old Japanese man, born of unrelated parents, with onset of hemiclonic and myoclonic seizures at age 6 months. He subsequently developed fever-provoked myoclonic seizures and generalized tonic-clonic seizures, often associated with status epilepticus. Other seizure types included atypical absence, myoclonic atonic, and focal dyscognitive seizures with cyanosis. These became less frequent and disappeared when he was 4 years of age, but refractory generalized tonic-clonic seizures persisted. The patient showed developmental stagnation and global developmental delay after onset of seizures, as well as ataxia of the limbs and mild pyramidal signs. EEG initially showed multifocal spike and slow waves, and later showed infrequent polyspikes, spikes, and slow waves. Brain imaging showed mild nonspecific atrophy with enlargement of the lateral ventricles.

Inheritance

The transmission pattern of EIEE52 in the family reported by Patino et al. (2009) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a boy, born of consanguineous Moroccan parents, with EIEE52, Patino et al. (2009) identified a homozygous missense mutation in the SCN1B gene (R125C; 600235.0008). In vitro functional cellular expression studies showed that the mutant protein was poorly expressed at the cell surface, despite robust intracellular expression, consistent with a trafficking defect to the membrane. Studies in Xenopus oocytes showed that the mutant protein was functional if it could be expressed at the cell surface. The inefficient trafficking of the mutant protein to the cell membrane at physiologic temperatures resulted in a functionally null SCN1B phenotype. The parents, who were heterozygous for the mutation, did not have seizures, suggesting that 1 functional SCN1B allele is sufficient for normal control of electrical excitability.

In a 25-year-old Japanese man, born of unrelated parents, with EIEE52, Ogiwara et al. (2012) identified a homozygous missense mutation in the SCN1B gene (I106F; 600235.0009). Functional studies of the variant and studies of patient cells were not performed. However, Ogiwara et al. (2012) noted that the domain of the protein affected by the mutation mediates interaction with cellular adhesion molecules. The patient was part of a cohort of 67 individuals with EIEE who did not have mutations in the SCN1A (182389) or SCN2A (182390) genes and underwent mutation analysis of the SCN1B gene.

Kim et al. (2013) did not find any pathogenic mutations in the SCN1B gene among 54 patients with EIEE in whom SCN1A mutations had been excluded, suggesting that SCN1B mutations are not a common cause of the disorder.

Animal Model

Chen et al. (2004) produced beta-1-null mice by gene targeting. Knockout mice exhibited ataxic gait, spontaneous seizures, growth retardation, and death around postnatal day 20. They showed slowing of action potential conduction, reduced number of mature nodes of Ranvier, alterations in nodal architecture, loss of sodium channel-contactin (see CNTN1, 600016) interactions, and abnormalities in the expression of Nav1.1 (SCN1A; 182389) and Nav1.3 (SCN3A; 182391) in pyramidal neurons CA2/CA3. Mutant mice had impacted esophagi, possibly attributable to enteric nervous system impairment. Chen et al. (2004) concluded that beta-1 regulates sodium channel density and localization, is involved in axo-glial communication at nodes of Ranvier, and is required for normal action potential conduction and control of excitability in vivo.

Patino et al. (2009) found that heterozygous Scn1b +/- mice did not have increased susceptibility to seizures. Electrophysiologic studies of hippocampal slices from Scn1b-null mice showed increased peak voltage of action potentials and amplitude of action potentials in CA3 neurons, consistent with neuronal hyperexcitability, but not in CA1 neurons. Changes in sodium current density were not observed in dissociated CA3 bipolar neurons.