A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-52 (DEE52) is caused by homozygous mutation in the SCN1B gene (600235) on chromosome 19q13.

Developmental and epileptic encephalopathy-52 (DEE52) is a severe autosomal recessive seizure disorder characterized by infantile onset of refractory seizures with resultant delayed global neurologic development. Affected individuals have impaired intellectual development and may have other persistent neurologic abnormalities, including axial hypotonia and spasticity; death in childhood may occur (summary by Patino et al., 2009 and Ramadan et al., 2017). Some patients with DEE52 may have a clinical diagnosis of Dravet syndrome (607208), which is characterized by the onset of seizures in the first year or 2 of life after normal early development. Developmental delay, impaired intellectual development, and behavioral abnormalities usually become apparent later between 1 and 4 years of age. Dravet syndrome may also include 'severe myoclonic epilepsy in infancy' (SMEI) (summary by Patino et al., 2009).

For a discussion of genetic heterogeneity of DEE, see 308350.

Patino et al. (2009) reported a dizygotic twin boy, born of consanguineous Moroccan parents, with a clinical diagnosis of Dravet syndrome. 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, consistent with a clinical diagnosis of Dravet syndrome. 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.

Ramadan et al. (2017) described 5 children with DEE52 from 3 unrelated consanguineous Saudi families. The proband in family 1 presented at age 8 months with status epileptics and an EEG consistent with focal secondary generalized epilepsy with bursts of high voltage spikes lasting up to 5 minutes without clinical manifestation. Brain MRI showed nonspecific atrophy. Her epilepsy was resistant to treatment and she died at age 9 years. A brother presented at age 2 months with treatment-resistant tonic-clonic and absence seizures, episodic abnormal eye movements, and recurrent singultus; he died at age 9 months. The proband in family 2 was a 10-year-old girl with epilepsy, profound psychomotor delay, microcephaly, generalized wasting, severe kyphoscoliosis, central hypotonia, and spastic quadriplegia. Her seizures began at age 2 months and were poorly controlled. Brain MRI at age 6 years showed multiple small infarcts with surrounding gliosis in the centrum semiovale, periventricular leukomalacia, mild ventricular dilatation, and mild dysplasia of the corpus callosum. A sister had a similar phenotype. Brain MRI showed diffuse atrophy, and an EEG showed slow posterior dominant rhythm with frequent bursts of spike and wave discharges. She died at age 8 years. The proband in family 3 developed multifocal, intractable epilepsy with myoclonus and tonic-clonic seizures at 20 days of age. He had severe developmental delay and 4-limb spasticity. Brain MRI showed mildly prominent lateral ventricles and extraaxial CSF space at the frontotemporal region suggestive of mild atrophy. EEG showed a slow background with frequent multifocal spikes consistent with epileptic encephalopathy. He died at age 3.5 years of bleeding from an esophageal varix. He had 2 sibs who died at ages 6 and 13 years with a similar phenotype.

The transmission pattern of DEE52 in the family reported by Patino et al. (2009) was consistent with autosomal recessive inheritance.

In a boy, born of consanguineous Moroccan parents, with DEE52, 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 DEE52, 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 early-onset seizures without mutations in the SCN1A (182389) or SCN2A (182390) genes who 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 early-infantile epileptic encephalopathy in whom SCN1A mutations had been excluded, suggesting that SCN1B mutations are not a common cause of that phenotype.

In affected members of 3 unrelated Saudi families with DEE52, Ramadan et al. (2017) identified homozygous mutations in the SCN1B gene: the same splicing mutation (600235.0010) in 2 families, and a missense mutation (Y119D; 600235.0011) in the third family. The mutations, which were found by sequencing of a multigene epilepsy panel and confirmed by Sanger sequencing, segregated with the disorder in the families and were not found in the ExAC database. No functional studies were performed.

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.