Epileptic Encephalopathy, Early Infantile, 18

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-18 (EIEE18) is caused by homozygous or compound heterozygous mutation in the SZT2 gene (615463) on chromosome 1p34.

Description

Early infantile epileptic encephalopathy-18 is a severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, early onset of refractory seizures, and thick corpus callosum and persistent cavum septum pellucidum on brain imaging (summary by Basel-Vanagaite et al., 2013).

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

Clinical Features

Basel-Vanagaite et al. (2013) reported 2 unrelated children with early-onset epileptic encephalopathy. Both showed severely delayed psychomotor development with hypotonia since infancy, lack of speech, and inability to sit or stand unsupported. A 10-year-old girl, born of unrelated Iraqi Jewish parents, first developed intractable seizures at age 4 years. Seizures were characterized by loss of consciousness, drooling, and perioral cyanosis, and sometimes followed by tonic-clonic generalized seizures. One of her brothers likely had the same condition; he had profound developmental delay and intractable seizures, and died at age 3 years from respiratory infection. The second child, a 9-year-old Spanish boy, developed intractable tonic and absence seizures at age 2 months. EEG in both patients showed abnormal background trace and prominent epileptiform abnormalities, but no suppression burst pattern. Both probands had common facial dysmorphic features, including high forehead, downslanting palpebral fissures, ptosis, and arched, laterally extended eyebrows. Brain MRI in both patients and in the deceased sib of the first patient showed short and thick corpus callosum and persistent cavum septum pellucidum.

Inheritance

The transmission pattern of EIEE18 in the families reported by Basel-Vanagaite et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients with early infantile epileptic encephalopathy-18, Basel-Vanagaite et al. (2013) identified biallelic truncating mutations in the SZT2 gene (615463.0001-615463.0003). The mutations were found by whole-exome sequencing and segregated with the disorder in the families. The presence of severe developmental delay before the onset of epilepsy in 1 patient suggested that SZT2 mutations also impair brain maturation independently of seizures.

Animal Model

Frankel et al. (2009) found that mutation in the Szt2 gene in mice increased seizure threshold and epileptogenesis.