Epileptic Encephalopathy, Early Infantile, 30

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-30 (EIEE30) is caused by heterozygous mutation in the SIK1 gene (605705) on chromosome 21q22.

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

Clinical Features

Hansen et al. (2015) reported 6 unrelated children with a severe neurodevelopmental disorder associated with early-onset refractory epilepsy. Seizure onset occurred shortly after birth or within the first months of life and included myoclonic, generalized tonic-clonic, and atonic seizures, as well as infantile spasms. All patients had severely delayed psychomotor development. Two patients died in infancy, and the 4 who survived showed severe cognitive impairment with poor or absent speech and autistic features. EEG showed variable abnormalities, such as burst suppression patterns, multifocal spikes, slowed background activity, and hypsarrhythmia. Brain imaging, when performed, was normal. Additional features included abnormal involuntary movements, poor spontaneous movement, poor visual and/or auditory responses, bruxism, poor feeding, and respiratory insufficiency.

Molecular Genetics

In 6 unrelated children with early infantile epileptic encephalopathy-30, Hansen et al. (2015) identified 6 different de novo heterozygous mutations, 3 missense and 3 truncating, in the SIK1 gene (see, e.g., 605705.0001-605705.0005). In vitro functional expression studies showed that all the mutant proteins identified, even the truncated ones, retained normal kinase activity. Studies in HEK293 cells showed that the missense mutant proteins had normal punctate nuclear localization, similar to wildtype, whereas the truncated proteins had a broader pattern of localization in the nucleus and cytoplasm as well as increased stability compared to wildtype.