Epileptic Encephalopathy, Early Infantile, 56

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-56 (EIEE56) is caused by heterozygous mutation in the YWHAG gene (605356) on chromosome 7q11.

Description

EIEE56 is a neurodevelopmental disorder characterized by early-onset seizures in most patients, followed by intellectual disability, variable behavioral abnormalities, and sometimes additional neurologic features, such as ataxia (summary by Guella et al., 2017).

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

Clinical Features

Guella et al. (2017) reported 4 unrelated females (subjects B, D, E, and F), ranging from 10 to 22 years of age, with early-onset seizures and intellectual disability. The seizures started within the first year of life for 3 patients; the onset of seizures in subject F was unknown, but her first documented seizure was at 6 years of age. Seizure types varied and included myoclonic, absence, generalized tonic-clonic, febrile, and focal motor with eyelid fluttering or limb jerks. Most patients had several types of seizures, and 1 patient had episodes of status epilepticus. EEG abnormalities included dysrhythmic background, atypical spike waves, sharp waves, polyspike waves, and generalized spike waves. Although multiple antiseizure medications were tried and some had seizure break-through or recurrence, most patients eventually had at least a partial response to treatment. All patients had intellectual disability, ranging from moderate to severe, as well as language delay. One patient had additional psychiatric issues, including attention deficit-hyperactivity disorder, anxiety, and obsessive compulsive traits, and another had autistic features. Additional variable features included scoliosis, joint hyperlaxity, ataxia, and coordination difficulties. Brain imaging was unremarkable in 3 patients, but showed atrophy with white matter loss in 1.

Molecular Genetics

In 4 unrelated patients with EIEE56, Guella et al. (2017) identified de novo heterozygous missense mutations in the YWHAG gene. The first patient (subject B), who was identified from a cohort of 42 individuals with epileptic encephalopathy who underwent sequencing of candidate genes, had an R132C (605356.0001) substitution. The subsequent patients were identified through collaboration with clinical and research databases. Two patients (subjects E and F) also carried the R132C mutation, and the fourth patient (subject D) had an E15A (605356.0002) substitution. Guella et al. (2017) found that a patient (ND27637) diagnosed with Lennox-Gastaut syndrome had previously been reported with a de novo heterozygous D129E substitution (605356.0003) in the YWHAG gene by the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013). The authors also noted that 2 other patients (AU027A and DDD4K.00159) with de novo heterozygous mutations in the YWHAG gene had been reported by De Rubeis et al. (2014) and the Deciphering Developmental Disorders Study (2017), respectively, but no clinical details had been provided. In vitro functional expression studies of the variants were not performed, but all were predicted to impair dimerization and/or phosphopeptide binding. Guella et al. (2017) noted that a decrease or increase in Ywhag in mice leads to delayed neuronal migration of pyramidal neurons in the developing brain (Wachi et al., 2016; Cornell et al., 2016) and that atypical neuronal migration has been implicated in epilepsy.

Animal Model

Wachi et al. (2016) found that ablation of the Ywhag gene in mice in utero resulted in delays in neuronal migration and morphologic defects in the cerebral cortex of the brain. Migrating neurons displayed a thicker leading process stem, and the basal ends of neurons were not able to reach the boundary between the cortical plate and the marginal zone. The results indicated that Ywhag plays an important role in radial migration by regulating the morphology of migrating neurons in the cerebral cortex.

Cornell et al. (2016) found that overexpression of Ywhag in utero in the developing mouse cortex resulted in delays in pyramidal neuron migration, similar to that observed with knockdown of Ywhag. The findings indicated that a balance of this gene expression is required during cortical development to prevent delays in neuronal migration.