Epileptic Encephalopathy, Early Infantile, 17

A number sign (#) is used with this entry because early infantile epileptic encephalopathy-17 (EIEE17) is caused by de novo heterozygous mutation in the GNAO1 gene (139311) on chromosome 16q13.

Heterozygous mutation in the GNAO1 gene can also cause neurodevelopmental disorder with involuntary movements (NEDIM; 617493).

Description

Early infantile epileptic encephalopathy-17 is a severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life and usually associated with EEG abnormalities. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements (summary by Nakamura et al., 2013).

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

Clinical Features

Nakamura et al. (2013) reported 4 unrelated girls with early infantile epileptic encephalopathy. Three patients had onset of intractable tonic seizures in the first weeks of life associated with suppression-burst pattern on EEG; the fourth patient presented with opisthotonic posturing and developmental delay at age 7 months. All had severely delayed psychomotor development, with lack of sitting and no speech; only 1 patient had head control. One child died at age 11 months. EEG studies were consistently abnormal, including hypsarrhythmia and multifocal sharp waves. One patient showed dystonia and another had severe chorea and athetosis. Brain MRI was abnormal in 3 patients, showing cerebral atrophy, delayed myelination, and/or thin corpus callosum.

Saitsu et al. (2016) reported 2 unrelated girls who presented in early infancy with epileptic encephalopathy. They had intractable complex-partial seizures and EEG abnormalities, including multiform discharges, slow-wave bursts, and hypsarrhythmia. They had severe intellectual disability and motor developmental delay. One patient had severe chorea and the other had hand stereotypies. Brain imaging showed progressive cerebral atrophy in both patients, and 1 patient had microcephaly and hypotonia. The patients were severely disabled with little or no eye contact or head control, and inability to sit, walk, or talk.

Molecular Genetics

In 4 unrelated girls with EIEE17, Nakamura et al. (2013) identified 4 different de novo heterozygous mutations in the GNAO1 gene (139311.0001-139311.0004). One of the patients was somatic mosaic for the mutation. The mutations in the first 2 patients were found by whole-exome sequencing, and the mutations in the second 2 patients were found by direct sequencing of the GNAO1 gene in 367 individuals with epileptic encephalopathy. In vitro functional expression studies showed that 3 of the mutations caused impaired protein localization to the plasma membrane, and electrophysiologic analysis showed that 3 of the mutations caused decreased GNAO1-mediated inhibition of calcium currents by norepinephrine compared to wildtype. The findings suggested that aberrant GNAO1 signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.

In 2 unrelated patients with EIEE17, Saitsu et al. (2016) identified de novo heterozygous missense mutations in the GNAO1 gene (see, e.g., 139311.0004).

Animal Model

Kehrl et al. (2014) found that mutant mice heterozygous for a G184S mutation in the Gnao1 gene died in the perinatal period or early in life due to sudden death associated with severe seizures and/or increased frequency of interictal epileptiform discharges. Homozygous mutant mice were essentially nonviable. Heterozygous mice showed enhanced sensitivity to seizure kindling with a GABA antagonist compared to controls. Heterozygous knockout mice, representing a loss of function, did not show such a phenotype, suggesting that the G184S mutation results in a gain of function. Kehrl et al. (2014) noted that several studies have shown that the G184S allele results in a gain of function effect and suggested that EIEE17 may also result from a gain of function mechanism.