Epileptic Encephalopathy, Early Infantile, 27

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-27 (EIEE27) is caused by heterozygous mutation in the GRIN2B gene (138252) on chromosome 12p12.

Heterozygous mutation in the GRIN2B gene can also cause autosomal dominant mental retardation-6 (MRD6; 613970), a similar disorder without early-onset seizures.

Early infantile epileptic encephalopathy-27 is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability of variable severity associated with early-onset seizures. Additional features may include hypotonia, abnormal movements, such as dystonia, and autistic features. Some patients may have structural malformations of cortical development on brain imaging. The phenotype is highly variable and reflects a spectrum of neurodevelopmental abnormalities that range from mild intellectual disability without seizures to an encephalopathy (summary by Platzer et al., 2017).

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

Lemke et al. (2014) reported 2 unrelated patients with early infantile epileptic encephalopathy. A boy presented with myoclonic seizures and spasms at age 4 months. At age 6 months, he lacked eye contact and had episodic hyperextension of the axial muscles. EEG showed multifocal bursts of irregular spike waves and bilateral generalized spike waves reminiscent of modified hypsarrhythmia. The seizures were poorly controlled until valproate was started. At age 2 years, he had severe hypotonia with inability to sit, dystonic movements of the fingers, and lack of speech. An unrelated girl presented at 7 weeks with spasms, lack of eye contact, and hypotonia. She also showed episodic hyperextension of axial muscles. EEG showed hypsarrhythmia. At age 5 years, she could not sit independently or speak. She had severe feeding problems, mild microcephaly, and autistic-like behavior, and continued to have occasional seizures.

Platzer et al. (2017) identified 48 individuals with de novo GRIN2B variants and reviewed 43 additional patients with de novo GRIN2B variants collected from the literature. These patients were identified through several research settings focusing on neurodevelopmental disorders. Variants in 86 of 91 patients were classified as putatively pathogenic; all 86 patients presented with developmental delay, intellectual disability (ID), and/or autism spectrum disorder (ASD). Detailed clinical data were available for 58 patients. Most (60%) had severe ID, 25% had moderate ID, and 15% had mild ID; 28% of patients had ASD. About half (52%) of patients had seizures with a variable age at onset (birth to 9 years), variable frequency, and variable seizure type. EEG patterns comprised hypsarrhythmia and focal, multifocal, and/or generalized epileptiform activity. Follow-up data on 22 patients showed that about half became seizure-free on conventional antiseizure medication, whereas half were refractory to therapy. Additional features included hypotonia (53%), resulting in tube feeding in 5 patients, spasticity (24%), abnormal dystonic, dyskinetic, or choreiform movements (10%), microcephaly (19%), and cortical visual impairment (7%). Neuroimaging showed malformations of cortical development in 6 (14%) of 44 patients imaged: abnormalities included polymicrogyria, abnormal gyri and sulci, hypoplastic corpus callosum, and hippocampal dysplasia. Four patients had cerebral atrophy.

In 2 unrelated children with EIEE27, Lemke et al. (2014) identified 2 different de novo heterozygous missense mutations in the GRIN2B gene (V618G, 138252.0010 and N615I, 138252.0011). The mutations were found by targeted massive parallel resequencing of 50 known EIEE genes plus candidate genes in 357 patients with epilepsy, including 91 patients with epileptic encephalopathy. The patients bearing mutations thus accounted for 2.2% (2 of 91) of that phenotypic group. In vitro functional expression studies showed that both mutations occurred in the ion channel-forming reentrant loop and resulted in increased calcium permeability and a gain of function.

In a large cohort of 86 patients with MRD6 or EIEE27, Platzer et al. (2017) identified de novo heterozygous missense or truncating mutations in the GRIN2B gene; multiple mutations were identified, including several of recurrent mutations. In vitro functional expression studies of some of the missense mutations showed that they resulted in altered channel function; some (e.g., S541R, V558I, and I655F) increased glutamate EC(50) values, indicating that higher concentrations of glutamate were needed to activate the receptors, consistent with a loss of function or haploinsufficiency. In contrast, other missense mutations (e.g., S810R, M818T, and A819T) increased glutamate and glycine potency, suggesting a potential gain-of-function effect with possible excitotoxicity. Most, but not all, of the missense mutations clustered within or close to ligand-binding sites or transmembrane domains. There was no correlation between missense versus truncating mutations and occurrence of seizures, although there was an association between truncating mutations and mild or moderate ID versus severe ID. In vitro studies showed that the NMDAR antagonist memantine could reduce membrane hyperactivity of some of the gain-of-function mutations, but treatment of patients with memantine did not reduce seizure frequency. Combining the results of several cohorts of over 10,000 patients with neurodevelopmental disorders and/or epilepsy who underwent genetic analysis by either gene panel sequencing or whole-exome sequencing, Platzer et al. (2017) estimated the frequency of GRIN2B mutations to be 0.2%.