A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-46 (DEE46) is caused by heterozygous mutation in the GRIN2D gene (602717) on chromosome 19q13.

Developmental and epileptic encephalopathy-46 (DEE46) is a neurologic disorder characterized by the onset of intractable seizures in the first months or years of life. Affected individuals show global developmental delay with failure to thrive, hypotonia, and hyperreflexia with variably impaired intellectual development. More severely affected individuals have almost no developmental progress and are unable to sit or speak, whereas others may achieve some milestones (summary by Tsuchida et al., 2018).

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

Li et al. (2016) reported 2 unrelated girls with severely delayed global development and onset of intractable seizures at 4 and 2 months of age, respectively. In the 8.5-year-old proband, EEG showed multifocal spike wave discharges, with hypsarrhythmia. She was seizure-free between about 3 and 5 years of age on levetiracetam; when this treatment was discontinued, seizures recurred with status epilepticus. She had very slow developmental progress with poor walking and few words. Other features included failure to thrive, poor feeding, dysphagia, constipation, mild cortical visual impairment, axial hypotonia, appendicular hypertonia, and minor dysmorphic features such as deep-set eyes, thick eyebrows, long eyelashes, tented upper lip, full cheeks, and widely spaced teeth. The other patient was a 2.7-year-old Tunisian girl with microcephaly, axial and orofacial hypotonia, and appendicular hypertonia who was unable to sit unassisted, speak words, or grasp objects. She had uncoordinated movements and was nondysmorphic except for severe pes planus.

Tsuchida et al. (2018) reported 3 unrelated patients with DEE46. The patients presented in the first months or years of life with global developmental delay and intractable seizures of various types. EEG showed multifocal discharges and diffuse spike and slow wave complexes. Additional variable features included jerky limb movements, hypotonia, myoclonus, hyperreflexia, ADHD, and autism. One patient could sit and roll over, but could not speak at age 8 years (Enjoji scale, less than 10). Another was able to walk and speak, but had impaired intellectual development (verbal IQ of 57, performance IQ of 68, and full-scale IQ of 58) at 15 years of age. The third patient, who was 8 years old, had no developmental progress beyond infancy and was unable to control his head, speak, or have eye contact. Brain imaging was normal in the first 2 patients; the third patient had loss of white matter volume, dilated ventricles, thin corpus callosum, and cerebral atrophy.

After Li et al. (2016) identified a mutation in the GRIN2D gene in 2 girls with early-onset epileptic encephalopathy and obtained in vitro data, they treated both patients with various NMDAR antagonists, including memantine and ketamine, as well as magnesium, which causes voltage-dependent inhibition. The older girl was treated with memantine at age 6.5 years, with variable response and no sustained improvement. She was eventually treated with ketamine and magnesium, which resulted in better seizure control. The younger girl was started on memantine at age 2.5 years, which resulted in better seizure control and some developmental improvement.

The heterozygous mutations in the GRIN2D gene that were identified in patients with DEE46 by Li et al. (2016) occurred de novo.

In 2 unrelated girls with DEE46, Li et al. (2016) identified a de novo heterozygous missense mutation in the GRIN2D gene (V667I; 602717.0001). The mutation was found by whole-exome sequencing in the first patient and by sequencing of a targeted epilepsy gene panel in the second patient. The mutation occurred at a highly conserved residue in the M3 transmembrane domain that forms the ion channel core. Voltage clamp studies in transfected Xenopus oocytes and HEK293 cells showed that the mutation increased the receptor responsiveness to glutamate and glycine agonists, decreased the sensitivity of the channel to negative allosteric modulators, prolonged the deactivation time, and increased the channel opening probability, all consistent with a gain-of-function effect on the NMDA receptor. Transfection of the mutation into rat cortical neurons showed that it resulted in increased neuronal excitotoxicity that could be blocked by the NMDAR antagonist memantine.

In 3 unrelated patients with DEE46, Tsuchida et al. (2018) identified heterozygous missense mutations in the GRIN2D gene (602717.0002-602717.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the available parents. Functional studies of the variants and studies of patient cells were not performed.