A number sign (#) is used with this entry because of evidence that autosomal dominant neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSD) is caused by heterozygous mutation in the GRIN1 gene (138249) on chromosome 9q34.

Homozygous mutation in the GRIN1 gene can cause autosomal recessive neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSR; 617820).

NDHMSD is a severe neurodevelopmental disorder characterized by profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, and a hyperkinetic movement disorder. Additional features may include cortical blindness, generalized cerebral atrophy, and seizures (summary by Lemke et al., 2016).

Hamdan et al. (2011) reported 2 unrelated patients with sporadic occurrence of intellectual disability. The first was a 10-year-old girl with moderate mental retardation. There was no evidence of epilepsy, and she had a normal neurologic exam and CT scan. The second patient was a 7.5-year-old male with severe mental retardation, partial complex seizures, hypotonia, and normal brain MRI.

Ohba et al. (2015) reported 4 unrelated patients ranging from 5 to 14 years of age with severe developmental delay or even absent development, profound intellectual disability, hyperkinetic movements, and onset of seizures in the first year of life. All were severely affected and bedridden with no head control or purposeful hand movements, very poor or absent eye contact, and no speech. Seizure types included spasm, myoclonic, and partial. EEG studies showed nonspecific focal and diffuse epileptiform abnormality, but no suppression-burst pattern or hypsarrhythmia. Abnormal movements included spastic quadriplegia with hyperreflexia, myoclonus, chorea, dyskinesia, and hand stereotypies; 2 patients had abnormal eye movements resembling oculogyric crises. Additional features included feeding problems with failure to thrive, sleep disorder, bruxism, and inappropriate crying or laughing. Brain imaging showed variable abnormalities, including enlarged ventricles, cerebral atrophy, and thin corpus callosum; 1 patient had cerebellar atrophy. The patients had mild dysmorphic facial features, including deep-set eyes and elongated face. Two patients had progressive microcephaly (-5 SD and -4.3 SD, respectively).

Lemke et al. (2016) reported 14 unrelated patients with NDHMSD and reviewed the phenotype of 9 previously reported patients, including the patients reported by Hamdan et al. (2011). Almost all patients had profound global developmental delay apparent from the neonatal period or early infancy and resulting in severe intellectual disability. Affected individuals usually never acquired the ability to walk and had absent or extremely limited verbal communication skills. A significant number of patients (71%) had severe hypotonia, and about 30% developed corticospinal signs consistent with spastic quadriparesis. The majority of patients (61%) showed choreatic, dystonic, or dyskinetic movement disorders, including oculogyric crises (22%). Nonspecific stereotypic movements were noted in 33% of patients. Most patients (70%) had epilepsy, which varied in age at onset (day 1 to 11 years) and in seizure semiology: patients had infantile spasms, tonic and atonic seizures, hypermotor seizures, focal dyscognitive seizures, febrile seizures, generalized seizures, and status epilepticus. Seizures were associated with abnormal EEG patterns, including hypsarrhythmia, focal, multifocal, and generalized spikes and waves. Some patients had refractory seizures, whereas others showed response to medication. The variability in the epilepsy phenotype was not considered to be consistent with classification as a 'developmental and epileptic encephalopathy' (DEE; see 308350). Behavioral abnormalities were common, and many patients were diagnosed with autism spectrum disorder. Other behavioral abnormalities included aggression and self-injurious behavior or disturbed pain perception (17%). Less common features included sleep disorder, feeding difficulties, requiring tube feeding in some patients, and microcephaly (26%). Several patients (22%) presented with cortical visual impairment or delayed visual maturation. Brain imaging, available for 19 patients, showed nonspecific volume loss or atrophy in 58% of patients. Lemke et al. (2016) noted that the least severely affected patient was 1 of the children reported by Hamdan et al. (2011). This patient was able to walk independently at age 18 months and had speech delay, but did not have seizures, movement disorder, or visual problems.

Chen et al. (2017) reported 2 unrelated patients with NDHMSD, a 12-year-old boy and a 25-year-old female. Both presented at birth with developmental delay and hypotonia associated with cognitive disability, but no seizures. The boy was able to walk with an ataxic gait at age 5, but had no useful language, and showed abnormal movements of the arms and legs, hyperactivity, and self-injurious behavior. Dysmorphic features included thin elongated face, thick eyebrows, deep-set eyes with hypotelorism, recessed chin, and high-arched palate. The 25-year-old woman had severe intellectual disability, but started walking with difficulty around age 2, acquired over 500 words, and was social with good eye contact. She also had abnormal involuntary movements. She had a thin elongated face with deep-set eyes and a marfanoid body habitus with joint hypermobility and scoliosis.

Clinical Variability

Fry et al. (2018) reported 11 unrelated patients with de novo heterozygous missense variants in the GRIN1 gene. The patients were ascertained from several cohorts of patients diagnosed with polymicrogyria or through clinical research programs who underwent exome sequencing. All mutations were missense mutations that were absent from the ExAC database, and occurred between residues 559 and 828. Most affected the S2 domain or the protein or the adjacent M3 helix. In vitro functional expression studies showed that 3 of the mutations (Y647C, R659W, and R794Q) increased the agonist potential of glutamate and glycine on the NMDA receptor, likely resulting in cytotoxicity and consistent with a gain of function. Another variant studied (N674I) had a different functional effect in expression studies, causing a reduction in glycine potency and a reduction in proton inhibition of the receptor. The patients had severe to profound developmental delay, abnormal movements, spasticity with inability to walk, intractable seizures, and cortical visual impairment. Many had microcephaly (up to -7.1 SD). Fry et al. (2018) noted that some previously reported patients with de novo GRIN1 mutations did not have brain imaging, and thus may have had polymicrogyria. The authors also postulated that the location of mutations within the gene may be associated with the development of polymicrogyria.

The heterozygous mutations in the GRIN1 gene that were identified in patients with NDHMSD by Lemke et al. (2016) occurred de novo.

In 2 unrelated patients with intellectual disability, Hamdan et al. (2011) identified de novo heterozygous mutations in the GRIN1 gene (E662K, 138249.0001 and ser560dup, 138249.0002). Functional studies in Xenopus oocytes showed that the E662K mutation resulted in a significant increase in NMDAR-induced calcium currents; excessive calcium influx through NMDAR could lead to excitotoxic neuronal cell damage. The ser560dup mutation resulted in loss of activity of the receptor, likely due to a change in the 3-dimensional structure at the receptor's channel pore entrance. The patients were part of a cohort of 95 cases of sporadic intellectual disability in whom 197 candidate genes were sequenced.

In 4 unrelated children with NDHMSD, Ohba et al. (2015) identified 4 different de novo heterozygous missense mutations at highly conserved residues in the GRIN1 gene (see, e.g., 138249.0003 and 138249.0005). The mutations were found by exome sequencing of 88 patients with early-onset epileptic encephalopathy and confirmed by Sanger sequencing. One of the patients was somatic mosaic for the mutation, with a mutant allele frequency ranging from 13.4 to 19.7% in various tissue samples. Functional studies of the variant and studies of patient cells were not performed, but structural analysis predicted that the mutations would impair NMDAR channel function.

Lemke et al. (2016) reported 14 unrelated patients with NDHMSD who carried heterozygous missense mutations in the GRIN1 gene (see, e.g., 138249.0006 and 138249.0007) and reevaluated 9 previously reported patients with a similar phenotype and similar missense mutations. Twenty-two of the 23 mutations were demonstrated to have occurred de novo; parental DNA from 1 patient was not available. The patients were ascertained from several diagnostic and research studies, and the mutations were found by next-generation sequencing methods. There were 16 different mutations identified in the 23 novel and published cases. All missense mutations clustered within or in close proximity to the transmembrane domains forming the intrinsic ion channel pore of the receptor, which shows a high level of conservation in different species. Electrophysiologic studies in Xenopus oocytes showed variable detrimental effects of the mutations on channel function when coexpressed with wildtype GRIN2B (138252). Some mutants resulted in a complete loss of channel function with no response to glutamate or glycine, whereas others resulted in partial loss of channel function with decreased affinity for glutamate and glycine compared to wildtype. Two mutations (A645S and R844C) showed no significant effects on current or agonist affinity, suggesting that they may alter receptor function through other mechanisms. Lemke et al. (2016) concluded that the disease mechanism is loss of NMDAR receptor function with a dominant-negative effect in patients with de novo heterozygous GRIN1 missense mutations, underscoring the importance of receptor subunits in neurodevelopment.

In 2 unrelated patients with NDHMSD, Chen et al. (2017) identified 2 different de novo heterozygous mutations in the GRIN1 gene, both of which resulted in the same G620R substitution (138249.0011 and 138249.0012). In vitro functional expression assays showed that the G620R mutation caused a significant decrease in the potency of glutamate and glycine and a decrease in current amplitude when coexpressed with both GRIN2A (138253) and GRIN2B (138252). G620R/GRIN2A complexes showed a mild reduction in trafficking of NMDAR to the cell surface, a strong decrease in sensitivity to magnesium inhibition, and enhanced sensitivity to zinc. G620R/GRIN2B complexes showed significantly reduced delivery of NMDAR protein to the cell surface and altered electrophysiology in response to extracellular modulators. Chen et al. (2017) concluded that the neurodevelopmental deficits resulted from complex effects on channel function, with a combination of decreased presence of G620R/GRIN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of G620R-containing NMDARs after birth.