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

Homozygous mutation in the GRIN1 can also cause developmental and epileptic encephalopathy-101 (DEE101; 619814), and heterozygous mutation in the GRIN1 gene can cause autosomal dominant neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSD; 614254).

NDHMSR is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development, severely impaired intellectual development, and involuntary movements, including stereotypic movements, spasticity, and dystonia. Affected individuals are usually unable to walk independently and have poor or absent speech. Some patients may have seizures (summary by Lemke et al., 2016).

Lemke et al. (2016) reported 2 brothers, born of consanguineous parents (family 1), with severe developmental delay, impaired intellectual development with absent speech, and autistic features. They also had hypotonia, spasticity, involuntary movements such as dystonia and restless movements, and self-injurious behavior. Neither patient had clinical seizures, but both showed abnormal EEG with spikes or spike-wave discharges during sleep in infancy. At age 11, 1 the EEG of 1 patient showed left temporal spikes. Brain imaging was normal.

Rossi et al. (2017) reported 2 sibs, born of consanguineous Moroccan parents, with neurodevelopmental delay and hyperkinetic movements without seizures. The patients presented in the first months of life with hypotonia, severe developmental delay, and involuntary stereotypic movements. One achieved standing with support at age 3.5 years, and the other was able to sit with support, but not stand, at age 3 years. One patient had poor eye contact, and in the other eye contact was present. Neither patient could speak. Neither patient had seizures; EEG was normal in 1 and not performed in the other. Dysmorphic features included frontal bossing and mild midface hypoplasia; one child had strabismus. Brain imaging in one patient showed mild cerebral atrophy and thin corpus callosum; brain imaging in the other patient was normal.

The transmission pattern of NDHMSR in the families reported by Lemke et al. (2016) was consistent with autosomal recessive inheritance.

In 2 sibs, born of consanguineous parents (family 1), with NDHMSR, Lemke et al. (2016) identified a homozygous missense mutation in the GRIN1 gene (R217W; 138249.0008). The mutation, which was found by next-generation sequencing approaches, segregated with the disorder in the family. In vitro functional expression studies showed that the R217W mutation did not affect channel current, but resulted in a significant increase in zinc inhibition when coexpressed with wildtype GRIN2A (138253). The carrier parents were unaffected, suggesting that haploinsufficiency for GRIN1 can be tolerated and is not pathogenic.

In 2 sibs, born of consanguineous Moroccan parents, with NDHMSR, Rossi et al. (2017) identified a homozygous missense mutation in the GRIN1 gene (D227H; 138249.0010). The mutation, which was found by massive parallel sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but Rossi et al. (2017) hypothesized that missense variants in the amino-terminal domain of the protein may be hypomorphic and pathogenic in the homozygous state, whereas the functionality of 1 allele, as observed in the parents, is sufficient to avoid clinical expression in heterozygous carriers.

Four sibs from 2 unrelated consanguineous families (Lemke et al., 2016; Rossi et al., 2017) with NDHMSR carried homozygous missense mutations in the GRIN1 gene (R217W, 138249.0008 and D227H, 138249.0010). Both mutations occurred in the amino terminus of the protein. In both families, the heterozygous parents were unaffected. Lemke et al. (2016) and Rossi et al. (2017) postulated that homozygosity for a mutation that results in a hypomorphic or complete loss-of-function allele results in clinical manifestations, whereas possession of 1 functional allele is sufficient to avoid clinical manifestations. This is in contrast to patients with heterozygous missense mutations in the GRIN1 gene that have a dominant-negative effect (614254).