A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with or without seizures and gait abnormalities (NEDSGA) is caused by heterozygous mutation in the GRIA4 gene (138246) on chromosome 11q22.

Neurodevelopmental disorder with or without seizures and gait abnormalities (NEDSGA) is an autosomal dominant disorder characterized by global developmental delay apparent from infancy or early childhood, resulting in variably impaired intellectual development that can range from profound with absent speech to mild with an ability to attend special schools. Most affected individuals show irritability, stiffness, and hypertonia early in life, which progresses to spasticity and impaired gait later. Some patients may develop seizures of variable severity early in life (summary by Martin et al., 2017).

Martin et al. (2017) reported 5 unrelated patients, ranging in age from 4 to 21 years, with a neurodevelopmental disorder apparent from early infancy or childhood. Three patients showed irritability, stiffness, hypertonia, and/or increased startle reflex in the neonatal period. The patients had mild to severe developmental delay with intellectual disability and poor or absent speech. The most severely affected patient (patient 2) was a 21-year-old man who developed intractable seizures at age 5 weeks and had spastic quadriplegia with inability to walk, absent speech, inability to follow commands, nystagmus, strabismus, contractures, choreiform movements, short stature, and microcephaly. He also had brain abnormalities on imaging, including cortical atrophy and thin corpus callosum. The 4 other patients were less severely affected and could walk, although most had a clumsy or stiff gait. Two of these 4 patients had spasticity, including 1 with disabling hyperekplexia, and a third had hypotonia in the neonatal period. Three of these 4 patients had seizures of variable severity, including 1 with status epilepticus. The least severely affected child (patient 5) had normal motor development and no seizures; she could attend special school at age 4, although she was intellectually disabled. Dysmorphic features were mild or absent among the patients, with the only common feature being large ears. More variable additional features included sleeping problems, feeding difficulties, optic nerve hypoplasia, and stereotypic hand movements.

The heterozygous mutations in the GRIA4 gene that were identified in patients with NEDSGA by Martin et al. (2017) occurred de novo.

In 5 unrelated patients with NEDSGA, Martin et al. (2017) identified 5 different de novo heterozygous missense mutations in the GRIA4 gene (138246.0001-138246.0005). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Four of the mutations occurred in the highly conserved SYTANLAAF motif, which plays an important role in channel activation and gating. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling suggested that the location of 3 of the variants in the SYTANLAAF motif oriented toward the center of the pore region would most likely lead to disturbance of the gating mechanism allowing leakage or an open state, whereas the fourth variant in that motif likely results in reduced channel permeability. The fifth variant (R697P; 138246.0005), in the extracellular domain, was predicted to interfere with the binding between monomers. The least affected child (patient 5) carried the R697P variant, suggesting some degree of genotype/phenotype correlation. The mutations were predicted to have a dominant functional effect rather than to cause a loss of function.