A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) is caused by heterozygous mutation in the NARS1 gene (108410) on chromosome 18q21.

Biallelic mutation in the NARS1 gene causes a similar neurodevelopmental disorder with overlapping features (NEDMILG; 619091).

Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) is characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, including ataxia and spasticity, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. Dysmorphic facial features may also be observed. Most patients have early-onset seizures; some may develop a demyelinating peripheral neuropathy. The clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).

Manole et al. (2020) reported 6 unrelated patients (patients 1-6) with a similar neurodevelopmental disorder associated with the same de novo heterozygous nonsense mutation in the NARS1 gene (R534X; 108410.0006). The patients, who ranged in age from 6 to 22 years, were ascertained through an international collaborative network of research and diagnostic gene sequencing laboratories. They presented in infancy with global developmental delay, mildly delayed walking, usually with an ataxic or broad-based gait, severe to profound impaired intellectual development, and dramatic speech and language impairment associated with a nasal pitch. Some showed stereotypic behavior. Most patients had progressive microcephaly (-2.2 to -5.5 SD), but brain imaging tended to be normal. All but 1 developed early-onset generalized tonic-clonic or myoclonic seizures. Three patients had a demyelinating peripheral neuropathy associated with distal muscle weakness, foot drop, pes cavus, and hyporeflexia, whereas others demonstrated spasticity with hypertonia and hyperreflexia. Less common features included tremor and dysarthria without evidence of cerebellar atrophy, scoliosis, kyphosis, and pectus abnormalities. There were variable dysmorphic features, such as sloping forehead, broad jaw, retrognathia, midface hypoplasia, upslanting palpebral fissures, low-set or dysmorphic ears, hypertelorism, short or long philtrum, upturned nose, wide mouth with thin upper lip and everted lower lip, wide-spaced teeth, long slender fingers, clinodactyly, and syndactyly.

The heterozygous mutations in the NARS1 gene that were identified in patients with NEDMILEG by Manole et al. (2020) occurred de novo.

In 6 unrelated patients (patient 1-6) with NEDMILEG, Manole et al. (2020) identified a de novo heterozygous nonsense mutation in the NARS1 gene (R534X; 108410.0006). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Cells derived from 1 patient showed a dramatic decrease in enzyme activity compared to wildtype. Expression of this mutation in zebrafish caused cyclopia and gastrulation defects. The authors postulated a toxic gain-of-function dominant-negative effect on NARS1 function. Two additional patients (patients 7 and 8) with a similar disorder but without microcephaly carried de novo heterozygous missense variants in the NARS1 gene (G509S and R322L) that were not present in the gnomAD database. Functional studies of these variants were not performed.