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

Heterozygous mutation in the NARS1 gene causes a similar neurodevelopmental disorder with overlapping features (NEDMILEG; 619092).

Neurodevelopmental disorder with microcephaly, language delay, and gait abnormalities (NEDMILG) is an autosomal recessive disorder characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. More variable features include hypotonia, early-onset seizures, and a peripheral demyelinating or axonal peripheral sensorimotor neuropathy. The disease follows a neurodegenerative course in many patients; clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).

Manole et al. (2020) reported 24 patients from 13 unrelated families (families 9-21) with a neurodevelopmental disorder associated with biallelic mutations in the NARS1 gene. The patients were ascertained through an international collaborative network of research and diagnostic gene sequencing laboratories. Eight families were consanguineous and of various origins, including Pakistani, Indian, and Libyan. The patients, who ranged in age from 2 to 33 years, presented in infancy with global developmental delay, delayed walking, moderately to severely impaired intellectual development, and poor or absent language development. They had a small head circumference, with most having frank microcephaly (range -2.0 to -8.7 SD). More than half had onset of partial or generalized seizures in the first months or years of life. More variable features included hypotonia, reduced muscle power, broad-based or ataxic gait, spasticity, scoliosis, and clinodactyly. Five patients had a demyelinating or axonal sensorimotor peripheral neuropathy manifest as pes cavus, distal muscle weakness and atrophy, impaired sensation, and decreased or absent reflexes. Brain imaging, when performed, was often normal, although some patients had nonspecific abnormalities, including cerebral atrophy, delayed myelination, thin corpus callosum, and decreased white matter volume. Several patients or their similarly affected sibs died in childhood. Three of the families (families 9, 17, and 19) were also reported by Wang et al. (2020), who noted that the patients had a degenerative disease course. Manole et al. (2020) emphasized the involvement of both the central and peripheral nervous system in this disorder.

The transmission pattern of NEDMILG in the families reported by Wang et al. (2020) and Manole et al. (2020) was consistent with autosomal recessive inheritance.

In 24 patients from 13 unrelated families with NEDMILG, Wang et al. (2020) and Manole et al. (2020) identified homozygous or compound heterozygous mutations in the NARS1 gene (see, e.g., 108410.0001-108410.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Most of the mutations were missense, although 2 families carried a nonsense or frameshift mutation on 1 allele. Affected members of 7 consanguineous families (families 9-15) carried the same homozygous R545C mutation (108410.0004). Fibroblasts derived from 3 unrelated patients with different mutations showed variably decreased NARS1 protein levels, impaired homodimerization, reduced cytoplasmic transferase activity, and decreased global protein synthesis compared to controls. These findings suggested that the mutations resulted in a loss of function. Induced neuronal progenitor cells derived from 2 unrelated patients were used to generate cultures of 3D cortical brain organoids (CO). Mutant organoids became progressively smaller with decreased diameter compared to controls beginning around division 52, modeling the microcephaly observed in the patients. Patient CO showed reduced generation of radial glial cells with abnormal neural rosette structure, depletion of rosettes and postmitotic neurons, and decreased proliferation and viability of progenitor cells compared to wildtype. RNA-seq analysis of patient cells detected abnormalities in cell cycle control and neuronal progenitor cell fate differentiation, suggesting a role for NARS1 in these processes.