This website provides information on patients with mutations in the NARS1 gene, including clinical data, molecular data, management and research options.

The syndrome caused by mutations in the NARS1 gene is a multisystem neurodevelopmental disorder characterized by microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia.

In our genetic studies, we found all individuals to present with global developmental delay (GDD) and intellectual disability, which varied in severity from moderate to profound. They had marked delays in language development. Motor development was also severely impaired, and one individual never acquired autonomous ambulation. Microcephaly was observed in the majority of cases (90%). These cases predominantly presented with primary microcephaly; however, secondary microcephaly was also noted.

Epilepsy was highly associated with the phenotype, affecting 23 cases (74.2%), with six individuals experiencing seizures below the age of one. The semiology of these attacks varied, with a mixture of partial, myoclonic, and generalized tonic-clonic seizures described. An ataxic gait, poor balance, and dysarthria were frequently detected on examination; this suggests an additional neurodegenerative process; however, no structural abnormality of the cerebellum was observed on imaging. A demyelinating peripheral neuropathy occurred in eight individuals (25%) who had distal leg muscle atrophy.

Dysmorphic features described included abnormal hands (e.g., clinodactyly, fetal finger pad, two-to-three-toe syndactyly, slender fingers) and/or feet (e.g., small feet, toe syndactyly, slender feet). Upslanting palpebral fissures was the most common facial dysmorphism reported. A broad forehead, wide mouth, wide-set teeth, and low-set ears with overfolded helices were also described. Skeletal abnormalities including scoliosis, pronounced thoracic kyphosis, and pes cavus were also noted. Behavioural traits associated with the phenotype included impulsivity, stereotypies with repetitive speech and/or hand movements, and selective feeding rituals.

Not all individuals with a mutation in the NARS1 gene have these features.

This website was created to share and collect information about clinic, management and research projects to gather more knowledge and provide better treatment of patients with mutations in the NARS1 gene.

Stephanie Efthymiou, PhD, Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, : London, UK, s.efthymiou@ucl.ac.uk

Henry Houlden, MD, PhD, Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK, h.houlden@ucl.ac.uk