NARS1-Related Neurologic Disorders

Excerpt

Clinical characteristics: NARS1-related neurologic disorders encompass NARS1-related neurodevelopmental disorder (NARS1-NDD), a neonatal- or childhood-onset phenotype with central nervous system and peripheral nervous system involvement, and NARS1-related hereditary neuropathy, an adolescent- or early adult-onset hereditary neuropathy.

NARS1-NDD manifests with global developmental delay, intellectual disability, microcephaly, ataxia, seizures, and, rarely, neurobehavioral/psychiatric manifestations. Change in muscle tone can manifest either as spasticity or as hypotonia. Peripheral neuropathy with atrophy predominantly of the distal lower limbs can be associated.

NARS1-related hereditary neuropathy manifests with mostly motor and sensory impairment involving weakness of predominantly the distal lower limbs and foot deformities, without prominent muscle atrophy. A few individuals have been described with isolated hereditary motor neuropathy associated with foot deformities, ankle contractures, kyphosis, hyperlaxity, and brisk reflexes.

To date, 54 individuals from 30 families with NARS1 pathogenic variant(s) have been reported.

Diagnosis/testing: The diagnosis of a NARS1-related neurologic disorder is established in a proband with suggestive findings and either biallelic or heterozygous NARS1 pathogenic variants in those with NARS1-NDD or a NARS1 heterozygous pathogenic variant in those with NARS1-related hereditary neuropathy identified by molecular genetic testing.

Management: Treatment of manifestations: Individuals with NARS1-NDD: multidisciplinary care by specialists in relevant fields including developmental pediatrics, speech and language therapy, neurology to manage seizures, physical therapy, orthopedics to manage scoliosis/kyphoscoliosis, nutrition/feeding, psychology to manage behavioral abnormalities, and medical genetics / genetic counseling. Individuals with NARS1-related hereditary neuropathy: follow standard practice for peripheral neuropathy.

Surveillance: Individuals with NARS1-NDD: monitoring at each visit or per the treating specialist.

Genetic counseling: NARS1-NDD can be inherited in an autosomal recessive or autosomal dominant manner. NARS1-related hereditary neuropathy is inherited in an autosomal dominant manner.

Autosomal recessive inheritance: If both parents are known to be heterozygous for a NARS1 pathogenic variant, each sib of an individual with autosomal recessive NARS1-NDD has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs of a proband with autosomal recessive NARS1-NDD are asymptomatic and are not at risk of developing a NARS1-related neurologic disorder. Carrier testing for at-risk relatives requires prior identification of the NARS1 pathogenic variants in the family.

Autosomal dominant inheritance: The proportion of individuals with an autosomal dominant NARS1-related neurologic disorder who have the disorder as the result of a de novo pathogenic variant varies by phenotype. All probands reported to date with autosomal dominant NARS1-NDD (whose parents have undergone molecular genetic testing) have the disorder as the result of a de novo NARS1 pathogenic variant. Some individuals with NARS1-related hereditary neuropathy have the disorder as the result of a de novo NARS1 pathogenic variant. Each child of an individual with an autosomal dominant NARS1-related neurologic disorder has a 50% chance of inheriting the pathogenic variant.

Once the NARS1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.