Expanding the DARS phenotype: late-adult onset myelopathy and leukoencephalopathy

Abstract

A significant proportion of adult-onset neurological disorders remain diagnostic odysseys despite extensive evaluation. Hypomyelination with Brainstem and Spinal Cord Involvement and Leg Spasticity (HBSL) is an autosomal recessive disorder caused by mutations in the cytoplasmic aspartyl-tRNA synthetase (DARS) gene involved in mRNA translation. Clinical features of patients with DARS mutations include developmental delay, leg spasticity, cerebellar dysfunction, cognitive impairment and epilepsy. Most reported cases have been infantile-onset with severe neurological disability and neuroimaging abnormalities. To our knowledge, late-or adult-onset cases have never been reported in the literature. Here, we report for the first time, with video documentation and six-year clinical follow-up, an ethnic Malay patient with onset of spasticity and ataxia in late-adulthood, carrying a pathogenic DARS mutation discovered via whole-genome sequencing. His clinical and radiological findings were consistent with HBSL, but this diagnosis was not considered as, up until now, HBSL has only been reported with childhood/adolescent-onset. This case highlights that HBSL/DARS mutations should now be considered in the differential diagnosis of adult-onset spastic paraplegia and/or leukoencephalopathy.