Novel Mutation of DARS2 Gene Leading to a Rapidly Progressive Early onset Leukoencephalopathy

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare autosomal recessive neurological disorder due to mutations in the DARS2 gene. The typical presentation is juvenile onset, with gradually progressive spasticity and ataxia. We describe a unique case of infantile-onset LBSL presenting with profound hypotonia and a rapidly progressive course. An extensive metabolic and initial genetic workup was unrevealing.A repeat brain MRI showed progressive confluent white matter T2 hyper-intensity within the brain and spinal cord. Re-analysis of the WES revealed compound heterozygous mutations in the DARS2 gene in trans. The first mutation (c.788G>A, p.Arg263Gln) has been previously reported as pathogenic. The second mutation (c.259G>A, p.Asp87Asn) is a novel mutation in the exon 3and reported likely pathogenic.

Our patient further expands the genotypic and phenotypic spectrum of LBSL. Additionally, this case emphasizes the significance of re-evaluation of WES if there are new clinical findings.

Keywords: Leukodystrophy, DARS2, hypotonia, lactate elevation, LBSL.