Reporting a novel mutation in the DARS2 gene in two siblings with Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). 

LBSL is a rare autosomal recessive hereditary disease, characterized by slowly progressive pyramidal and cerebellar dysfunction, often with concomitant dorsal column dysfunction. Here we report two siblings with LBSL and a novel c.1192-2A>G mutation in the DARS2 gene.

Two siblings, a 49-year-old male and 42-year-old female carried a diagnosis of Charcot Marie Tooth disease (CMT), syringomyelia, motor neuropathy and leukodystrophy of unknown cause. During the early childhood, they both developed bilateral foot drop. Their symptoms slowly progressed and were wheelchair bound at 18 years of age.  Neurological examination was significant for areflexia in the lower limbs more than the upper limbs. Distal lower extremity muscles atrophy along with contractures of the fingers and foot are noted. There was also decreased pinprick, proprioception sensation in a grading fashion bilaterally in the legs along with absent vibration sensation below the knees. Because their clinical presentation was atypical for CMT, an MRI was obtained which showed bilateral symmetrical T2 hyperintensities involving the supratentorial white matter predominantly in the periventricular region, cerebellar peduncles, and brain stem. In addition, there was confluent diffuse restriction abnormalities in the cervical and thoracic spinal cord involving the dorsal columns, and the lateral corticospinal tracts. All these imaging findings were characteristic of LBSL. Genetic analysis identified two heterozygous variants in DARS2: c.228-15C>A and a novel variant c.1192-2A>G that is predicted to be pathogenic in both the patients.