Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation

Clinical characteristics Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction (decreased position and vibration sense) in most individuals. The neurologic dysfunction involves the legs more than the arms. The tendon reflexes are retained. Deterioration of motor skills usually starts in childhood or adolescence, but occasionally not until adulthood. Dysarthria develops over time. Occasional findings include epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. Individuals with neonatal or early-infantile onset have a severe disease course often associated with early death. Those with childhood onset have slow progression with wheelchair dependence in the teens or twenties. Adult onset is associated with slow progression and mild impairment. Diagnosis/testing The clinical diagnosis of LBSL can be established in a proband with characteristic abnormalities observed on brain and spinal cord MRI using MRI-based criteria. The molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic variants in DARS2 identified by molecular genetic testing. If molecular results are inconclusive, a functional assay to identify reduced MtAspRS enzyme activity in lymphoblasts can confirm the diagnosis. Management Treatment of manifestations: Supportive therapy includes: physical therapy and rehabilitation to improve motor function and prevent contractures and scoliosis; and antiepileptic drugs, speech therapy, special education, and social work support as needed. Surveillance: Assess for new neurologic manifestations at each visit; monitor those with seizures as needed; consider brain MRI every few years to monitor progression; monitor developmental progress and educational needs at each visit throughout childhood; assess for family support needs at each visit. Genetic counseling LBSL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DARS2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the DARS2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.