LBSL (leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation) is a rare genetic disorder characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction (decreased position and vibration sense) in most patients. Manual dexterity becomes impaired to a variable degree. Associated problems include dysarthria, mild cognitive decline and learning problems, and epilepsy. LBSL is diagnosed by identification of biallelic pathogenic variants in DARS2, encoding mitochondrial aspartyl tRNA synthetase and characteristic abnormalities observed on the brain and spinal cord MRI. Most of the literature consists of case reports and case series and there are only limited data that provide details on genotype-phenotype correlations. There is very little quantitative or semi-quantitative information about neurocognitive and neuromotor impairment in LBSL. There are currently no targeted therapies or guidelines about supportive therapies for LBSL.
In this study, we will conduct retrospective chart and imaging reviews and prospective longitudinal virtual assessments of individuals with LBSL.
We hypothesize that 1) there will be a broad phenotypic spectrum of neuromotor and neurocognitive deficits in LBSL patients; 2) most impairment will likely be related to gait; 3) there will be a threshold of impairment in gait that is associated with poorer quality of life for these patients; 4) and that even in patients with apparently mild disease there will be neurocognitive deficits related to cortical and cerebellar white matter abnormalities.
Answering these hypotheses will form the basis of a better understanding of the natural history of LBSL. It will help further characterize the expected level of impairment based on a patient's genotype. This will be particularly helpful for providing anticipatory guidance for newly diagnosed infants and children with LBSL. The information will also help identify priorities for existing supportive therapies and help clarify the common or clinically meaningful symptoms that should be targeted for new treatments.
