An Evaluation of LBSL Mutations and their Effect on Patient Outcomes

Shannon Connelly

Mentor: Drs. Bela Turk and Amena Fine, Kennedy Krieger Institute.

Date/Time: December 10th, 2024 at 12:00pm.

Abstract: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare genetic disorder that is caused by multiple variants on the DARS2 gene. This causes different phenotypic outlooks for the patients and causes various severities of their symptoms. The objective of this study was to be able to predict these phenotypic outlooks of the patients by their specific DARS2 mutations. By doing this, patients will be able to better understand their disease outlook and providers can better specialize their treatment plan. We used published LBSL mutation data and their corresponding phenotypic data to organize the mutations into categories for data analysis. Statistical analysis correlating age of onset to mutation type (intronic/intronic, missense/intronic, missense/missense, nonsense/intronic, nonsense/missense) showed a statistically significant difference between at least one of the mutation groups, specifically missense/missense vs. intronic/intronic and missense/intronic and nonsense/missense vs. missense/intronic. An analysis looking at the domain structures in which the mutations were affected also showed a statistically significant difference in the age of onset between groups with the catalytic domain mutations showing a lower average than the AC binding domains and the combination of catalytic/AC binding domain mutations. These findings may indicate a more severe outlook for LBSL patients who have two catalytic, two missense, or a nonsense and a missense mutation.