Recognizing the Evolution of Clinical Syndrome Spectrum Progression in Individuals with Single Large-Scale mitochondrial DNA deletion syndromes (SLSMDS)

Introduction Single large-scale mtDNA deletions (SLSMD) result in Single Large Scale Deletion Syndromes (SLSMDS). SLSMDS presentations have classically been recognized to encompass at least three distinct clinical phenotypes, Pearson Syndrome (PS), Kearns-Sayre Syndrome (KSS), and Chronic Progressive Ophthalmoplegia (CPEO). Methods Facilitated review of electronic medical records, manual charts, and REDCap research databases was performed to complete a retrospective natural history study of 32 SLSMDS participants in a single health system seen between 2002 and 2020. Characteristics evaluated included genetic and clinical laboratory test values, growth parameters, signs and symptoms, demographics, and patient reported outcome measures of fatigue, quality of life, and overall function. Results Detailed cohort characterization highlighted that a recurrent deleted region involving MT-ND5 occurs in 96% of SLSMD subjects regardless of clinical phenotype, which tended to evolve over time. Higher blood heteroplasmy correlated with earlier age of onset. GDF-15 was elevated in all SLSMD subjects. A PS history yielded negative survival prognosis. Furthermore, increased fatigue and decreased quality of life were reported in SLSMD subjects with advancing age. Conclusion Retrospective natural history study of SLSMDS subjects demonstrated the evolution of classically considered PS, KSS, and CPEO clinical presentations within affected individuals, which may inform future clinical trial development.