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).

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.

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.

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. Competing Interest Statement RG is a consultant for Minovia Therapeutics and Nurture Genomics. MJF is engaged with several companies involved in mitochondrial disease therapeutic preclinical and/or clinical-stage development. MJF is co-founder and Chief Scientific Advisor of Rarefy Therapeutics LLC; an advisory board member with equity interest in RiboNova Inc.; a scientific advisory board member and paid consultant with Khondrion, and Larimar Therapeutics; has served as a paid consultant for Astellas (formerly MitoBridge), Casma Therapeutics, Cyclerion Therapeutics, Imel Therapeutics, Mayflower, Inc., Minovia Therapeutics, Mission Therapeutics, Myto Therapeutics, NeuroVive Pharmaceutical AB, Precision Biosciences, Primera Therapeutics, Inc., Reneo Therapeutics, Stealth BioTherapeutics, and Vincere Bio; and/or a sponsored research collaborator for Adjuvia Therapeutics, Astellas, Cyclerion Therapeutics, Epirium Bio, Imel Therapeutics, Khondrion, Merck, Minovia Therapeutics, Mission Therapeutics, NeuroVive Pharmaceutical AB, PTC Therapeutics, Reneo Therapeutics, RiboNova, Saol Therapeutics, Standigm, and Stealth BioTherapeutics. MJF also has received royalties from Elsevier and speaker fees from Agios Pharmaceuticals and GenoMind. AG is a paid consultant for Reneo Therapeutics, Cyclerion/Tisento Therapeutics, and UCB Therapeutics. None of the other authors have relevant conflicts of interest to declare. Funding Statement This work was supported in part by an investigator-initiated sponsored research award from Minovia Therapeutics (Falk PI) and from the Childrens Hospital of Philadelphia Mitochondrial Medicine Frontier Program. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All human participants research was performed per Childrens Hospital of Philadelphia (CHOP) Institutional Review Board approved study #08-6177 (Falk PI). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present work are contained in the manuscript