P451: Mitochondrial diseases represent 3% of all diagnosis in the Undiagnosed Diseases Program

Introduction: The NIH-Undiagnosed Diseases program (UDP) has completed prospective clinical evaluations on nearly 1400 participants since 2009, and a review of diagnosis identified over that time revealed 3% of our confirmed diagnosis are due to mitochondrial diagnosis.Mitochondrial diseases can be caused by variants in both nuclear (nDNA) and mitochondrial DNA (mtDNA) and can be inherited or sporadic.They are often diagnosed in children with severe multi-system presentations that are progressive and often have poor outcomes.In the UDP population we have identified late-onset presentations sometimes without symptoms until the 5th or 6th decade.The mitochondrial diagnosis found in the UDP have ranged from recognized mitochondrial DNA syndromes such as Kearns-Sayer syndrome to muscle-related mitochondrial depletion syndromes.Methods: Participants enrolled in the UDP protocol undergo extensive retrospective chart reviews, prospective multidisciplinary evaluations, diagnostic tests, and a wide-range of genetic strategies targeted to their phenotype and other objective findings.We can also perform detailed muscle biopsies for supercomplex assembly, respiratory chain enzymology, mtDNA and qPCR for mtDNA copy number, and immunohistochemical and pathology examinations.The UDP participants diagnosed with mitochondrial diseases have been diagnosed up to 70-years of age.Over time we have developed a systematic approach to evaluating patients with suspected mitochondrial diseases and in some cases, we have applied those clinical tests agnostically for patients with unexplained complex phenotypes.Once we identified 3% of our diagnosed population had mitochondrial disease, we looked deeper into why those participants had not been diagnosed before their UDP evaluations.Results: UDP participants diagnosed with mitochondrial diseases were found to have mostly late-onset, unusual presentations, in several cases, participates had pathogenic mtDNA and nDNA variants contributing to rare presentations.In other cases, participants received care from multiple subspecialists for isolated symptom management, and all the symptoms were not considered related until their UDP admissions. Conclusion:The UDP research provides the opportunity to complete comprehensive records reviews coupled with multidisciplinary evaluations and post admission efforts that can lead to making mitochondrial disease diagnosis for participants with atypical presentations.This leads to referrals to mitochondrial clinical specialists, mitochondrial-specific treatment research, and family support groups.