East Montgomery Times

Researchers at the Children's Hospital of Philadelphia (CHOP) have made significant progress in understanding mitochondrial DNA deletion diseases. These findings, published in Genetics in Medicine, shed light on genetic causes, symptoms, and disease progression, potentially guiding future clinical trials.

Mitochondrial diseases are disorders affecting mitochondria, essential energy-producing components in cells. Specific forms such as Pearson syndrome, Kearns-Sayre syndrome (KSS), and chronic progressive external ophthalmoplegia (CPEO) result from single large-scale mitochondrial DNA deletions (SLSMD). Despite similar genetic causes, these syndromes manifest differently: Pearson syndrome is often identified in infancy due to growth issues and anemia; KSS appears with multi-system symptoms during childhood; CPEO typically affects adults with eye muscle problems.

Understanding these rare diseases is challenging due to limited diagnoses and early mortality. CHOP researchers analyzed data from 30 cases between 2002 and 2020 using modern electronic medical record techniques for a retrospective natural history study.

Dr. Rebecca Ganetzky stated, “Although these are the three named syndromic phenotypes in the spectrum SLSMD syndromes, the spectrum is actually broader and includes patients whose symptoms do not meet any of their strict diagnostic criteria.” This study aims to broaden patient enrollment for future trials by accurately informing the clinical presentation spectrum of SLSMD disorders.

The research identified shared molecular details among patients. A recurrent deletion within gene MT-ND5 was found in 96% of cases regardless of phenotype evolution over time. Additionally, elevated levels of biomarker peptide growth differentiation factor 15 (GDF-15) were noted across all patients. Higher blood levels of SLSMD heteroplasmy correlated with earlier disease onset while older age linked to increased fatigue and reduced quality of life.

Dr. Marni Falk highlighted the efficiency of analyzing historical clinical data: “Even though some of the earliest data used in this study were collected more than two decades ago, this study demonstrates how we can effectively analyze clinical data to retrospectively inform the natural history for rare diseases in a fraction of the time.” She emphasized that such cohort studies aid rapid responses to challenges faced by patients amid evolving drug and genetic therapies.

This research received support from Minovia Therapeutics and CHOP's Mitochondrial Medicine Frontier Program.

Ganetzky et al., "Recognizing the Evolution of Clinical Syndrome Spectrum Progression in Individuals with Single Large-Scale mitochondrial DNA deletion syndromes (SLSMDS)." Genet Med. Online February 18, 2025. DOI: 10.1016/j.gim.2025.101386.