Recognizing the evolution of clinical syndrome spectrum progression in individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDS))

(Press-News.org) Philadelphia, February 20, 2025 – Researchers from the Mitochondrial Medicine Program at Children’s Hospital of Philadelphia (CHOP) have better characterized a spectrum of what were classically considered discrete mitochondrial DNA deletion disease syndromes. The findings offer new insights into genetic causes, potential symptoms, and disease progression, and may inform future clinical trial development. The findings were published today in the journal Genetics in Medicine.

Mitochondrial disease refers to a group of disorders that affect the mitochondria, which are tiny compartments present in almost every cell of the body that generate most of our energy. Certain forms of mitochondrial disease – Pearson syndrome, Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) – are each caused by single large-scale mitochondrial DNA (mtDNA) deletions (SLSMD), which involve the loss of a large segment within the small DNA genome that is found exclusively in the mitochondria.

While the genetic cause of these SLSMD syndromes is similar, the affected tissues and clinical presentations can vary wildly. Pearson syndrome is typically diagnosed in infancy due to growth failure and anemia; KSS might develop as progressive multi-system symptoms during mid-childhood; and CPEO typically presents in adults with eye muscle movement problems. Understanding the natural history study of these rare diseases is particularly challenging because so few patients are diagnosed in any stage and some cases can lead to early death.

To better understand SLSMD’s molecular and clinical scope, researchers compiling information and data from 30 known cases seen at CHOP between 2002 and 2020 was performed using modern techniques for analyzing electronic medical records to more quickly and nimbly conduct a retrospective natural history study.

“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,” said first study author Rebecca Ganetzky, M.D., an attending physician in Mitochondrial Medicine and the Director of Mitochondrial Biochemical Diagnostic Test Development at CHOP. “This retrospective natural history study was designed more accurately inform the spectrum of clinical presentation for SLSMD disorders. This will enable future clinical trials to enroll a greater range of patients and evaluate a wider range of clinical endpoints that effectively describe symptom and quality of life effects in meaningful ways to patients across the disease spectrum.”

Many of these patients share certain molecular details. For example, this study found that a recurrent deleted region within the gene MT-ND5 occurred in 96% of SLSMD patients, regardless of their eventual clinical phenotype, which tended to evolve from one category to the next in certain patients over time. Additionally, the biomarker peptide growth differentiation factor 15 (GDF-15) was highly elevated in all SLSMD patients in this study, regardless of clinical features. Higher levels in blood of SLSMD heteroplasmy– a phenomenon unique to mtDNA reflecting the presence of both normal and deleted genomes in a patient – correlated with earlier age of disease onset. As a patient’s age increased, greater fatigue and lower quality of life were reported.

“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, a technique we believe could be readily used for a variety of other rare diseases,” said senior study author Marni Falk, M.D., an attending physician and Executive Director of the Mitochondrial Medicine Program at CHOP. “The field of new drug and genetic therapies is evolving at a rapid pace, and cohort studies like this help us better define many features of rare diseases to be able to more nimbly respond to the challenges faced by these patients.”

This study was supported in part by an investigator-initiated sponsored research award from Minovia Therapeutics and from the Children’s Hospital of Philadelphia 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.

About Children’s Hospital of Philadelphia:  

A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu. 

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