CHOP Researchers Discover New, Aggressive Form of Mitochondrial Disease

The findings reveal new clues about the disease’s underlying biology

Published on in CHOP News

Marni FalkResearchers in the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia (CHOP) recently reported on a newly discovered, particularly severe and progressive mitochondrial disease that has helped them better understand some of the underlying biology of these conditions, while also having the potential to better inform future treatment decisions.

Mitochondrial disease may be caused by genetic mutations in either the body’s nuclear DNA, which is found in the nucleus of our cells, or by genetic mutations or deletions in our mitochondrial DNA (mtDNA), a separate chromosome found specifically in the mitochondria. While mtDNA common mutation disorders recur across families and ethnic groups, single large-scale mtDNA deletions of thousands of base pairs have long been thought to occur sporadically when the affected individual was only an egg or embryo.  This scenario would make it very unlikely that these deletions would be inherited by an affected individual’s siblings, and only possible to pass down the disease to the future children of an affected woman since such mtDNA deletions have long been thought to be maternally-inherited.

However, this long-standing assumption proved not to be the case for a 14-year-old Chinese boy with a form of mitochondrial disease that resulted in a broad spectrum of severe symptoms, including hearing loss, vision loss due to both optic atrophy and retinal degeneration in a condition known as Kearns-Sayre syndrome, growth failure, heart arrhythmia, and Leigh syndrome that manifests with complex neurological problems from severe metabolic strokes. In a case study published in the journal PLoS ONE, the single mtDNA deletion did not occur sporadically but instead resulted from a nuclear gene disorder caused by a mutation in SSBP1, a “housekeeping” gene that helps regulate mtDNA replication and keeps it stabilized as the mtDNA genome is being copied. 

Working together with Dr. William Copeland at the National Institutes of Environmental Health Sciences, the research team showed that this SSBP1 gene mutation causes the single, large-scale mtDNA deletion to recur over time. This genetic diagnosis increased the risk of mtDNA deletion recurrence in family members from about 4% to approximately 50% for individuals who carry the SSBP1 pathogenic variant.  Recognizing that a single large-scale mtDNA deletion may be caused by a nuclear gene disorder for some individuals also changes the likelihood they will respond to specific therapeutic approaches being developed - they may not respond to therapies that target or replace the mtDNA deletion itself but rather require the nuclear gene change to be targeted.

Marni Falk, MD, an attending physician and Executive Director of the Mitochondrial Medicine Frontier Program and senior author of the study, explained that some newer therapies being developed for this type of mitochondrial disease work by reducing mtDNA deletion levels by methods such as mitochondrial replacement technology or stem cell therapies. However, recognizing that there is a nuclear gene cause that would continually generate mtDNA deletions in this case, means those methods would not be expected to work, and developing other methods that act directly upon the SSBP1 mutation would be required.

“Using a series of very sophisticated genomic and functional validation methods, we have demonstrated that it is possible for a nuclear gene disorder to severely disrupt mitochondrial DNA replication and cause single large-scale mtDNA deletions,” Falk said. “The complex clinical manifestations of this child’s mitochondrial disease ran a spectrum of severe symptoms in many organ systems, and holds important implications for advising parents about their family’s recurrence risk and available reproductive options to assist them in the decision to have future children, so the serious nature of accurately diagnosing the cause for this disorder cannot be overstated.”

Gustafson et al. Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes. PLoS One. 2019; 14(9): e0221829. DOI: 10.1371/journal.pone.0221829.

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