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Advances towards personalized medicine in mitochondrial diseases thanks to the analysis of new gene variants
published on 17/07/2024
A CABD study, led by UPO professor Carlos Santos Ocaña, identifies new genetic variants of the COQ7 gene and their relationship with Coenzyme Q10 deficiency in pediatric patients.
The research identifies genetic clues that can improve diagnosis and treatment of mitochondrial diseases.
Mitochondrial diseases, which primarily affect energy production in cells, are a diverse group of rare, infrequent diseases that can cause a wide range of symptoms and affect various organs of the body. It is estimated that there are about 300 different mitochondrial diseases, each with its own particularities.
Due to their complexity and the variability of their symptoms, they pose a great challenge for the medical and scientific community as well as for patients and their families, so their research is crucial to advance their knowledge and develop better diagnostics and treatments.
In this line, a research group from the CABD led by Carlos Santos Ocaña, Professor of Cell Biology at the Pablo de Olavide University, is coordinating a study that opens the way to identifying markers for the diagnosis, severity and prognosis of the disease, also enabling some personalization in applied therapies.
Coenzyme Q10 deficiency, heterogeneous symptoms and different severity levels
The work led by the CABD scientific team closes the clinical and molecular diagnosis of three pediatric patients showing a mitochondrial disease: in all three cases the pathology is caused by the presence of pathological variants of the COQ7 gene, which encodes a protein involved in the synthesis of Coenzyme Q10. This molecule is essential for the proper functioning of cells and overall health; its role in energy production, antioxidant protection, and support for cardiovascular and muscular health makes it crucial for human well-being.
In addition to closing the diagnosis with functional tests, the research team conducted additional studies to try to explain the heterogeneity of the symptoms shown by the patients, despite sharing variants of the same gene and despite showing a common CoQ10 deficiency.
As the researcher Carlos Santos explains “we have definitively diagnosed three patients showing a mitochondrial disease with Coenzyme Q10 deficiency caused by different variants (mutations) of the COQ7 gene. Although the three patients share this deficiency, their symptoms are actually very heterogeneous, as is the severity of the disease, ranging from a very severe case with early death of the patient to a much milder case that improved with treatment with CoQ10”.
The research demonstrates how variants in the COQ7 gene produce structural changes in the COQ7 protein, changes that in turn alter the function of this protein. This may be obvious, but more importantly, depending on where the structural change occurs, the effects of the alteration can be very different. “Imagine a termite attack on a wooden building. Even if the attack is of the same magnitude, if it affects the foundations, the building may collapse, whereas if the attic railing is affected, the solution is simply to change the railing,” explains the CABD researcher.
The study has thus demonstrated that the structural changes generated by each variant identified in patients alter the function of the COQ7 protein in a specific way, and that the combination of these variants, which is determined by the patient's genetic context, explains not only the severity of the disease but also the highly variable effect of the therapy available for the treatment of CoQ10 deficiency.
Graphical abstract that summarizes the most relevant information from this study
New genetic variants: more precise diagnostics and personalized treatments
In addition to promoting understanding and expanding knowledge about the heterogeneity of mitochondrial diseases, this research is relevant because it adds three new pathological variants of the COQ7 gene as a cause of CoQ10 deficiency, which facilitates the molecular diagnosis of new cases, facilitates genetic counseling for families and, finally, allows patients access to specific therapies and new clinical studies.
“These types of studies are a small step towards personalized medicine. Knowing how the variant detected in the patient affects will allow us to predict the progression of the disease and also to determine the best therapies for each case,” says Carlos Santos, who adds that ”each knowledge accumulated in the study of mitochondrial diseases will favor the work of clinicians to speed up diagnosis and facilitate access to possible therapy.”
The research, published in the Journal of Inherited Metabolic Disease, has involved the participation of the Sant Joan de Déu, Vall d'Hebron, Santiago de Compostela and La Fe hospitals in Valencia, and several teams from the Center for Biomedical Research Network on Rare Diseases (CIBERER), coordinated from the CABD group 'Regulation of coenzyme Q synthesis and its implications in mitochondrial health', led by Professor of Cell Biology at the University Pablo de Olavide Carlos Santos Ocaña.
Fabra MA, Paredes-Fuentes AJ, Torralba Carnerero M, et al. New variants expand the neurological phenotype of COQ7 deficiency. J Inherit Metab Dis. 2024; 1-22. https://doi.org/10.1002/jimd.12776
This press release was prepared in collaboration with 'unidad técnica de comunicación de la UPO'.
