Scientists at the Indiana University School of Medicine have gained new insights into Barth syndrome, a rare genetic disorder that primarily affects males.
Utilizing genetic data from a patient at Riley Children’s Health, the team identified factors that contribute to neutropenia, a dangerous blood complication frequently seen in people with Barth syndrome. These findings, recently published in Stem Cell Reviews and Reports [1], could help guide the development of targeted treatments for neutropenia and may lead to more effective therapies for Barth syndrome and other serious disorders.
Barth syndrome is caused by mutations in the Tafazzin gene, which makes an enzyme required for the formation and survival of healthy mitochondria in cells.
Mitochondria are the essential energy-producing structures in all cells that help fuel the body, and it is estimated that every 30 minutes a child is born who will develop a mitochondrial disease by age 10.
When mitochondria don’t function properly, it can result in weakened heart function, extreme fatigue, below-average growth and muscle weakness — all symptoms of Barth syndrome. The genetic disorder also causes immune system issues like neutropenia, which occurs when the body doesn’t produce enough neutrophils, a type of white blood cell that helps fight infections.
“Neutropenia can present before birth in Barth syndrome patients and is also a commonly diagnosed condition in premature and critically ill newborns,” said Simon Conway, PhD, a professor of pediatrics and biochemistry and molecular biology at the IU School of Medicine and senior author of the study.
Neutropenia’s causes are not well known, and its effects differ from one Barth patient to another, so there's an urgent need to understand what's driving the condition and how to target it. We're able to do that better by using patient-derived animal and cell culture models.Simon Conway, PhD, professor, IU School of Medicine
IU researchers created a patient-derived model, or a knock-in mouse model, by using the gene editing tool CRISPR-Cas9 to introduce a unique single-point DNA mutation from a Riley Children's patient with Barth syndrome[2] into the same DNA location of a mouse. This resulted in a highly accurate model that mirrors the patient’s specific disease features.
In this study, researchers found that the mouse models had issues in mature blood cells and blood stem cells, along with bone marrow defects. Young knock-in mice had neutropenia, but the condition was surprisingly not present in adult models. However, both young and aged mice had low levels of infection-fighting white blood cells in all phases of life.
The patient’s own white blood cells also showed damaged mitochondria, but the scientists discovered these issues could be prevented using an existing FDA-approved drug called Cyclosporine A. The drug is commonly used to prevent infections after organ transplants or as an autoimmune disease treatment.
The study underscores that problems with mitochondria caused by the Tafazzin mutation are also likely behind the blood-related issues in Barth syndrome.
“We will continue using this clinically-relevant model of Barth syndrome to examine how specific gene changes impact the progression of blood and bone marrow issues in this devastating mitochondrial disease,” Conway said. “It also opens the door to testing new treatments that could help patients with Barth syndrome or similar blood disorders.”
The research team plans to further explore how this mutation affects blood-forming stem cells and whether gene-editing approaches could correct the immune defects in patient-derived cells. Multiple laboratories from the Herman B Wells Center for Pediatric Research[3] and the IU School of Medicine are contributing to this work.
"This collaboration is a powerful example of precision medicine in pediatric rare disease research happening here at IU and Riley," said Reuben Kapur, PhD, director and program leader of the Hematologic Malignancies and Stem Cell Biology Program at the Wells Center, a researcher with the IU Melvin and Bren Simon Comprehensive Cancer Center and co-author of the study. "By bringing together expertise across disciplines and creating patient-tailored models, we’re moving closer to developing treatments for Barth syndrome and other serious diseases."
This research was supported by funding from the National Institutes of Health and Riley Children’s Foundation.
Additional IU co-authors of the study include Elizabeth A. Sierra Potchanant, Maegan L. Capitano, Baskar Ramdas, Donna M. Edwards, Scott Cooper, James Ropa, S. Louise Pay, Aditya Sheth, Paige L. Snider and Ngoc-Tung Tran. They were joined by Hilary J. Vernon from the Johns Hopkins University School of Medicine.
References
1) https://link.springer.com/article/10.1007/s12015-025-10945-1
2) https://medicine.iu.edu/blogs/pediatrics/barth-syndrome-breakthrough
3) https://medicine.iu.edu/research-centers/pediatrics
(Newswise/NS)