Researchers from Manchester University NHS Foundation Trust (MFT) and The University of Manchester have made significant strides in understanding the genetic causes of Perrault syndrome, a rare condition linked to hearing loss and infertility. The research, published in The American Journal of Human Genetics, uncovers changes in the DAP3 and MRPL49 genes that cause the syndrome, offering new diagnostic avenues and potential treatments for affected individuals.
Perrault syndrome, a rare genetic disorder, typically causes hearing loss and in women, early menopause or infertility. Other symptoms can include learning difficulties, developmental delay, and nerve damage. Historically, many individuals with this condition were unable to receive a conclusive genetic diagnosis, but the discovery of genetic mutations in these two genes now provides a clearer understanding.
Professor Bill Newman, Consultant in Genomic Medicine at MFT and Rare Conditions Co-Theme Lead at the NIHR Manchester BRC, co-led the research and highlighted the importance of these findings in advancing diagnosis and treatment. “Identifying the genetic causes of rare conditions like Perrault syndrome is crucial for providing accurate diagnoses and developing new treatments,” he said. Previously, up to half of all individuals with Perrault syndrome had no confirmed genetic diagnosis, but the new discoveries will help provide answers for more patients.
The study builds on research initiated in 2011 at The Manchester Centre for Genomic Medicine, where initial investigations identified a novel gene linked to Perrault syndrome. Since then, research has uncovered eight different genes associated with the condition. This new research, involving global collaborations, expands that understanding and lays the foundation for more widespread genetic testing and earlier diagnoses.
One personal story featured in the research is that of 56-year-old Sam, who was diagnosed with Perrault syndrome at the age of 28. Sam, who has been profoundly deaf since infancy, was fitted with hearing aids before her first birthday, a common feature of the syndrome. Other symptoms included short stature, small ovaries, and the absence of menstruation. Through this research, Sam was found to carry a mutation in the DAP3 gene, which is vital for the proper function of mitochondria, the energy-producing components of cells.
Genetic testing, as Professor Ray O’Keefe, co-lead of the study, explains, offers families a chance to diagnose the condition earlier and access the necessary care and support sooner. “Genetic testing can remove the need for unnecessary investigations and ensure that patients are closely monitored, leading to more timely interventions and better genetic counseling for family members.”
The DAP3 gene is essential in every cell of the body, particularly in mitochondria, which are crucial for cell energy. When mitochondria malfunction, tissues such as the auditory system and the ovaries are especially vulnerable, which may explain why these issues are central to Perrault syndrome. Researchers believe that the mitochondrial defects associated with this syndrome lead to hearing and ovarian problems in affected individuals.
The research team is optimistic that the findings could lead to a comprehensive understanding of the genetic underpinnings of Perrault syndrome. Professor Newman added, “Understanding how these genes interact could eventually lead to a universal treatment that addresses all genetic variants of Perrault syndrome.”
Additionally, the researchers have begun using skin cells from individuals with Perrault syndrome to create hearing nerve cells, providing a promising approach for developing targeted treatments. This ongoing work offers hope not only for those affected by this rare condition but also for insights into more common forms of hearing loss.
Dr. Ralph Holme, Director of Research at RNID, emphasized the broader implications of the research, noting that although ovarian problems primarily affect women, men can also be affected by Perrault syndrome and should be considered in genetic screening. Holme also pointed out that understanding rare forms of hearing loss can offer valuable lessons for addressing more widespread hearing impairments.
As the research progresses, the team remains committed to further exploring all genes linked to Perrault syndrome and improving diagnostic and therapeutic strategies for affected individuals. The ultimate goal is to create personalized treatments that target the specific genetic causes of the condition, potentially transforming the lives of many.
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