Thanks to the generosity of an anonymous donor, Massachusetts General Hospital researchers have made a breakthrough in understanding the cause of X-linked dystonia parkinsonism (XDP), a rare and severe neurodegenerative disease. The discovery involves a genetic defect thought to be central to the condition’s development.
“This would not have been possible without the commitment and determination of our donors.”
Key support for the research came from the donor-funded Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP), which opened in 2014 at Mass General’s Charlestown Navy Yard research facilities. “It allowed us to greatly accelerate this research,” says Nutan Sharma, MD, PhD, director of the CCXDP and one of the researchers involved.
“Seeing the great progress our group at the CCXDP has made in just three years has been undeniably thrilling,” says D. Cristopher Bragg, PhD, “This would not have been possible without the commitment and determination of our donors.
Insights into Parkinson’s Disease
XDP occurs only among individuals with ancestry from the island of Panay in the Philippines. It causes the death of certain cells in the brain. Symptoms begin around age 40 with dystonia – involuntary muscle contractions that can force the body into abnormal, sometimes twisted positions. They eventually proceed to Parkinson’s-like symptoms, such as slow movements and a shuffling gait. Patients become more disabled as the disease progresses and often die from complications such as infections or pneumonia.
Because XDP is rare, it is nearly impossible to get research funding from government agencies or drug companies. But the XDP researchers say their findings could lead to important advances in other neurodegenerative diseases, especially ones involving movement disorders.
“We already know that 40 percent of patients with Parkinson’s disease also suffer from dystonia,” says Dr. Sharma, who is also director of the Dystonia Clinic at Mass General.
Rarity Makes Funding Difficult
The breakthrough by the MGH team was published recently in two related articles, one in the journal, Cell, and the other in The Proceedings of the National Academies of Science (PNAS). Together they represent the collaboration between the laboratories of Michael Talkowski, PhD, Dr. Bragg, and Laurie J. Ozelius, PhD, as well as the clinical team directed by Dr. Sharma. All work at the Mass General Department of Neurology and the CCXDP.
“Even though the first clinical descriptions of this disease were published more than 40 years ago, it has been difficult to determine its cause or what might be done to treat it,” says Dr. Talkowski, who is also part of the Mass General Center for Genomic Medicine.
The lack of progress was partly due to the disease being largely contained to a small, impoverished island where access to medical care is lacking.
“At Mass General, we believe all disease is significant,” Dr. Bragg says. “Studying rare syndromes can often unlock the mysteries of more common disorders.”
“At Mass General, we believe all disease is significant,” Dr. Bragg says. “Studying rare syndromes can often unlock the mysteries of more common disorders.”
With CCXDP support, Drs. Talkowski, Ozelius and Bragg, working with Dr. Sharma, mounted the largest genomics study ever performed for XDP. They analyzed 792 DNA samples from individuals with XDP and their unaffected relatives. They also examined historical samples from studies dating back to the initial descriptions of the disease. They were able to access this large number of individuals because CCXDP actively tries to meet the social needs of XDP patients in Panay
Donor Commitment Makes Difference
The CCXDP’s work includes a Community Advocate Program staffed by Panay residents, usually wives or children of individuals with XDP. Supported by the center, they frequently visit patients in their homes, monitor their well-being and help them get transportation to clinics
“The Community Advocate Program has played an important role in our ability to have a meaningful number of samples,” Dr. Bragg says, “but also provides an essential support network for these individuals. The time that Nutan [Sharma] and I have spent in the Philippines with these patients has been the most meaningful experience of my scientific career so far,” Dr. Bragg says
“We cannot definitively say this mechanism is the sole cause of XDP. There is still much work to do,” says Dr. Talkowski. “But it is a major step forward in understanding the defects that occur in patients’ cells.
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