Scientists at Brigham and Women's Hospital and Harvard Medical School have developed a targeted genetic test to improve diagnosis for X-linked dystonia-parkinsonism (XDP), a rare and disabling movement disorder that affects primarily men of Filipino ancestry.
The work will be presented at the Association for Molecular Pathology (AMP) 2025 Annual Meeting & Expo , taking place Nov. 11–15 in Boston.
XDP causes symptoms like those of Parkinson's disease, such as muscle spasms, tremors and abnormal postures and movements. It usually first presents in the face, jaw or neck. As it progresses, speech, walking and independent living becomes more difficult. Early recognition helps patients access support, plan their care and access appropriate genetic counseling.
Several neurological disorders have similar symptoms, which makes getting an accurate diagnosis for XDP specifically quite difficult and slow.
An abnormal region in the TAF1 gene is responsible for the disease. That region contains subtle DNA changes, known as disease-specific single nucleotide changes (DSCs), and they are not routinely analyzed by commercial gene panels or whole-exome sequencing.
Eirini Christodoulou, Ph.D., is a clinical fellow in pathology at Harvard University and a laboratory genetics and genomic fellow at Brigham and Women's Hospital, where she led the new study.
She and her team designed the new test to sequence three key DSCs associated with XDP. They validated the test in eight patients already known to carry the mutation, seven people who do not have the mutation, and three others suspected of having it. The test correctly identified all the positive cases and led to the proper diagnosis of the three suspected to have it, two of whom had received negative results from standard genetic testing.
"Our test picked up cases that routine sequencing methods such as exome sequencing and panel testing have missed," Christodoulou said. "We need to identify these cases that would otherwise remain hidden and end diagnostic odysseys, particularly in patients whose symptoms overlap with other movement disorders."
X-linked diseases are caused by changes on the X chromosome, and they affect males disproportionately because they have only one X chromosome. Women have two X chromosomes, so if they inherit the mutation on one copy, the other copy can compensate. Most women are carriers and do not develop the full syndrome, although some may show mild symptoms.
There is no cure for XDP, but medications can help with movement and muscle symptoms. Some patients undergo deep brain stimulation. Physical, speech and occupational therapy are key components of patient care plans.
The mutation for XDP, which is also known as Lubag disease, is believed to have arisen generations ago and is strongly linked to families from the Philippines island of Panay. Among the many reasons XDP is underdiagnosed: limited awareness among clinicians outside of Filipino communities.
In their abstract, the authors of the study wrote: "Including this testing as part of the diagnostic differential may increase the diagnosis rate in this population and reduce the costs associated with a diagnostic odyssey for these patients. Ordering providers need to be aware that currently only custom XDP-specific assays assess and report this disease haplotype. Therefore, this test should be ordered alongside other tests in individuals who are at high suspicion for this condition."
The study was overseen by Eirini Christodoulou, Ph.D., and will be presented by her during a poster session at 9:15 a.m. on Saturday, Nov. 15 , at the Thomas M. Menino Convention and Exhibition Center in Boston. Christodoulou's poster number is G001.
About AMP
