Scientists at Brigham and Women’s Hospital and Harvard Medical School have created a targeted genetic test aimed at improving the diagnosis of X-linked dystonia-parkinsonism (XDP), a rare movement disorder predominantly affecting men of Filipino ancestry. This significant advancement will be presented at the Association for Molecular Pathology (AMP) 2025 Annual Meeting & Expo, scheduled for November 11–15 in Boston.
XDP manifests symptoms similar to those of Parkinson’s disease, including muscle spasms, tremors, and abnormal postures. Initial symptoms often appear in the face, jaw, or neck. As the disorder progresses, individuals may face increasing challenges with speech, mobility, and daily activities. Early diagnosis is crucial, as it allows patients to access necessary support, plan their care effectively, and receive appropriate genetic counseling.
Diagnosing XDP can be complex due to the overlap in symptoms with various neurological disorders. The underlying cause of XDP is linked to an abnormal region in the TAF1 gene, containing specific DNA changes known as disease-specific single nucleotide changes (DSCs). These DSCs are not typically analyzed in standard commercial gene panels or whole-exome sequencing, contributing to diagnostic delays.
Dr. Eirini Christodoulou, a clinical fellow in pathology at Harvard University and a laboratory genetics and genomic fellow at Brigham and Women’s Hospital, spearheaded the development of this new genetic test. The team designed the test to sequence three key DSCs associated with XDP. The test was validated in a study involving eight patients already known to carry the mutation, seven individuals without the mutation, and three additional patients suspected of having the disorder. Remarkably, the test accurately identified all positive cases and provided correct diagnoses for the suspected patients, two of whom had previously received negative results from standard genetic testing.
Dr. Christodoulou stated, “Our test picked up cases that routine sequencing methods such as exome sequencing and panel testing have missed. 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 occur due to mutations on the X chromosome, disproportionately affecting males who possess only one X chromosome. Women, having two X chromosomes, often act as carriers and may not exhibit the full syndrome, although some can display mild symptoms. Currently, there is no cure for XDP, but medications are available to manage movement and muscle symptoms. Some patients may also undergo deep brain stimulation, while physical, speech, and occupational therapies play essential roles in patient care.
The mutation responsible for XDP, also referred to as Lubag disease, is believed to have emerged generations ago and is particularly prevalent among families from the Philippines, especially from Panay Island. One of the reasons for the underdiagnosis of XDP is the limited awareness among healthcare professionals outside Filipino communities.
In their study abstract, the authors highlighted the importance of including this genetic testing in the diagnostic process. “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,” they noted. They emphasized that providers should be aware that only custom XDP-specific assays currently assess and report this disease haplotype, urging that this test be ordered alongside other evaluations for individuals highly suspected of having this condition.
Dr. Christodoulou will present her findings during a poster session at 9:15 a.m. on Saturday, November 15, at the Thomas M. Menino Convention and Exhibition Center in Boston. Her poster number is G001.
