Researchers at the Collaborative Center for X-linked Dystonia-Parkinsonism (XDP) are working to identify the genetic roots of XDP and to develop new ways to treat this degenerative disorder.

Laurie Ozelius, MD with postdocs
Laurie Ozelius, MD discussing transcriptomics data with postdoctoral fellows Aloysius Domingo, MD, PhD and Rachita Yadav, PhD

What is X-linked Dystonia-Parkinsonism?

XDP is an adult-onset, genetic movement disorder which affects individuals who descend from the Philippine Island of Panay. It is a neurodegenerative disease that evolves over the course of many years, resulting in significant disability and a shortened life span.

Phases of XDP

XDP generally presents in three different clinical phases.

Dystonic Phase

People with dystonia have involuntary, sustained muscle contractions. These involuntary muscle contractions can cause twisting, repetitive movements and abnormal postures. The twisting seen in XDP patients happens because the brain sends signals that tell muscles to tighten and contract involuntarily.

In XDP, dystonia can occur in any part of the body and may spread to other body parts during disease. It can manifest in many ways, including twisting/dragging a foot, repeated jaw opening and closing, abnormal turning or posture of the neck, tongue protrusion, mouth pursing or excessive eye blinking. Many patients begin showing symptoms in their forties, but the age of onset can vary greatly.

When one part of the body is affected, it is called focal dystonia.

Over time, more muscles become affected, leading to twisting and uncomfortable postures with muscle spasms. After five years, most patients have developed a generalized dystonia, where many different muscle groups and body parts are affected.

Dystonia and Parkinsonism

The next phase of XDP usually begins 7-15 years after onset of focal dystonia. During this phase, the patient has features of both generalized dystonia as well as parkinsonism.

Parkinsonism involves the development of symptoms that are classically associated with Parkinson's disease, but can also be seen in many other conditions. These involve slowing of movements, shuffling gait, development of a hand tremor and reduction of facial expression. Patients with XDP do not have Parkinson's disease, which is not a genetic condition and is caused by a different mechanism.

Parkinsonism Phase

By 15 years after onset, XDP patients primarily show features of parkinsonism. In 6% of patients, XDP manifests primarily as parkinsonism, without evidence of dystonia.

Prognosis

As XDP progresses, patients become more disabled and are eventually unable to work. In the late stages of disease, patients become dependent on others, immobile and unable to care for themselves. Patients with XDP have a reduced life expectancy due to the complications of the disease.

Not all patients present with the same symptoms or progress at the same rate.  CCXDP clinical researchers are currently conducting natural history studies in the Philippines and North America to define the full spectrum of disease to understand this variation.  These studies are crucial for eventual clinical trials and may provide insights that allow earlier interventions to improve patient outcomes.

Genetics

Recent CCXDP-funded research studies have shown that XDP is most likely caused by a disease-specific SINE-VNTR-Alu (SVA)-type retrotransposon insertion in an intron of the human TAF1 gene. The SVA contains a hexameric sequence (CCCTCT)n, the length of which is polymorphic among patients and inversely correlated to age of disease onset. The insertion results in aberrant TAF1 mRNA splicing and partial intron retention which decreases levels of the full-length transcript.

Resources for Researchers

Researcher with microscope
William Hendriks, PhD in the lab

Induced Pluripotent Stem (iPSCs)

A collection iPSCs including affected men and women, unaffected controls, and carrier females is available at WiCell, Inc. CRISPR corrected lines in which the SVA has been excised from affected male iPSC lines are also available.

Lymphoblasts

Lymphoblasts from dystonia patients including XDP (DYT3) and controls may be requested from the Dystonia Mass General Brigham Research Bank at MGH by contacting Trisha Multhaupt-Buell, MS, CGC

DNA

DNA from dystonia patients including XDP (DYT3) are available at Coriell or from the Dystonia Mass General Brigham Research Bank at MGH by contacting Trisha Multhaupt-Buell, MS, CGC

Fibroblasts

An extensive collection of fibroblasts from dystonia patients, including XDP (DYT3), were recently deposited at RUCDR Infinite Biologicals and will come online on a rolling basis.  Fibroblasts may also be requested from the Dystonia Mass General Brigham Research Bank at Mass General by contacting Trisha Multhaupt-Buell, MS, CGC.

Please note that fibroblasts are a limited resource. Availability will depend on how often lines are requested.

Post mortem brain tissue

Samples from a limited number of postmortem XDP brains are available for research. Control tissue is not currently available.

Please note that due to the precious nature of this resource, a supplementary application and review by the XDP Brain Bank Tissue Committee is required before tissue distribution. Please contact Ellen Penney, MD, PhD to request tissue.

Antibodies

Novel anti-C-TAF1 rabbit monoclonal antibody are available by request by contacting Amy Alessi, PhD.

De-identified clinical data

Please contact Clinical Program Research Manager, Trisha Multhaupt-Buell, MS, CGC for additional information.