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.
What is X-linked Dystonia Parkinsonism?
X-linked dystonia parkinsonism (XDP) was first reported by Lillian Lee, MD, MHA, et al in 1976. It is an adult-onset, genetic movement disorder that predominantly affects males who descend from the Philippine Island of Panay.
XDP is a progressive disease in which patients have significant degeneration of the medium spiny neurons in the striosome (one of two complementary chemical compartments in the striatum, part of the forebrain).
Phases of XDP
XDP disease progression can typically be divided into three phases, though this does not apply in every case.
In the majority of patients, XDP begins with involuntary muscle contractions that can occur in any part of the body. These contractions can manifest in many ways, including excessive eye blinking, repeated jaw opening and closing, or twisting/dragging a foot. Over the course of 2-5 years more muscles become affected, leading to twisting and uncomfortable postures.
When one part of the body is affected, it is called focal dystonia. When many muscle groups are affected, a patient is said to have generalized dystonia.
Dystonia and Parkinsonism
The next phase of XDP usually begins 7-15 years after the onset of focal dystonia. During this phase, the patient has features of both generalized dystonia and parkinsonism. The parkinsonian features include bradykinesia (slowness of movements and reflexes), shuffling gait and rest tremor.
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. Many patients have responded well to deep brain stimulation as a treatment for dystonic symptoms.
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 complications of disease.
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
Induced Pluripotent Stem (iPSCs)
A collection iPSCs including affected men and women, unaffected controls, and carrier females is available at Wicell, Inc.
Lymphoblasts from dystonia patients including XDP (DYT3) and controls may be requested from the Dystonia Partners Research Bank at MGH by contacting Trisha Multhaupt-Buell, M.S., CGC
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 Partners Research Bank at MGH by contacting Trisha Multhaupt-Buell, M.S., 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 Science Officer Amy Alessi, PhD, for additional information.
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, M.S., CGC for additional information.