X-Linked Dystonia-Parkinsonism

Information for patients and families

Christopher Stephen, MD, MRCP (UK)Nutan Sharma, MD, PhD

X-Linked Dystonia-Parkinsonism (XDP)- What is it?

Multiple names XDP DYT3 by dystonia classification “Lubag” – local Filipino term describing twisting postures in

early stages

Rare, adult-onset, progressive genetic neurological movement disorder

Almost entirely affects men who descend from the Philippines island of Panay

Can have symptoms of dystonia, Parkinsonism or bothf

First reported in 1975 by Dr. Lillian Lee in the Philippines who established the XDP Study Group in 1980s to focus research towards a cure

Where did XDP originate?

The Philippines –population 98.4 million

Distribution from ancestral migration from Panay

12 million of Filipino descent overseas including USA, UK and Japan

than AZ

How common is XDP?

Information from the XDP registry, Philippines

Registry started by Dr. Lee in the Philippines

508 cases (as of February 2010)

Vast majority male - 500 males and 8 females

Prevalence in the island of Panay is 5.24 per 100,000

Prevalence in the Philippines is 0.34 per 100,000

What is dystonia? Movement disorder

Involuntary, sustained muscle contractions resulting in twisting, repetitive movements and abnormal postures

Can affect any part of the body including limbs, hands, torso, face, neck or vocal cords

Distribution Focal – one body part

involved Segmental or multifocal -

multiple body parts Generalized – many body

parts Breakefield et al. Nat Rev Neurosci 2008

What is Parkinsonism? Movement disorder

Symptoms which are classically associated with Parkinson’s disease but can also be seen in many other conditions

Symptoms include Tremor when at rest Slowness of movement Handwriting smaller Reduced facial expression Shuffling walking Poor balance

Brainmind.com

Course of disease

Very variable

Age of onset ~40 years old (range 12-64)

Presentation

Most present with focal dystonia ▪ More common – legs, jaw, neck and tongue▪ Less common – arms and rarely trunk or tremor

Rarely presents with Parkinsonism (milder course)▪ Rest tremor, slowness, small handwriting, shuffling walking

(sud-sud)

Progression of disease

3 clinical phases

1. Dystonia – focal (e.g. one foot) then often becomes generalized (by normally 5 years of symptoms) Common - twisting/dragging a foot, repeated jaw opening and

closing, abnormal turning or posture of the neck, tongue protrusion, mouth pursing or excessive eye blinking

Rare - bending of the trunk or tremor May have “sensory tricks” - improvement in dystonia by

touching certain areas (particularly neck dystonia)

2. Dystonia and Parkinsonism (7-15 years of symptoms)

3. Parkinsonism predominates (15+ years of symptoms)

Clinical course of XDP

Lee LV et al. Int J Neurosci 2011

YEARS SINCE INITIAL PRESENTATION

1 2 7 10 15

Focal dystonia

Dystonic phase, dystonia spreads

Dystonia + Parkinsonism

Parkinsonian phase

Pure Parkinsonism with minimal dystonia have a slow, mild, often non-disabling course

Diagnosis and diagnostic considerations

Diagnosis – by clinical picture, family tree and definitive genetic testing

Given variable presentation, XDP may be confused with a number of other conditions Primary dystonic disorder – focal or generalized Parkinson’s disease or other causes of

Parkinsonism

Clues are the adult onset, clinical pattern and ancestral connection to the Philippines particularly the island of Panay

Lee LV et al. Int J Neurosci 2011

What evaluations are needed?

Assessment by a neurologist

Speech and swallowing evaluation

Nutritionist

Physical therapy/Occupational therapy

Genetic counsellingLee LV et al. Int J Neurosci 2011

What are the genetics of XDP?

Inherited by an X-linked (sex-linked) recessive manner

Likely caused by a mutation in the TAF1 gene on the X-chromosome

Clinical genetic testing is available at only a few locations worldwide

Patients should see a genetic counselor before testing

A positive result has implications not only for the patient but also other members of the family and any children

What are the genetics of XDP?

Caused by an abnormality in a gene (mutation) which interferes with the way genes work and affects normal cell processes

Males generally affected as they have only one X chromosome (XY) whereas females have two (XX).

The presence of an additional, healthy X chromosome protects females that have 1 abnormal gene.

What are the genetics of XDP?

Females with 1 copy generally have no symptoms and are called healthy carriers

Females very rarely affected – may occur if inherit 2 copies of the gene – one from a carrier mother and the other from an affected father

Due to carrier females the disease gene may hide in families until there is an affected male

What is the risk of others in the family? Others may find they are at

risk if a person tests positive for XDP

Risk to children If affected male

▪ All daughters carriers▪ No sons affected

If carrier female▪ 50% risk for daughters to be

carriers▪ 50% risk for sons to be

affected

Risk to brothers and sisters of affected male depends on carrier status of mother

Treatment of XDP – Medical therapy

Directed at symptoms – dystonia or Parkinsonism

Medications for dystonia All stages

Anti-cholinergics - Trihexyphenidyl (Artane) Benzodiazepines – clonazepam (Klonopin)

Multi-focal or generalized Tetrabenazine (Xenazine)

Advanced dystonia Zolpidem (Ambien)

Botulinum toxin injections Focal dystonia (particularly neck, eyelids,

tongue and jaw) May worsen swallowing if injected in tongue

or neck

Treatment of XDP – Medical therapy

Directed at symptoms – dystonia or Parkinsonism

Medications for Parkinsonism Levodopa (Sinemet)

Particularly in pure Parkinsonism and become less effective with more dystonia

Dopamine agonists Can be less effective than levodopa and

may worsen dystonia Pramipexole (Mirapex) Ropinirole (Requip)

Treatment of complications of disease

Swallow evaluation Guides diet modifications and other

techniques to reduce the risk of aspiration Physical Therapy and Occupational Therapy

Improvement in mobility and assistive devices

May prevent formation of contractures and delay bed-bound state

Nursing care Observation for pressure sores

Surgical treatment -Deep Brain Stimulation (DBS)

Neurosurgical treatment for XDP

What is it? Delivers electrical stimulation to the

brain in order to alleviate neurological symptoms

Surgically implanted wire (lead or electrode) inserted into the brain

Stimulation target is globus pallidus Powered by an implantable pulse

generator placed under the skin in the chest, similar to a cardiac pacemaker

Stimulation adjusted non-invasively

Surgical treatment –Deep Brain Stimulation (DBS)

What is it used for? Parkinson’s disease Essential tremor Genetic dystonias like XDP

How does it work? Does not damage healthy

brain tissue Blocks electrical signals

from targeted areas in the brain

Surgical treatment –Deep Brain Stimulation (DBS)

What are the benefits? Can improve symptoms by 50-

60% in genetic dystonias but is variable

Limited data regarding use in XDP but appears similarly effective

Lasts at least 10 years

What are the risks? 1-2% risk of bleeding in the brain

or stroke 3-4% risk of surgical infection Generator needs replacement

after 3-9 years depending on type

Why have Filipinos not heard of XDP?

For many years, Filipino families did not have an understanding of what XDP was

Due to the drastic presentation was often a source of family shame

As a result, patients were often confined to their homes or hidden from the community due to the significant social stigma associated with disease.

Through education and outreach, the Collaborative Center for XDP hopes to lift the burden of shame and provide support for XDP patients and their families.

The Collaborative Center for XDP

A consortium of international experts working together to accelerate the pace of discovery in XDP.

2 main sites in collaboration for a cure Dr Sharma’s team at MGH

(coordinating center) Dr Lee’s team in the

Philippines.

The Collaborative Center for XDP

Our goals Accelerate research directed

towards effective treatments, and a cure

Raise awareness of the disease locally and internationally

Expand access to clinical care and treatments in the Philippines and abroad 

Offer support to families who are suffering from XDP through outreach and advocacy

The Collaborative Center for XDP

A How will we do this? - TEAMWORK  The Center has reached out to

experts all over the world to direct their talents to the problem of XDP:

Geneticists to find the causative mutation

Neuroscientists and cell biologists to determine why neurons in the brain malfunction or die

Clinicians to develop and trial effective treatments

Advocacy, education and interventional programs locally

The Collaborative Center for XDP

What are we doing in the Philippines? Determining the scope of

the disease burden and where needs are greatest in collaboration with the XDP Study Group

Expanding access to treatment Improving clinical infrastructure Empowering patients, care-

givers, advocates and communities

Building tissue banks to provide scientists with the tools they need to advance XDP research

The Collaborative Center for XDP

Our voluntary research involves assessing patients and family members

We are collecting: Medical and family history

information Perform a physical examination Blood sample (DNA genetic analysis) Skin biopsy (fibroblast cell line)

We will then use this information to: Form a bank of XDP patients and

families Allow detailed analysis of the

genetics to find targets for treatments and potential cures

Patient resources

American Dystonia Society www.dystoniasociety.org

Movement Disorders Society of the Philippines

The MGH XDP Center www.massgeneral.org/xdp

Further information regarding the Center and our research

Visit the XDP Center website http://www.massgeneral.org/xdp-center

Contact the XDP Center director, Nutan Sharma, M.D., Ph.D., at (617) 643-208

OR

Contact the genetic counselor and research coordinator, Trisha Multhaupt-Buell, MS at (617) 726-5470 tmulthaupt@partners.org