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

2.  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

3.  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

4.  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

5.  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

6.  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

7.  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)

8.  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)

9. Lee LV et al. Int J Neurosci 2011 YEARS SINCE INITIAL PRESENTATION 1271015 Focal dystonia Dystonic phase, dystonia spreads Dystonia + Parkinsonism Parkinsonian phase Pure Parkinsonism with minimal dystonia have a slow, mild, often non-disabling course

10.  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

11.  Assessment by a neurologist  Speech and swallowing evaluation  Nutritionist  Physical therapy/Occupational therapy  Genetic counselling Lee LV et al. Int J Neurosci 2011

12.  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

13.  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.

14.  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

15.  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

16.  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

17.  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)

18.  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

19.  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

20.  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

21.  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

22.  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.

23.  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.

24.  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

25.  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

26.  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

27.  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

28.  American Dystonia Society www.dystoniasociety.org www.dystoniasociety.org  Movement Disorders Society of the Philippines  The MGH XDP Center www.massgeneral.org/xdp www.massgeneral.org/xdp

29.  Visit the XDP Center website http://www.massgeneral.org/xdp-center 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.orgtmulthaupt@partners.org