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Christopher Stephen, MD, MRCP (UK) Nutan Sharma, MD, PhD
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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
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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
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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
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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
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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
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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)
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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)
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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
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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
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Assessment by a neurologist Speech and swallowing evaluation Nutritionist Physical therapy/Occupational therapy Genetic counselling Lee LV et al. Int J Neurosci 2011
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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
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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.
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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
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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
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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
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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)
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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
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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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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
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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
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