DYT6 mutations relative to THAP1 domains

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Transcript DYT6 mutations relative to THAP1 domains

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
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Rare, adult-onset, progressive genetic neurological
movement disorder
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Almost entirely affects men who descend from the
Philippines island of Panay
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Can have symptoms of dystonia, Parkinsonism or bothf
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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
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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
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Registry started by Dr. Lee in the Philippines
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508 cases (as of February 2010)
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Vast majority male - 500 males and 8 females
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Prevalence in the island of Panay is 5.24 per 100,000
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Prevalence in the Philippines is 0.34 per 100,000
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Movement disorder
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Involuntary, sustained
muscle contractions
resulting in twisting,
repetitive movements and
abnormal postures
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Can affect any part of the
body including limbs, hands,
torso, face, neck or vocal
cords
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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
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Symptoms which are
classically associated
with Parkinson’s disease
but can also be seen in
many other conditions
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Symptoms include
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Tremor when at rest
Slowness of movement
Handwriting smaller
Reduced facial expression
Shuffling walking
Poor balance
Brainmind.com
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Very variable
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Age of onset ~40 years old (range 12-64)
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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
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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)
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2. Dystonia and Parkinsonism (7-15 years of symptoms)
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3. Parkinsonism predominates (15+ years of symptoms)
YEARS SINCE INITIAL PRESENTATION
1
Focal
dystonia
2
7
Dystonic phase,
dystonia spreads
10
Dystonia +
Parkinsonism
Pure Parkinsonism
with minimal
dystonia have a
slow, mild, often
non-disabling
course
Lee LV et al. Int J Neurosci 2011
15
Parkinsonian phase
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Diagnosis – by clinical picture, family tree
and definitive genetic testing
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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
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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
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Speech and swallowing evaluation
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Nutritionist
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Physical therapy/Occupational therapy
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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
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Males generally affected as
they have only one X
chromosome (XY) whereas
females have two (XX).
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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
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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
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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
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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
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Risk to brothers and sisters
of affected male depends
on carrier status of mother
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Directed at symptoms – dystonia or
Parkinsonism
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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
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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)
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
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What is it?
 Delivers electrical stimulation to the
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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
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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
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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
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Due to the drastic presentation was often a source
of family shame
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As a result, patients were often confined to their
homes or hidden from the community due to the
significant social stigma associated with disease.
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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.
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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
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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, caregivers, advocates and
communities
 Building tissue banks to provide
scientists with the tools they
need to advance XDP research
Our voluntary research involves
assessing patients and family
members
 We are collecting:
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 Medical and family history
information
 Perform a physical examination
 Blood sample (DNA genetic analysis)
 Skin biopsy (fibroblast cell line)
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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
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Movement Disorders
Society of the Philippines
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The MGH XDP Center
www.massgeneral.org/xdp
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Visit the XDP Center website
http://www.massgeneral.org/xdp-center
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Contact the XDP Center director,
Nutan Sharma, M.D., Ph.D., at (617)
643-208
OR
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Contact the genetic counselor and
research coordinator, Trisha
Multhaupt-Buell, MS at
(617)
726-5470 [email protected]