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
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
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
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
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
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
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)
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)
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
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
Assessment by a neurologist
Speech and swallowing evaluation
Nutritionist
Physical therapy/Occupational therapy
Genetic counselling
Lee LV et al. Int J Neurosci 2011
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
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.
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
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
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
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)
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
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
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
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
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.
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.
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
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
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:
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
American Dystonia
Society
www.dystoniasociety.org
Movement Disorders
Society of the Philippines
The MGH XDP Center
www.massgeneral.org/xdp
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 [email protected]