(Reedited) The Effect of Focal Task Specific Dystonia in Pianists

The Effect of Focal Task-Specific Dystonia on
Pianists: An Analysis of Literature and A Case Study
By
Jaundelle Dwyer
1230045
Dissertation submitted to the Faculty of Science and Technology at
Anglia Ruskin University Cambridge campus of the requirements for the
Degree Biomedical Sciences BSc
2015
1
Table of Contents
Page
List of Tables
List of Figures
Abstract
Chapter:
I. Introduction……………………………………………………………………………...5
Hypothesis……………………………………………………………………………....8
Aims……………………………………………………………………………………...9
Key Neurological Concepts…………….……………………………………………...9
The Nervous System………………………………………………………………….10
Neurons………………………………………………………………………………...10
Basal Ganglia…………………………………………………………………………..11
II. Methods and Techniques……………………………………………………………..14
Literature search……………………………………………………………………….14
Inclusion and Exclusion……………………………………………………………….18
Case Study……………………………………………………………………………..19
III. Results and Discussion………………………………………………………………..22
Bioinformatics Analysis………………………………………………………………..22
Bioinformatics Discussion……………………………………………………………..29
Case Study – Interview Results………………………………………………………30
Case Study
Discussion………………………………………………………………...33
IV. Defining Focal Task-Specific
Dystonia……………………………………………….35
Definitions and Classifications of
Dystonia………………………………………......35
Causes of Focal Task-Specific
Dystonia……………………………………………..38
Loss of
Inhibition………………………………………………………………………..40
Symptoms of Focal Task-Specific Dystonia…………………………………………41
Diagnosis of Focal Task-Specific
Dystonia…………………………………………..41
2
Hormones……………………………………………………………………………….43
Drug-Drug Interactions………………………………………………………………...43
Psychology……………………………………………………………………………...44
V. Genetic Association to Focal Task-Specific Dystonia……………………………...46
Classifications of Genes……………………………………………………………….46
TOR1A
Protein………………………………………………………………………….48
Twin Studies and Familial Genetics with Focal Task-Specific
Dystonia………….50
VI. Treatments of Focal Task-Specific
Dystonia………………………………………...51
Botulinum Toxin BT…………………………………………………………………….51
Drugs…………………………………………………………………………………….54
Stereotactic Surgery……………………………………………………………………
54
Transcranial Direct Current Stimulation & Transcranial Magnetic
Stimulation…..54
Deep Brain
Stimulation………………………………………………………………...55
Psychotherapy – Behaviour Techniques…………………………………………….55
Physiotherapy-Sensor Motor
Training………………………………………………..56
Biofeedback………………………………………………………………………….....56
General Discussion…………………………………………………………………….58
VII. Conclusion………………………………………………………………………………60
Summary of Key Points………………………………………………………………..60
Suggestions for Further
Study………………………………………………………...62
Acknowledgements…………………………………………………………………….62
References……………………………………………………………………………………....63
Appendix 1……………………………………………………………………………………….76
Appendix 2……………………………………………………………………………………….85
Appendix 3……………………………………………………………………………………….89
3
List of Tables
Page
Table 1. Hypothesis of Research………………………………………………………….9
Table 2. Search Terms Used in Database……………………………………………...15
Table 3. Main Books Included…………………………………..………………………..18
Table 4. Summary of Amino Acids in TOR1A isotopes…………………………………
26
Table 5. Classifications of Dystonia’s by Age………………………………………..
…..36
Table 6. Classifications of Dystonia’s by Affected Body
Part…………………………..37
4
Table 7. Molecular Classifications of Hereditary Dystonia’s………………………..46-
47
List of Figures
Page
Figure 1. Image of Coronal Section of Human Basal Ganglia………………………..12
Figure 2. Connections in the Basal Ganglia and Cerebral Cortex……………………13
Figure 3. Science Direct Database………………………………………………………15
Figure 4. Saved to Refworks……………………………………………………………...16
Figure 5. Flowchart of Literature Search………………………………………………...17
Figure 6. 3-D Structure of TOR1A protein……………………………………….
……....23
Figure 7. Alignment of TOR1A….
………………………………………………………...23
5
Figure 8. DNA Sequence of
DYT1………………………………………………………..24
Figure 9. Alignment of Two
Isotopes……………………………………………………...25
Figure 10. Amino Acid Sequence Comparison of TOR1A-1 and TOR1A-
2………….28
Figure 11. Amino Acid composition of Isotope 1…………………………………………
29
Figure 12. Amino Acid composition of Isotope 2…………………………………………
30
Figure 13. Frequencies of Amino Acids of Isotopes TOR1A-1 and TOR1A-2
……….30
Figure 14. Sensory Motor Loop………..
………………………………………………….41
Figure 15. Focal Task-Specific Hand…………………………………………….………42
Figure 16. The Release of Acetylcholine in Nerve Terminals……………….
………....53
Abstract
Background
6
Focal Task-specific Dystonia (FTSD) is a neurological movement disorder in which
hands that perform specific tasks result in the typical focal hand Dystonia
characteristics.
Aims
The aims of this Literature review were to assess the relationship between genetic
associations and efficient treatments in pianists with focal task-specific dystonia.
Methods
A variety of literature articles, books and databases were used to obtain information
based on relationships between genetics and treatments for focal task-specific
Dystonia in pianists. Case study was conducted in order to attain information in
relation to focal task-specific dystonia in pianists.
Results
After reviewing the similarities of the protein alignments and the results from the
case study it was clear that there were no significant difference in the effectiveness
of treatments, however there are risks that carriers of DYT1 can develop focal task-
specific hand Dystonia at later stages in life.
Conclusion
Focal task-specific dystonia can be explained in relation to environmental and
genetic effects on the muscles in the hands of pianists. Although there is no cure
there are many efficient methods of treatment to help alleviate the dystonia
symptoms.
7
Organisation of the Text
Chapter one consists of a brief introduction and definition of focal-task specific
dystonia, aims, hypothesis and an overview of keys neurological concepts as well as
8
the methods and techniques. Chapter two is methods and techniques: questions
from a case study will be included. Chapter three includes the results and discussion
of bioinformatics analysis and the case study. Chapter four discusses further
research of the definition of focal-task specific dystonia; considering the
classifications. It also contains the symptoms of focal task specific dystonia, as well
as the causes and diagnosis of the disorder as well as the possible relationship
FTSD may have with repetitive stress injury. It also discusses loss of inhibition. Later
in the chapter genetic association in focal-task specific dystonia is also evaluated as
well as the treatments for the disorder. It also includes a general discussion of all of
the information obtained from the articles, books and internet. The final chapter
includes a summary of key points and suggestions of further studies.
CHAPTER I
1.0 INTRODUCTION
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Dystonia derives from the Greek word dys which means abnormal and tonia from the
word tonos, meaning tension (Martin, 2010). Dystonia is a neurological movement
disorder where sustained muscle contractions, cause twisting of the affected region
of the body into an abnormal position. Movements are repetitive which can vary from
slow and athetotic (Balint and Bhatia, 2014). Dystonia is initiated or negatively
influenced by voluntary action; it is also associated with excess muscle activation
(Albanese et al., 2013). Focal dystonia affects only one body part or region, e.g.
lower cranial regions (jaw, tongue and lower face). Focal dystonia in pianists usually
occurs within the arms (shoulder girdle, upper arm and hands). Focal task-specific
dystonia (FTSD) is characterised as the degradation or loss of voluntary control of
overlearned complex and skilled movement in a specific sensory-motor task
(Altenmüller and Jabusch, 2009). Take into consideration hypothetically the following
scenario: that one is a pianist, and is aware of the pressure to perform at the highest
level. One day she is rehearsing, and notices after a while that she cannot articulate
the higher-register notes cleanly. This happens again the following week, and her
teacher notices. Like most musicians she increases her practices and focuses on the
higher-register where she had the problem originally. Unfortunately, the problem only
worsens and she develops an uncontrollable tremor and her fingers start to twist into
a fixed position for a period of time. During this period, her abilities to play the piano
decrease immensely, until the point where she has to retire. If in such a situation
what would one do? Who would one go to for help if needed? Would one accept
diagnosis from doctors? Musicians whom suffer with FTSD face similar situations
and are often left to confront questions like those on a daily basis.
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1.1 Hypothesis
Table 1: The Hypothesis of Research
Research Question What is the Effect of Focal Task-

Specific Dystonia on Pianists?
Hypothesis There is a significant link between
focal-task specific dystonia in pianists
and genetics and repetitive strain
injury.
Null Hypothesis There is no significance link between

focal-task specific dystonia in pianists
and genetics and repetitive strain
injury.
1.2 Aims
The purpose of this dry project was to create awareness and understanding of focal
task-specific dystonia (FTSD) in relation to pianists. An examination of professional
scientific literature was undertaken in order to answer the following questions:
1. What is focal task-specific dystonia?
2. Is dystonia inherited?
3. What causes FTSD?
4. What are the possible symptoms of FTSD?
5. What are the treatments for FTSD?
6. Does FTSD overlap with repetitive stress injury?
In addition to answering these questions a case study of FTSD is included with the
intention to provide information that will help to explore the possible influences on
FTSD.
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1.3 Key Neurological Concepts
The human brain is an extremely complex organ that has been explored and studied
over many years. Despite the great amount of knowledge on the brain, new
discoveries are reported frequently and there is still more that mankind still are
unaware of in relation to the brain, that are yet to be explored. Study of the brain is
referred to as neurology, dating back to the late nineteenth century (Albanese et al.,
2013).
1.4 The Nervous System

The nervous system is characterised as the control panel for the human body, and is
responsible for maintaining the unconscious and conscious body functions. The
nervous system is divided into three domains; the peripheral nervous system (PNS),
the central nervous system (CNS) and the autonomic nervous system (ANS). The
peripheral nervous system consists of 12 pairs of cranial nerves that enter and leave
the upper region of the brain, and 31 pairs of spinal nerves that are connected to
either sides of the spinal cord at each vertebra. The PNS is divided into the
autonomic nervous system and the somatic nervous system. The autonomic (ANS)
control the smooth muscles, heart, glands, and many other organs and is located in
the CNS also. It is made up of the parasympathetic and sympathetic nervous system
which activates the body to adapt and cope with neural and hormonal stress that
results in the fight or flight response. The parasympathetic nervous system
conserves energy by slowing down the activity of most organs, and also activates
the digestive system to renew the energy lost. The somatic nervous system is made
up of motor neurons that maintain and operate the skeletal muscles. The central
nervous system (CNS) includes the spinal cord and the brain. The main function of
12
the CNS is to generate reactions sensory signals inside and outside of the human
body (Garett, 2015).
1.5 Neurons
The nervous system is made up of four main components; blood vessels, neurons,
sensory organs and the glia. Neurons transmit information through electrical signals
and are responsible for the thoughts, emotions, memories and movement. A neuron
is composed of the cell body which is filled with liquid known as the cytoplasm and
contains the nucleus. The neuron also contains the dendrites which are extensions
that branch out from the cell body in order to receive information from other neurons
via electrical impulses. It also contains the axon which extends from the cell body
like a tail, surrounded by myelin sheaths which are classed as protective insulators
and transmits cell signals through action potentials which causes the terminals to
release neurotransmitters in order to communicate with an organ or muscle, or
another neuron. The glial cells are known as nonneuronal cells that support many
different functions of the neurons; working as the glue that protects and connects.
Finally the blood vessels carries nutrients and also removes the waste products
produced (Garett, 2015).
1.6 Basal Ganglia

The neurophysiology of dystonia has been researched and many different theories
have been deduced. Brin et al suggested that idiopathic dystonia’s are linked to
lesions in the basal ganglia. The basal ganglia modulate the activity of the cortical
and brain stem motor systems. It uses information from the primary and secondary
motor regions and also the somatosensory cortex to integrate and smooth
movements. The basal ganglia is characterised as a collection of motor nuclei within
13
the forebrain, in the cerebral hemispheres between thalamus and cortex, which
divides into distinct functional groups (fig 1) (Purves, et al., 2004). One of the largest
groups is called corpus striatum, which consists of the putamen and caudate. In
figure 2, the connections within the cerebral cortex (Steiner and Tseng, 2010).
VL/VA complex of the thalamus
Caudate nucleus
Putamen
Globus pallidus,
internal and external
segments
Subthalamic nuclei
Figure 1: Image of a coronal section through the brain that shows the anatomical
locations of each structure involved in the basal ganglia pathway (Purves, et al.,
2004).
14
Figure 2: The connections of a rat basal ganglia within the cerebral cortex, which
was used as it is the best image to show these connections that occur within the
brain. (A) An illustration of the input and output within the basal ganglia. The cerebral
cortex provides input to the striatum, where it consists of the caudate-putamen (CPu)
and the nucleus accumbens. The output that comes out of the basal ganglia arises
from GABA neurons in the internal of the globus pallidus (GPi) and the substantia
nigra pars reticulata (SNr). The GABA neurons provide inhibitory inputs to the
thalamic nuclei, which consists of mediodorsal (md), ventral lateral (vl), ventral
anterior, intralaminar/parafascicular (pf), pedunculopontine nucleus (PPN) and
superior colliculus (SC), as well as the nucleus (Steiner and Tseng, 2010).
In order to initiate gross motor movement the basal ganglia is reliant on the source of
sensory input. The putamen receives the input from the primary and secondary
sensorimotor cortex in the parietal lobe. Abnormalities of the sensorimotor cortex is
assumed to lead to dysfunctions of movement (Ekman, 2007).
15
Chapter II
2.0 Methods and Techniques
Certain methods and techniques were used in order to obtain sources for this
literature review to establish what FTSD in relation to pianists; when searching for
literature to find published journals and books. After thoroughly analysing and
checking them, they were scored on how efficient the information was.
2.1 Literature Search

A systemic review usually aims to identify, appraise, select, and synthesise high
quality research evidence relevant to the question investigated. The databases used;
PubMed, Science Direct, Medline, Wiley, and Web of Science were searched from
the years 1990 to 2015. All literature included was written in English. The reasons
why some the literature is more than 30 years old is because some understandings
within this field have not been developed that significantly in more than three
decades and also it was also to make sure that relevant studies were not ignored.
The following key words were used in different orders and combinations by using the
word ‘AND’: Dystonia, focal dystonia, writer’s hand cramp, musician’s dystonia,
hand, focal–task specific dystonia, effect, cause, symptoms, basal ganglia, pianists,
brain, genetic, inherited, exercise, physiotherapy, treatment, electromyography, EMG
feedback, stretching, strengthening, botulinum toxin and repetitive strain. The words
that was excluded from the search by using the word ‘NOT’: Parkinson's disease,
Cerebral palsy, selective peripheral denervation, and rhizotomy. Table 2 illustrates
the order in which a search would occur in a database for online journals.
16
Table 2: search terms used in databases.
Database First step First term Second Third term Additional

term options
Medline Advanced Focal Musicians Pianists (go to
Search Dystonia settings and
select date
newest)
Wiley Online Advanced Focal Musicians Pianists 1807
Library Search Dystonia
Science Advanced Focal Pianists Treatments 1997
Direct Search Dystonia
Web of Add two Focal Dystonia Genetics Send to
Science more search Refworks
bars
Figure 3: Science Direct database.
17
Additionally to the literature search reference lists of the journals were found during
the search to retrieve future journals. As well as using Web of Science, journals were
able to be saved to endnote online through Refworks as shown in figure 4. To obtain
some articles that were out the universities access the resource of the interlibrary
loans were available to retrieve these journals to attain the information needed.
Figure 4: Save to Refworks.
After selecting the correct article Web of Science has the resources to save to
Refworks. There are then options to then save the record content of which consists
of:
 Author, title, source
 Author, title, source, abstract
 Full record
 Full record and cited references
18
Once the option wanted is selected it is then sent to Refworks.
Potentially relevant journals

found (n=209)
Journals excluding based on

the title or the abstract
(n=159)
Articles that were assessed more

(n=50)
Article that did not match the

criteria (n=16)
Potential articles scored

(n=36)
Figure 5: Flowchart of the literature search of articles.
209 articles were initially found, 159 were excluded based on title and/or abstract, 50
were assessed more. Of these, 16 did not match the criteria, leaving 34 potential
articles to be used.
The books that were also included were either found within the university library or
online or found through reference lists in journals. Examples of some of these books
are summarised in table 3.
19
Table 3: The main books included.
Author, year of Title of Book Recommended

publication interventions
Garett, B. L., 2015 Brain and Behaviour : An Nervous system,
Introduction to Biological autonomic nervous
Psychology system, peripheral
nervous system, spinal
cord, brain, somatic
nervous system,
parasympathetic,
sympathetic, central
nervous system.
Purves, D. et al., 2004 NEUROSCIENCE Basal ganglia, brain stem,
corpus striatum, putamen,
caudate, promotor cortex,
thalamus, inhibitory
connections, motor
components, cerebral
hemispheres.
2.2 Inclusion and Exclusion Criteria for Journal Selection

Inclusion and Exclusion criteria was created in order to select the best journals for
the literature review.
Inclusion criteria
1. Article is no older than 40 years.
2. Article is written in English.
20
3. Article is found in one of the following databases: PubMed, Science Direct,
Web of Science, Wiley and Medline.
4. Article is about Focal Dystonia in Pianists.
5. The outcome of the measure is mentioned.
6. Intervention should be splinting, physiotherapy, muscle strengthening, muscle
stretching, EMG feedback, chiropractory, massage therapy, hypnosis,
relaxation therapy and acupuncture. Herbal therapies such as almond oil,
amylase enzyme treatment and geranium oil.
Exclusion Criteria
1. Intervention is rhizotomy and selective peripheral denervation.
2.3 Case Study

In order to conduct an interview the first thing that was needed to be done was draw
up questions to ask the participant A that relates to the research question. Then the
next step was to fill out an ethics form, create a participant information sheet,
consent form and send them to the ethics committee. The follow questions were
concluded:
1. How old are you?
2. What instrument do you play?
3. How many years have you known of your dystonia condition?
4. In what part of your body did your dystonia first appear?
5. What is your history of dystonia?
21
6. What is your past medical history that you are prepared to reveal?
7. Have you experienced any of the following? (Please answer “yes”, “no” or
“prefer not to answer” to each part i, ii and iii. Further details are not required.)
i. Neurological condition
ii. *Psychiatric condition (e.g. depression, anxiety, obsessive-compulsive
disorder)
iii. Repetitive strain injury
8. What do you think first triggered your dystonia?
9. What are your daily dystonia triggers?
10. What are your common dystonia symptoms?
11. When do you experience these dystonia symptoms?
12. How does your dystonia condition affect your lifestyle?
13. What examinations / investigations for dystonia have you had?
14. What treatments have been given to alleviate the symptoms of dystonia?
15. What doses do you take?
16. How often do you take medications for dystonia?
17. Have you / would you try an alternative therapy for dystonia?
18. Is there anything that temporarily eases the symptoms of dystonia?
22
19. Have you experienced any side effects (either long or short term) from these
treatments?
20. Does anyone else in your family have dystonia? (Please answer “yes”, “no”
or “prefer not to answer”. Further details are not required.)
21. Have you ever been treated for any other form of dystonia or muscle
contraction problem?
These questions were sent to the Anglia Ruskin University Ethics Committee panel
of three; two being internal and one being external. All members of the committee
were anonymous thus the project supervisor and researcher were unaware of who
was reviewing the questions. Philip Warburton was the chair of the committee to
ensure that all ethical issues were explored and clear decisions were made and
recorded. The ethics application was reviewed and improved five times before being
accepted due to the ethical issues that could be caused by some of the questions
asked, hence some questions were modified and question 6 was deleted, as shown
above. Questions 7 and 20 were also altered to provide ‘yes’ or ‘no’ and ‘prefer not
to answer’ responses only instead of the original question that said ‘prepared to
reveal’.
23
Chapter III
3.0 Results and Discussion
3.1 Bioinformatics Analysis

Luscombe, et al., 2001, conducted an investigation where they collected a variety of
data from functional genomics and also gene sequences, which gave interest into a
new field, bioinformatics. They define bioinformatics in relation to the transcriptional
regulatory system. It is conceptualized as the macromolecules that are then applied
by the “informatics” techniques, which derive from mathematical disciplines, in order
to understand and organise the information that is associated with these molecules,
on a wide scale.
The aims of bioinformatics is to use a variety of these computational techniques in
order to perform structural and sequence alignment, phylogenetic tree, gene
identification as well as prediction of the 3D protein structure and function. In relation
to FTSD various bioinformatics techniques were used in order to distinguish the
similarities between the proteins DYT1 two isotopes of TOR1A.
24
Figure 6: 3D structure of
TOR1A protein (Swede Group,
2015).
Figure 7: Alignment of TOR1A with the faulty amino acids. At the first Amino acid V
to F and A to F inhibits sequence signal cleavage, where the A and V regions are
highlighted. V to N is where N-glycosylation occurs. At 101 K to A there is a loss of
ATP binding. N to Q reduces N-glycosylation as shown in K and N. At 151 N to Q the
reduction of N-glycosylation occurs again. At amino acid E, the loss of ATP
hydrolysis occurs within the E to Q region which localizes the nuclear envelope (SIB
& GeneBio, 2011).
25
Figure 8: DNA sequence of DYT1, showing the inframe deleted nucleotides GAG,
which represents the E amino acid (GLU, glutamic acid) in the TOR1A protein chain.
With the use of Uniprot the torsin protein amino acids are presented with the option
of converting it into the FASTA format in order to put both isotopes of Torsin-1A into
any database to show the alignment as shown below.
26
TOR1A_HUMAN Torsin-1A isotope 1
MKLGRAVLGLLLLAPSVVQAVEPISLGLALAGVLTGYIYPRLYCLFAECCGQKRSLSREA
LQKDLDDNLFGQHLAKKIILNAVFGFINNPKPKKPLTLSLHGWTGTGKNFVSKIIAENIY
EGGLNSDYVHLFVATLHFPHASNITLYKDQLQLWIRGNVSACARSIFIFDEMDKMHAGLI
DAIKPFLDYYDLVDGVSYQKAMFIFLSNAGAERITDVALDFWRSGKQREDIKLKDIEHAL
SVSVFNNKNSGFWHSSLIDRNLIDYFVPFLPLEYKHLKMCIRVEMQSRGYEIDEDIVSRV
AEEMTFFPKEERVFSDKGCKTVFTKLDYYYDD
TOR1B_HUMAN Torsin-1A isotope 2
MKLGRAVLGLLLLAPSVVQAVEPISLGLALAGVLTGYIYPRLYCLFAECCGQKRSLSREA
LQKDLDDNLFGQHLAKKIILNAVFGFINNPKPKKPLTLSLHGWTGTGKNFVSKIIAENIY
EGGLNSDYVHLFVATLHFPHASNITLYKARMEVWNPFLDVIGFGVSLLWDEIWEFYVEMS
EPGKRFMSQFPLERCRS
The FASTA format of the two isoform’s sequences of the torsinA protein were
entered into the Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo/) input box
and submitted. It then produces the alignment of the two isoforms, in order to see the
similarities in the two isoforms of the protein.
1A-1 MKLGRAVLGLLLLAPSVVQAVEPISLGLALAGVLTGYIYPRLYCLFAECCGQKRSLSREA 60
************************************************************
1A-1 LQKDLDDNLFGQHLAKKIILNAVFGFINNPKPKKPLTLSLHGWTGTGKNFVSKIIAENIY 120

************************************************************
1A-1 EGGLNSDYVHLFVATLHFPHASNITLYKDQLQLWIRGNVSACARSIFIFDEMDKMHAGLI 180

1A-2 EGGLNSDYVHLFVATLHFPHASNITLYKARMEVWNPFLDVIGFGVSLLWDEIWEFYVEMS 180
**************************** ::::* :::**: :::. :
1A-1 DAIKPFLDYYDLVDGVSYQKAMFIFLSNAGAERITDVALDFWRSGKQREDIKLKDIEHAL 240

1A-2 EPGKRFMSQFPLERC---------------------------RS---------------- 197
: * *:. : * **
1A-1 SVSVFNNKNSGFWHSSLIDRNLIDYFVPFLPLEYKHLKMCIRVEMQSRGYEIDEDIVSRV 300

1A-2 ------------------------------------------------------------ 197
1A-1 AEEMTFFPKEERVFSDKGCKTVFTKLDYYYDD 332

1A-2 -------------------------------- 197
Figure 9: Alignment of the two isoforms of DYT1 protein.
27
The asterisks “*” and highlighting indicates the position where there is a similarity in
both protein’s amino acid sequence. The “:” shows the conservation between the two
protein groups which are strongly similar in relation to the clustal scoring > 0.5 in the
Gonnet PAM 250 matrix. The “.” Specifies the weakly similar properties within the
two protein groups of =< 0.5 in the Gonnet PAM 250 matrix (Larkin et al., 2007).
Table 4: Summary of the amino acids in the alignments in TOR1A isotopes.
Dystonia isoforms Code in Protein Number of
sequenc amino
e figures acids
Early-onset Torsin-1A isotope 1 O14656 TorsinA 332
generalised (UniProt
dystonia Consortium,
2015)
Early-onset Torsin-1A isotope 2 O14656- TorsinA 197
generalised 2 (UniProt
2015)
In order to work out the percentage of the similarities the two FASTA formats of the
isotopes are entered into (http://www.ebi.ac.uk/Tools/psa/emboss_water/), EMBOSS
Water and submitted which shows the exact amount of similarities and percentage.
This database calculated the similarities as 170/198, which produced the similarity
28
percentage as 85.9%. It also calculated the identity as 157/198 (79.3%) and the
gaps in the alignment as 12/198 (6.1%).
1 1 MKLGRAVLGLLLLAPSVVQAVEPISLGLALAGVLTGYIYPRLYCLFAECC 50
||||||||||||||||||||||||||||||||||||||||||||||||||
2 1 MKLGRAVLGLLLLAPSVVQAVEPISLGLALAGVLTGYIYPRLYCLFAECC 50
1 51 GQKRSLSREALQKDLDDNLFGQHLAKKIILNAVFGFINNPKPKKPLTLSL 100
||||||||||||||||||||||||||||||||||||||||||||||||||
2 51 GQKRSLSREALQKDLDDNLFGQHLAKKIILNAVFGFINNPKPKKPLTLSL 100
1 101 HGWTGTGKNFVSKIIAENIYEGGLNSDYVHLFVATLHFPHASNITLYKDQ 150

||||||||||||||||||||||||||||||||||||||||||||||||.:
2 101 HGWTGTGKNFVSKIIAENIYEGGLNSDYVHLFVATLHFPHASNITLYKAR 150
1 151 LQLW------IRGNVSACARSIFIFDEMDKMHAGLIDAIKPFLDYYDL 192

:::| |...|| .::||:.:.:..:.:..|.|:..:.|
2 151 MEVWNPFLDVIGFGVS------LLWDEIWEFYVEMSEPGKRFMSQFPL 192
The alignments shown above display the similarities within both isotopes.
Comparisons of Amino Acid Sequence Sim-

ilarity of TOR1A-1 and TOR1A-2
100.00%
90.00%
80.00%
Identity 157/198
70.00%
60.00%
Percentage
50.00% Similarity 170/198

40.00%
30.00% Gaps 12/198
20.00%
10.00%
0.00%
TOR1A-1 TOR1A-2
Differences in TOR1A-1 and TOR1A-2
Figure 10: A double amino acid sequence comparison between the two isotopes of
TOR1A protein. The blue bars represent the number of identities in each isotope.
The red bars represent the similarities and the green bars show the number of gaps.
29
The two isotopes FASTA can then be entered into the ExPASy ProtParam in order to
see all of the amino acid composition within each of them, specifically looking at
Glutamic Acid where the mutation occurs to see if there is a difference in each of the
protein chains as shown in figures 10 and 11. These differences are illustrated in the
graph in figure 12.
Figure 11: Amino acid composition of isoform Torsin-1A isotope 1.
30
Figure 12: Amino acid composition of isoform Torsin-1A isotope 2.
Frequencies of The of Amino Acids in TOR1A-1 and

TOR1A-2
16
14
12
10
Frequency
8
6
4
2
0
Ala Arg Asn Asp Cys Gln Glu Gly His Ile Leu Lys MetPhe Pro Ser Thr Trp Tyr Val Pyl Sec
Composition of Amino Acids
TOR1A TOR1B
Figure 13: Frequencies of amino acids of isotopes TOR1A-1 and TOR1A-2.
31
3.2 Bioinformatics Discussion
The comparisons between TOR1A-1 and TOR1A-2 show similar frequencies for the
following amino acids; Ala, Thr, Pyl and Sec. The amino acids Asp, Gly and Leu
have the greatest difference in frequencies between the two isotopes. The
similarities between the two isotopes overall worked out to be 157 which is 79.3%,
suggesting that the isotopes are very similarities in their protein chain of amino acids.
In relation to the classical hypothesis of the basal ganglia network or circuits, the two
isotopes are suggested to be related to the striatal medium neurons that express
D1R which contributes to the direct pathway and also the expression of D2R which
contributes to the indirect pathway. Reduction of the striatal D2R binding activity is
suggested to occur within focal dystonic patient’s PET scans (Perlmutter et al.,
1997). Reductions of the striatal torsinA and D2R activity and function through a cell-
autonomous mechanism results in motor deficits (Dang et al., 2005). These results
gives idea that the possibility of gene therapy that non-specifically targets the
defective protein processing may not be the best approach, however the mutated
GAG regions of the TOR1A proteins may be the target of specificity. Inhibiting the
expression of mutant torsinA, through the hairpins of RNA that mediate allelic-
specific suppression, could alternatively save cells from the dominant-negative
effect, which might restore the normal distribution of the wild-type torsinA (Gonzalez-
Alegre et al., 2005).
32
3.3 Case Study – Interview Results
Researcher: “How old are you?”
Participant A: “45”
Researcher: “What instrument do you play?”
Participant A: “Piano”
Researcher: “How many years have you known of your dystonia condition?”
Participant A: “20 years”
Researcher: “In what part of your body did your dystonia first appear?”
Participant A: “Right hand”
Researcher: “What is your history of dystonia?”
Participant A: “1995 first happened as a copy typist. Working 7 hours of copy typing
a day, first noticed when copy typing the first index finger collapsed. First instinct was
to just ignore at first. Had a break and then tried to continue typing again but never
recovered. Then went to see a GP who put me on antibiotics and ibuprofen for a
month. The condition was still the same. Then was referred to National Hospital of
Neurology. Attended there ever since.”
33
Researcher: “Have you experienced any of the following? (Please answer “yes”,
“no” or “prefer not to answer” to each part i, ii and iii. Further details are not
required.)
ii. Psychiatric
*
condition (e.g. depression, anxiety, obsessive-compulsive
disorder)
iii. Repetitive strain injury”
Participant A: i. “Yes”
ii. “No”
iii. “Yes”
Researcher: “What do you think first triggered your dystonia?”
Participant A: “Repetitive strain in left hand taking cortisone injections for it so
overworking right which put stress on right hand.”
Researcher: “What are your daily dystonia triggers?”
Participant A: “Playing and writing”
Researcher: “What are your common dystonia symptoms?”
Participant A: “Arm contracts fingers also curl in.”
Researcher: “When do you experience these dystonia symptoms?”
Participant A: “When playing.”
34
Researcher: “How does your dystonia condition affect your lifestyle?”
Participant A: “As a musician it affects it a lot but in general not at all but it depends
on career choice and when writing sometimes.”
Researcher: “What examinations / investigations for dystonia have you had?”
Participant A: “Observed while played piano. Observation of holding a
pen.”
Researcher: “What treatments have been given to alleviate the symptoms of
dystonia?”
Participant A: “Botox”
Researcher: “What doses do you take?”
Participant A: “Vary dependent on how bad the contractions are each time.”
Researcher: “How often do you take medications for dystonia?”
Participant A: “Every 4 months.”
Researcher: “Have you / would you try an alternative therapy for dystonia?”
Participant A: “Yes if it would help but not open to surgery. Only tDCS by a student
specialist.”
Researcher: “Is there anything that temporarily eases the symptoms of dystonia?”
Participant A: “Only the Botox and zinc, green and yellow foods. Iron”
35
Researcher: “Have you experienced any side effects (either long or short term) from
these treatments?”
Participant A: “Weakness from Botox.”
Researcher: “Does anyone else in your family have dystonia? (Please answer
“yes”, “no” or “prefer not to answer”. Further details are not required.)”
Participant A: “No”
Researcher: “Have you ever been treated for any other form of dystonia or muscle
contraction problem?”
3.4 Case Study Discussion

Participant A being a 45 year old female that plays piano for 20 years, that suffered
from focal hand dystonia in the right hand, coincides with the research question. The
participant also explained that they had overused or misused their hands by copy
typing for a minimum of 7 hours a days as well as being a musician. These results
suggest that the somatosensory response to the over use of the muscles in
participant’s A right hand caused the index fingers to collapse and develop the
dystonia traits. Participant A confirming that they had a no history of a psychiatric
disorder but had experienced both a neurological disorder and repetitive strain injury
before reinforces the fine line between repetitive strain has with focal task specific
disorder and how easy it is to misdiagnose patients if physicians or specialists do not
understand know how to manage the symptoms of dystonia. Playing and writing
36
being daily triggers and the common symptoms for participant A is contractions in
the arm and the fingers curling in which are the typical symptoms and traits that focal
task-specific patients that suffer with dystonia in the hands undergo. The symptoms
affect the participant’s lifestyle only as a musician and when trying to write
sometimes. Participant A saying they had repetitive strain injury can be questioned in
relation to also misdiagnosis of dystonia for repetitive strain in the left hand, which
left them untreated for the right condition for a great period of time that caused them
to misuse the other hand resulting in dystonia in the right hand. The only
examinations the participant has ever experienced was observational, where they
were required to play the piano and also holding a pen whilst writing. The only
treatments the patient has ever received has been botulinum toxin suggesting that
the efficacy of the toxin is positive (Karp, 2004). The variations of doses suggest that
it is dependent on the intensity of the contractions within the 4 period of each session
from seeing the specialist. Participant A admitting that they are open to alternative
therapies and also try to increase their zinc, iron, yellow and green food intake.
Langham, 2011, suggested that pickled green olives, spinach and broccoli are rich
with vitamin E, which is an antioxidant that and assumed to decrease inflammation
and transports oxygen to the nerves and muscles. It also repairs nerve and muscle
damage which reduces the muscle spasms. Muscle weakness from the botulinum
toxin injections, similarly researchers suggest that with the increased frequency of
injections there is an increased risk of systemic weakness to the treated area and
areas sounding (Crowner et al., 2010). Participant A having no relative with dystonia
and no other form of dystonia reinforces the data above that there is no link between
37
focal hand dystonia and the other forms; as the participant developed the condition
at a late stage in their life and does has not experienced any other form of dystonia.
Chapter IV
4.0 DEFINING FOCAL TASK-SPECIFIC DYSTONIA
4.1 Definitions and Classifications of Dystonia

In order to completely understand Focal Task-Specific Dystonia (FTSD), first the
origins need to be considered as well as the terminology, classification and diagnosis
in general. In February 1984, an ad hoc committee of the Dystonia Medical
Research Foundation provided a definition that is still used today. The revised
definition:
“Dystonia is a movement disorder characterized by sustained or intermittent muscle
contractions causing abnormal, often repetitive, movements, postures, or both.
Dystonic movements are typically patterned, twisting, and may be tremulous.
Dystonia is often initiated or worsened by voluntary action and associated with
overflow muscle activation.” (Albanese et al., 2013)
However (Albanese et al., 2013), suggested that there were several faults in this
definition. The first expression used “sustained muscle” denotes one specific
38
manifestation of dystonia, it also ignores any other less sustained manifestation.
Muscle spasms and contractions may be continuous, forcing limbs and trunk into
sustained postures, but they may also be as continuous or irregular as
blepharospasm. Second, the quality of “abnormal postures” is not specified in the
definition. Postural changes may be caused by a number of things such as fixed or
dynamic, tonic or spasmodic and many more combinations. Third, there are
particular characteristic of dystonia, such as the role that is played by movement
initiation, the stereotypical nature and pattern of movements within an individual, and
an excess of activation of extraneous muscles, are not thoroughly expressed in the
1984 definition.
The 21st century classification system can be clinically categorised according to
temporal pattern, age of onset (table 5), associated features (table 6) and body
distribution (Klein, Marras and Münchau, 2015). The age at which the dystonia first
appears, is very important in indicating the severity and possible development of
symptoms. In most cases, the younger the age at onset, the greater the chance of
symptoms developing and spreading to other parts of the body within in small
amount of time (Zilber et al., 1994). The body distribution refers to how much of the
body is affected which is discussed in table 5.
Table 5: Classifications of Dystonia by Age (Klein, Marras and Münchau, 2015).
Age of Onset
Infancy (neonatal – 2 years)
Childhood (3-12 years)
Adolescence (13-20 years)
39
Early adulthood (21-40 years)
Late adulthood (>40 years)
Table 6: Classifications of Dystonia’s by the Affected Body Part.
Types of Dystonia Number of Details

Body the
Parts
Affected
Focal 1  Hand and arm (writer's cramp)

 Mouth (oromandibular dystonia, musician's
cramp)
 Larynx (dystonic adductor dysphonia, "whispering
dysphonia")
 Eyelids (blepharospasm)
 Neck (cervical dystonia, previously known as
spasmodic torticollis)
Segmental ≥2  Brachial (1 arm & trunk; both arms ± neck ±
contagious trunk)
muscle  Crural (1 leg & trunk; both legs ± trunk)
groups  Axial (neck and trunk)
Multifocal ≥2 non- Facial-brachial (blepharospasm & writer’s cramp)
40
contagious
muscle
groups
Hemidystonia Ipsilateral arm & leg
Generalised ≥3 Trunk & ≥2 other sites; ± leg involvement
Classification in this way allows the summation of the dystonia phenotypes such as
focal isolated dystonia with onset in adulthood. The first term “focal” refers to one
localised are of the body affected, in the case of in pianists. The next term is “task-
specific” characterises the clinical nature of the dystonic movements only when
completing a specific task. Dystonia is once again is a neurodegenerative syndrome
of involuntary muscle contractions, that results in the frequent twisting repetitive
movements, or abnormal postures. A spasm that occurs in a piano player when
attempting to play a note, the inability lift hand, the inability to sustain a note without
rapidly trembling, cramping and sustained postures inhibiting pianists from playing.
4.2 Causes of FTSD

There are many different causes of Dystonia such as behavioural causes, injury,
genes, trauma, brain lesions, and lots more. In relation to focal-task specific
dystonia, an increasing amount of research focuses on the idea that the condition is
a product of the overuse which results in a disorder in the somatosensory cortex
(Lim, Altenmüller and Bradshaw, 2001).
The ‘healthy’ neurological process required for piano players can be broken down
and described in two steps: auditory perception and self-actualisation. The player
initially internally will hear what he or she wants to play, built upon a specific sound
41
concept-e.g., time signature, dynamic level, the ideal tone quality etc. The body then
creates the sounds exploiting the instrument (piano) through an attempt to match the
sound. This in turn creates a circuit or neural pathway, in which the concept of sound
is the initiator that directs the motor cortex to transmit signals to the muscles that ae
needed to the actions that will create a sound matching the concept. The movements
of the piano player such as: extend arms, extend fingers, sit up straight and tap
fingers through the facilitated output pathway. Whilst this is occurring the brain is
receiving sensory information, the hearing the conceptual (actual) sound and the
kinaesthetic sense of playing, which stimulates the input on the neural pathway.
These two pathways the motor cortex output and the somatosensory input, create a
circuit that regulate and control the motor functions. While the sensory input is for
making adjustments is essential, it is auditory perception or sound realisation that
produces the output function that is the force behind ‘healthy’ piano playing (Tubiana
and Amadio, 2009) as shown in figure 13.
42
Figure 14: Sensory-motor loop. Within the loop the information flows from the
supplementary motor cortex to the caudate nucleus and putamen and from there is
transferred to the globus pallidus and the substantia nigra, where it continues to the
thalamus and then back to the supplementary motor cortex (Patestas and Gartner,
2006).
If, however, sensory input becomes the focus of a piano player’s attention, then a
disruption of the motor cortex pathway may occur. In consideration to professional
musicians whom often perform and practice on their instrument for many hours,
several times a day. If these hours of practice become too extensive or a vehicle for
misuse or overuse, intense focus on the sensory input, this can cause overactive
impulses in the sensory pathway which can become problematic. This is then
transmitted from the striatum to the GPi, which leads to excessive inhibition of the
GPi and excessive disinhibition of the motor cortical regions and is regarded as
enhanced facilitation (Mink, 2003). It is also assumed that there is a decrease in the
striatal dopamine receptors binding in D2 and D3. This causes signals from the
sensory input to interfere and fuse with the motor cortex output which would result in
the continuous contractions within the hands, involuntary movements, and also
causing the fingers to curl in, due to the pull of the muscles as illustrated in figure 14
(Karimi et al., 2010).
43
Figure 15: An image of a hand displaying the symptoms of FTSD; the fingers curl in
due to the contractions (Konczak and Abbruzzese, 2013).
4.3 Loss of Inhibition

Rosales and Dressler, 2010 suggested that there is a loss of inhibition at several
points of the neuroaxis in dystonia. Abnormal short intracortical inhibition (SICI) was
observed when transcranial magnetic stimulation was used (Ridding et al., 1995).
Although a decrease in short intracortical inhibition; medicated by GABA-A (Di
Lazzaro et al., 2000), was seen in both motor cortices of patients, which suffer from
writer’s cramp, which suggests a primary dystonic defect. On the other hand, the
alterations in the GABA-B-mediated long intracortical inhibition and the silent periods
were only tested on the affected writer’s hand limb suggests a symptomatic dystonic
effect (Ridding et al., 1995).
4.4 Symptoms of FTSD

The initial signs of focal-task specific dystonia in pianists may be subtle that may be
unnoticed for a certain period of time. Less controlled pianists with slight spasms or
cramps while playing short or soft (piano) passages. This can easily be mistaken for
lack of practice or playing badly that day, having a ‘bad play day’.
44
A concise definition for focal-task specific dystonia can be expressed from through
the classification of dystonia methods. Dystonia usually occurs in one finger and
rarely spreads to the other fingers. The most affected fingers are ulnar digits (fingers
4 and 5) (Rosales, 2012). It was suggested by Rosales, 2012, that these two fingers
are not supposed to be used for prolonged, highly complex and rapid movements
demanded of those patients with focal hand dystonia. Frucht, 2009, also proposed
the idea that there is hypermobility within the joints when ulnarly deviated grip to
instruments thereby resulting in a susceptibility of these fingers to the development
of dystonia. Ioannou and Altenmüller, 2014, classified task-specific focal hand
dystonia as muscular incoordination and loss of motor control when playing an
instrument.
4.5 Diagnosis of FTSD

The definition and classification of dystonia is intricate and complex. The following
discussion is initially aiming to clarify the misunderstanding of dystonia. It is
understandable that with the disorder being elusive, it makes it more difficult to
obtain an accurate diagnosis, which can be damaging to a musician’s career, which
may lead to the avoidance of a diagnosis of any sort altogether. Although any
physician is capable of diagnosing dystonia with doing the right amount of research,
the best option or recommendation is a neurologist. Typically a physician whom
suspects their patients has symptoms of dystonia usually is referred to an
appropriate specialist. Unfortunately due to the difficulty of diagnosing dystonia in
musicians, several referrals or opinions may be required before a diagnosis is
rendered. A physical and neurological examination is taken to help diagnose patients
(Stacy, 2012).
45
The diagnosis of idiopathic focal hand dystonia relies on the clinical evaluation which
identifies the features that are consistent with dystonia and excludes secondary
causes. Patients with other disorders may present similar complaints, however the
displayed symptoms of combined painless, task-specific uncontrolled spasms, and
abnormal posture illustrate dystonia.
Most studies that conducted structural MRIs failed to show any sign of neural
degeneration within patients with primary dystonia (Rosales, 2012), despite subtle
white and grey matter micro-structural modifications were stated (Black, Ongur and
Perlmutter, 1998). Although, results have found that when using voxel-based
morphometry there was increased volumes in the putamen (133), cerebellum (135),
sensorimotor cortex (132) and globus pallidus (134), however other decreased
volumes in the sensorimotor cortex (137), putamen (136), thalamus and cerebellum
(137,136).
Repetitive strain injury (RSI) is clinically diagnosed as an occupational cause of hand
pain and a disability that can easily be mistaken for dystonia (Stacy, 2012).
Repetitive stress injury is pain within the affected arm or hand. The dystonic
symptoms may progress from the pain present only during the use of the limb, pain
is persistent even when resting, and limbs may swell or show signs of inflammation.
Similar to dystonia, repetitive stress injury can be considered traumatic or strenuous,
repetitive hand use, awkward joint positions and prolonged unnatural postures.
However, unlike dystonia limbs are still able to function although they are impeded
by pain (Stacy, 2012).
46
4.6 Hormones
Researchers found that 149 men with 23 women that had focal hand dystonia, there
was no effect on contraceptive hormones, pregnancy and menstrual stages on
dystonia in comparison to women without dystonia (Rosset-Llobet, Pascual-Leone,
and Fàbregas-Molas, 2012).
4.7 Drug-drug interactions

Dystonia’s are reported to arise from a drug-induced change of the dopaminergic-
cholinergic within the basal ganglia. Majority of drugs used cause dystonia reactions
through the nigrostriatal dopamine D2 receptor blockade, resulting in an excess of
striatal cholinergic output. The D2 receptors are assumed to produce an acute
dystonia reaction (Marsden and Jenner, 1980).
Age is considered to decrease the risk of the development of dystonia due to the
decline D2 receptors. Volkow et al., 1998, found that as age decreased so did motor
function, which results in impaired performance when performing tasks. Interventions
to increase dopamine activity is assumed to improve performance for the elderly.
4.8 Psychology
Depressive, sensitive, anancastic and hysterical traits were investigated in patients
with focal hand dystonia. Anxiety was found to be higher in the group with dystonia
patients in comparison to the control group (Jabusch, Müller, and Altenmüller, 2004);
(Cottraux, Juenet and Collet, 1983).
47
Chapter VI
5.0 Genetic Association to FTSD
5.1 Classifications of genes

Hermann Oppenheim is assumed to be the first case of genetic DYT1 dystonia in
1911 the paper entitled, “U¨ ber eine eigenartige Krampfkrankheit des kindlichen und
jugendlichen Alters [About a peculiar cramping sickness in children and adolescents]
(Dysbasia lordotica progressiva, Dystonia musculorum deformans” (Klein and Fahn,
2013). Oppenheim coined the definition of “dystonia” as oppose to misdiagnosing it
48
as ‘hysteria’. Oppenheim helped researchers initiate investigations into genetics in
dystonia and classify the different types of dystonia’s by the genes, locus,
chromosomal, clinical characteristics and many more ways.
There are currently a list of 25 DYT polymorphisms of hereditary dystonia, only 16

from DYT1-16 have are shown in table 7.
Table 7: A Molecular Classification of Hereditary Dystonia.
Locus Gene Chromosomal Designation Clinical Reference

location characteristics
DYT1 TorsinA (TOR1A) 9q32-34 Early-onset Only in one limb. Ozelius et al.,
primary dystonia 1997
DYT2 Unknown Unknown Autosomal Early-onset, Zlotogora,
recessive segmental or 2004
generalised.
DYT3 TATA-binding protein- Xq13.1 X-linked Prevalent in the (Makino et al.,
associated Philippines. 2007)
factor-1 (TAF1) Segmental or
generalized
dystonia
DYT4 Unknown Unknown “nonDYT1” cervical and (Ahmad et al.,
49
laryngeal dystonia 1993)
DYT5 GTP 14q22.1- / Dopa- Dramatic response (Ichinose et
Also cyclohydrolase I q22.2 responsive/ to L-dopa. al., 1994)
known (GCH1) Dystonia- Concurrent
as parkinsonism parkinsonism.
GCH1
DYT5 Tyrosine 11p15.5 Segawa Same as Lüdecke et al,
hydroxylase syndrome DYT5/GCH1 1995
dystonia
DYT6 Unknown 8p21-q22 adolescent- Rarely generalises, Almasy et al.,
onset of mostly segmental 1997
mixed type
DYT7 Unknown 18p11.3 adult-onset focal Writer’s cramp, Leube et al.,
torticollis, 1999
blepharospasm and
dysphonia
DYT8 Myofibrillogenesis 2q35 paroxysmal Attacks of Rainier, 2004
regulator-1 (M non-kinesigenic choreoathetosis
R1) PNKD dyskinesia influenced by
alcohol, fatigue,
stress etc.
DYT9 Unknown 1p21-p13.3 paroxysmal Similar to DYT8 Auburger et
choreoathetosis although spastic al., 1996
with episodes of paraplegia attack
spasticity and occur between
ataxia
DYT10 Unknown 16p11.2-q12.1 paroxysmal Attacks of Tomita et al.,
kinesigenic choreoathetosis 1999
choreoathetosis initiated by abrupt
movement
DYT11 Epsilon- sarcoglycan 7q21/ myoclonus responsive to Rudzińska et
(SGCE) DRD2 11q23 dystonia alcohol al., 2012
DYT12 Alpha-3 subunit of 19q12-q13.2 rapid-onset Develops over Zaremba et
the N,K-ATPase dystonia- hours or weeks al., 2004
(ATP1A3) parkinsonism
DYT13 Unknown 1p36.32-/ multifocal/ Focal or segmental Valente et al.,
p36.13 segmental with onset within the 2001
dystonia cranial-cervical
region or axial
muscles, hands,
upper limbs
DYT15 Unknown 18p11 alcohol- Alcohol responsive Grimes et al.,
50
responsive 2002
myoclonic
dystonia
DYT16 Protein kinase, 2q31.3 young-onset Generalised, Camargos et
interferon inducible dystonia- progressive al., 2008
double stranded parkinsonism
RNAdependent
activator
(PRKRA)
Table 7 is smaller than the other tables because it’s a large table that was not fitting
properly on the pages.
5.2 TOR1A Protein

The gene TOR1A in chromosome 9q32-9q34 was identified by (Ozelius et al., 1997).
A 3-bp deletion (GAG) is assumed to occur in Exon 5 of TOR1A, which is associated
with the majority of the cases of early-onset primary generalised dystonia. Some
cases are similar and others are sporadic. Torsin1A is expressed in the human
tissues ubiquitously, which encodes for the two isoforms Torsin1A-1 and Torsin1A-2.
The GAG deletion mutation subsequently results in the loss of glutamic acid in the
carboxy terminus of the protein (Ozelius et al., 1999). Despite DYT1 dystonia being a
very uncommon dystonia it has been reported to be around 0.2 to 0.5 per 100,000
within the general population of Europe with the prevalence of DYT1 GAG deletion.
Although, Kamm, 2006 reported that Ashkenazi Jews have a higher frequency
around 1 per 2,000 to 6000 people.
The cellular and molecular functions of torsinA are still not distinct but are essential
to understand exactly what focal task specific dystonia is. Ozelius et al., 1997,
established that from the amino acid sequence, torsinA derives from ATPase and is
associated with a variety of cellular activities (AAA+). The torsinA protein carries an
51
N-terminal signal sequence, a single AAA+ module, and two biochemical-confirmed
glycosylation sites (LIU, ZOLKIEWSKA and ZOLKIEWSKI, 2003). The AAA+ module
consists of four motifs: a Walker A motif which regulates the binding of nucleotides; a
Walker B motif which is essential for ATPase activity; a sensor 1 that is needed for
nucleotide hydrolysis; a sensor 2 is important for both nucleotide binding and
hydrolysis (Hanson and Whiteheart, 2005). In comparison to the three motifs that
conserve and are important in the way AAA+ proteins function, sensor 2 determines
the specificity of the protein (Joshi, Baker and Sauer, 2003).
TorsinA is located within the lumen of the endoplasmic rough endoplasmic reticulum
(ER) and nuclear envelope (Nery et al., 2011). Nery et al., 2008, investigated the
interactions of torsinA between proteins in the outer membrane of the nuclear
envelope and the cytoskeleton involved in nuclear polarisation, as well as in the
inner and outer nuclear envelope membranes that contribute to the nuclear envelope
morphology. The participating proteins through the rough ER component of the
secretory pathway is also included (Hewett et al., 2008). Researchers suggested
that the overexpression of torsinA within the cultured cells inhibits processing of
polytopic plasma membrane proteins e.g. dopamine transporters. The
overexpression of torsinA is also caused by the set arrangement of the vesicular
monoamine transporter within the membrane inclusions (Misbahuddin et al., 2005).
The GAG deletion mutation penultimately causes in the chain cycle of a decrease in
the release of dopamine into the synaptic cleft and manage to the dopamine
receptors. Which causes interference with the signals and motor cortex output,
resulting in the typical focal task-specific dystonic spasms and mannerisms.
52
5.3 Twin studies and familial genetics with FTSD
The theoretical risk of in familial cases for siblings carrying the DYT1 gene was 21%
and in an isolated case was 14%. There is no research on the risk of having a
severely affected child (Nemeth, 2002). Waddy et al., 1991, also found that 10-20%
of patients with task specific dystonia’s have a family history with the condition.
Chapter V
6.0 Treatment of FTSD
There is no known cure for FTSD or any other form of dystonia. Instead, there are
treatments for dystonia to help alleviate the symptoms. Even in the 21 st century no
treatment has been universally found successful for focal-task specific dystonia, all
treatments have only produced minimal success (Adler, 2000). There are a variety of
methods available for FTSD, complementary and alternative. Complementary
treatments or therapies include botulinum toxin injections, psychotherapy, oral
treatments, physiotherapy, transcranial direct stimulation & transcranial magnetic
53
stimulation, deep brain stimulation, and surgery. An alternative treatment is
biofeedback.
Comprehensive
6.1 Botulinum Toxin (BT)

Botulinum toxin types A and B (BT-A and BT-B) have been clinically proved to be
safe and is most commonly used treatment is botulinum toxin injections for focal
hand dystonia and writer’s hand cramp (Rossetto et al., 2006). As with all dystonia
treatments, botulinum toxin is prescribed with the intention of alleviating the
symptoms, not curing the disorder (Rosales and Dressler, 2010). BT is effective in
blocking neuromuscular junctions by electric stimulation of the peripheral nerve
(Eleopra, Tugnoli and de Grandis, 1997). BT disrupts neurotransmission of
acetylcholine by cleavage of the presynaptic fusion proteins; SNAP-25 for BT-A and
synaptobrevin for BT-B (Dressler and Adib Saberi, 2005). BT-A enters the neurons
by binding the synaptic vesicle protein SV2 (Mahrhold et al., 2006), then undergoes
endocytosis and translocation into the cytosol, which causes it to exert its light chain
proteolytic activity (Rossetto et al., 2006), as shown in figure 15.
54
Figure 16: The release of acetylcholine in the nerve terminals in the packaged
vesicles. The vesicle membrane fuses with the synaptic vesicle protein SV2,
releasing the transmitter into the synaptic cleft. The process is mediated by the
SNARE proteins (Okun, 2009).
Karp, 2004 proposed steps to illustrate how to treat a patient with a botulinum toxin
injection. The first step in treating hand dystonia is carefully evaluating and selecting
the muscles for injection. The patient is examined during resting and tasking period
to specifically activate the dystonia; pianist while playing the piano and resting.
Although the complexity of such movements, makes it difficult to determine which
movements are a normal pattern for that activity of playing and which are dystonic.
The analysis of dystonic patterns may be further complicated by involuntary
55
movements. It is then helpful, to have the patient participate in other activities that
may provoke the dystonia without the associated involuntary movements or
compensation. Writing with the non-dominant hand, which will induce the dystonia in
the dominant, resting hand, is one strategy.
After an injection, the BT complex dissociates and diffuses into the target tissues.
The spread is effective and fast phenomenon by BT dose, the size of the needle and
injection technique (Pickett, 2009). Although clinical observations are usually
adequate for selecting muscles in most patients, if treatments fails or if the abnormal
movements are more complex, wire EMG are resourceful. Wires are inserted in two
to three muscles, where the BT injection is then inserted in one or two sites in each
muscle, depending on the volume of the injection given and the size of the muscle
(Molloy et al., 2002). The initial doses of botulinum toxin A (BOTOX, Allergan, Irvine,
CA) used at Karp, 2004, institution range from 2.5 U which are used in small muscle
such as hand intrinsics to 50 U for large proximal arm muscles such as triceps and
biceps (Karp, 2004).
Despite the main aim is to physiologically weaken the dystonic features and over-
contracting muscles with the BT injection, it also reverses some of the underlying
physiological abnormalities in dystonia patients. Whereas there may be no change in
the EMG muscle contraction pattern in patients even if they benefit (Karp, 2004). It
also causes muscle weakness (Contarino et al., 2007)
56
6.2 Drugs
If patients become tolerant or resistant to anticholinergics such as Trihexyphenidyl,
baclofen, which is a γ-aminobutyric acid (GABA) agonist, should be considered and
can be added to the anticholinergic (Bressman, 2000).
6.3 Stereotactic surgery

Using the Vim, Voa, Vop, centromedian nucleus, pulvinar and subthalamic region as
targets thalamotomies were performed on patients with generalised dystonia
(Delnooz and van de Warrenburg, 2012). Improvement rates have varied between
15 to 25 % and have been higher for patients with primary dystonia (Delnooz and
van de Warrenburg, 2012). Taira and Hori, 2003 carried out thalamotomies carried
out on 12 patients with focal hand dystonia and reported that improvements were
made in the Writer’s Cramp Rating Scale (WCRS) in the patients directly after
surgery. Although two patients relapsed five months after surgery.
6.4 Transcranial direct current stimulation (tDCS) and Transcranial magnetic

stimulation (TMS)
Transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation
(TMS) are non-invasive alternative forms of treatment to modulate the function and
stimulate the brain. Delnooz and van de Warrenburg, 2012, describes that
transcranial direct current stimulation works (tDCS) by sending low current through
two electrodes that are placed in the region of the brain. This induces the
intracerebral current flow and alters the neuronal excitability, without the production
action potentials unlike transcranial magnetic stimulation (TMS) which is
characterised by the magnetic field on the outside of the scalp which induces an
electric field that also creates neuronal excitability to produce action potentials
(Ridding and Rothwell, 2007), resulting in change in the functioning of the brain.
57
Reports on tDCS were suggested to be effective task-specific focal dystonia
(Benninger et al., 2011; Buttkus et al., 2009).
6.5 Deep Brain stimulation

It was reported that patients with focal hand dystonia showed positive feedback after
the stereotactic lesion of the nucleus ventrooralis of the thalamus (Goto et al., 1997).
Taira and Hori, 2003, carried a study on twelve patients with FTSD where they
performed stereotactic nucleus ventrooralis (Vo) Thalamotomy. The stereotactic
target that was selected was at the junction of the anterior and posterior of the Vo
nucleus. Although all patients complained in a difficulty in writing, the WCRS score
decreased significantly after the Vo thalamotomy.
6.6 Psychotherapy-behavioural techniques

Through maladaptive plasticity of the brain including abnormalities in sensorimotor
integrations FTSD may arise (Cogiamanian, Barbieri and Priori, 2009). Odergren,
Stone-Elander and Ingvar, 1998, conducted a study where four patients with focal
hand dystonia were investigated; two male, two female. A video camera was used to
focus on right hand movements, which were shown on a screen to the patients
constantly. Conditions were set to enable that the writing of the subjects would not
differ from normal by putting a table for the subjects to place the arm right arm for
support whilst writing during the scan. The follow tasks were performed:
1. Drawing horizontal lines from left to right.
2. Writing “Twinkle, twinkle little star” at the beginning of the scan.
3. At the same time as the scan.
4. 30 seconds before the scan.
5. 120 seconds before the scan.
58
These four tasks were completed in a randomised order within three sections, each
subject experienced 12 PET scans. Subjects were instructed to remain writing at a
constant pace without stopping until the scan had ended. The results showed that
the duration of writing correlated to the progressive decrease of activity in the
patients’ angular gyri and left supramarginal.
6.7 Physiotherapy-sensor motor training

This treatment or therapy overlooks the digit exhibiting the distinctive dystonic
symptoms. The therapy is called sensory motor returning (SMR) (Candia et al.,
2002). Within it 1 or various digits are immobilised and practice is also given in
performing individual movements of the affected dystonic focal finger in coordination
with movements of with the other fingers. The exercises are performed on each
musicians’ instrument. The treatments were reported to be beneficial for 2 guitarists
and 6 pianists (Candia et al., 2002).
Alternative Treatments
6.8 Biofeedback
Biofeedback is used to re-educate the brain to improve normal excitation and
inhibition (Mai and Marquardt, 1994). The role of the feedback is to provide
information the status of the muscle contraction for the patient. The aim is then to re-
train the patient to turn a specific set the muscles being in FTSD in pianists in the
hands “on” or “off”. The system can then be readjusted dependent on sensitivity to
the underlying firing of the muscles within the hand (Cogiamanian, Barbieri and
Priori, 2009).
59
6.9 General Discussion
Focal task-specific dystonia in pianists is a vital problem that needs to be solved
within the musician medical field. Past research has found that there is a lack of
reporting in the media in this field to make the public aware of the risks. Within this
literature review it is clear that the syndrome is effected by genetic and
environmental factors. In order to solve this problem the need for more effective
ways of testing, diagnosing and treating the syndrome is what is required of
medicine for the future. The results from the case study and bioinformatics displayed
in chapter 3 indicated that the regulation of mutated TOR1A is assumed to be one of
the causes for FTSD. It also suggested that there is a plausible opportunity to
decrease the risk of developing FTSD through genetic therapy that specifically
inhibits the expression in the GAG regions where the mutation happens via the
hairpins of the RNA that mediate the areas allele-specific suppression. The results
also insinuate that the overuse of the hand muscles is linked to the loss of inhibition
and maladaptive plasticity that results in dystonic traits. This gives an opportunity to
explore ways to see the limit of use of muscles to avoid dystonia and reinforcement
of the efficiency of the treatments that are discussed in chapter 6. Although the
research attained from the case study is based on one person therefore the findings
cannot be generalised. The time period limit of 1 hour to interview the participant and
restriction of questions due to ethical issues limits the chances of obtaining more
information about participant A’s condition, however the participant may become
tired and their answers may be altered due to their lack of concentration after a
while.
60
Currently researchers are investigating the best post-acute rehabilitation in order to
maximise the motor function in task-specific patients. Neuromodulation techniques
are used such as non-invasive stimulation (transcranial magnetic stimulation [TMS],
transcranial direct current stimulation [tDCS]) and stimulation or blockage of the
peripheral nerves (Page et al., 2015).
DNA chip microarrays are used to screen SNPs within a few hours in order to
diagnose phenotypic variations in patients. The chip developed by Affymetrix, which
will be allows researchers to use a pharmocogenetic assays which enables the
genetic analysis of the metabolic pathways within drug assays such as botulinum
toxin for focal task specific dystonia (Limaye, 2013).
61
Chapter VII
7.0 Conclusion
7.1 Summary of Key Points

The purpose of this literature review was to create an understanding and promote
awareness of focal task-specific dystonia in pianists. An examination of medical,
scientific and professional literature was used in order to answer the following
questions:
In the simplest terms possible, what is FTSD?
FTSD is a neurological movement disorder affecting pianists where sustained
muscle contractions, causing twisting of the hands into an abnormal position which
can occur when playing, inhibiting the abilities to perform.
What are the symptoms of FTSD and are there any signs to help early
detection?
Focal task-specific focal hand dystonia is characterised by the muscular coordination
and loss of voluntary motor control during playing the piano (Ioannou and
Altenmüller, 2014). Initially the symptoms that commonly are displayed when
playing, can be easily ignored and difficult to detect. Potential warning signs consist
62
of the implications of a decrease in playing abilities, despite increased practice and
spasms or fingers curling in also inhibiting playing to a certain degree.
What are the causes of FTSD?
Investigations to attain a complete understanding of the cause of FTSD are still in
the motion. The most up to date assumption is that the disorder is a result of
maladaptive plasticity (Candia et al., 2002). This is due to the brain developing a
dysfunctional response as a result of damage to the sensorimotor systems. FTSD is
also assumed to be affected by the neurobiological networks when participants
suffered from stress and anxiety (Cottraux, Juenet and Collet, 1983).
How is FTSD diagnosed and treated?
The best diagnosis attained is from a neurologist familiar with the neurological
disorder, other professionals may also be brought on to provide a definitive
diagnosis. A physical diagnosis and neurological examination usually occurs.
Treatments include physiotherapy, oral therapy, psychotherapy, transcranial direct
stimulation & transcranial magnetic stimulation, deep brain stimulation, surgery and
botulinum toxin. Alternatively there is biofeedback. However, there is no research
justifying that any treatment is 100% more effective than the other. Unfortunately
current research does not discuss the ways that FTSD can be prevented.
What is the genetic association to FTSD?
Investigations in genetics have been used to classify the types of dystonia’s by
genes, locus, chromosomal and clinical characteristics. FTSD is associated with the
gene TOR1A which encodes for the torsinA protein. This protein is assumed to have
63
a GAG deletion mutation which causes glycosylation and the risk of misfolding with
the protein structure. The GAG deletion mutation causes a reduction in the release
of dopamine that interferes with neuron cell signals and motor cortex output result in
FTSD.
Bioinformatics
The alignments of all the proteins of the different types of dystonia’s showed that
despite the similarities that were shown, TOR1A was different to the rest of the
proteins.
Case Study
The case study was conducted in order to obtain information in relation to the best
treatments and risk of inheritance of focal task-specific dystonia and the impending
link to repetitive strain injury.
7.2 Suggestions of Further Study

Research on DNA chip microarrays and TMS are suggested to be the future possible
forms of treatment for FTSD which gives hope to within the next couple of years a
cure may be found.
7.3 Acknowledgements
The completion of this literature review would have not been possible without the
support of many people. In particular I would like to give thanks to:
Richard Jones for the patience, guidance and encouragement as well as critical
discussions given in order to complete this review, as well as in my own personal
development.
64
I am also very grateful for the support and approval from Phil Warburton and the
whole panel from the ethics committee of my ethics application.
Special thanks also to participant A, whom was open to answering all questions and
participating within the case study.
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envelope and cytoskeleton. Journal of Cell Science, 121(20), pp. 3476–3486.
doi: 10.1242/jcs.029454.
62. Odergren, T., Stone-Elander, S. and Ingvar, M. (1998) Cerebral and
cerebellar activation in correlation to the action-induced dystonia in Writer’s
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cramp. Movement Disorders, 13(3), pp. 497–508. doi:
10.1002/mds.870130321.
63. Ozelius, L., Hewett, J., Page, C., Bressman, S., Kramer, P., Shalish, C., de
Leon, D., Brin, M., Raymond, D., Corey, D., Fahn, S., Risch, N., Buckler, A.,
Gusella, J. and Breakefield, X. (1997). The early-onset torsion dystonia gene
(DYT1) encodes an ATP-binding protein. Nat Genet, 17(1), pp.40-48.
64. Ozelius, L., Page, C., Klein, C., Hewett, J., Mineta, M., Leung, J., Shalish, C.,
Bressman, S., de Leon, D., Brin, M., Fahn, S., Corey, D. and Breakefield, X.
(1999). The TOR1A (DYT1) Gene Family and Its Role in Early Onset Torsion
Dystonia. Genomics, 62(3), pp.377-384.
65. Page, S. J., Cunningham, D. A., Plow, E. and Blazak, B. (2015) It Takes Two:
Noninvasive Brain Stimulation Combined With Neurorehabilitation, Archives of
Physical Medicine and Rehabilitation, 96(4), pp. 89–93. doi:
10.1016/j.apmr.2014.09.019
66. Patestas, M. and Gartner, L. P. (2006). A textbook of neuroanatomy. 1st
edition. Malden, MA: Blackwell Publishing.
67. Perlmutter, J., Stambuk, M. K., Markham, J., Black, K. J., McGee-Minnich, L.
and Jankovic, et al., J. (1997). Decreased (18F) spiperone binding in
putamen in idiopathic focal dystonia. J Neuroscience, 17, pp. 843–850.
68. Pickett, A. (2009). Dysport®: Pharmacological properties and factors that
influence toxin action, Toxicon, 54(5), pp. 683–689. doi:
10.1016/j.toxicon.2009.03.020.
69. Purves, D. et al., 2004. NEUROSCIENCE. THIRD EDITION ed. Sunderland:
Sinauer Associates.
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70. Rainier, S. (2004). Myofibrillogenesis Regulator 1 Gene Mutations Cause
Paroxysmal Dystonic Choreoathetosis. Archives of Neurology, 61(7), p.1025.
71. Ridding, M., Sheean, G., Rothwell, J., Inzelberg, R. and Kujirai, T. (1995).
Changes in the balance between motor cortical excitation and inhibition in
focal, task specific dystonia. Journal of Neurology, Neurosurgery &
Psychiatry, 59(5), pp.493-498.
72. Rosales, R. L., 2012. DYSTONIA –THE MANY FACETS. In: T. Smiljanic, ed.
DYSTONIA –THE MANY FACETS. Rijeka: InTech, pp. 45-47.
73. Rosales, R. and Dressler, D. (2010). On muscle spindles, dystonia and
botulinum toxin. European Journal of Neurology, 17, pp.71-80.
74. Rossetto, O., Morbiato, L., Caccin, P., Rigoni, M. and Montecucco, C. (2006).
Presynaptic enzymatic neurotoxins. Journal of Neurochemistry, 97(6),
pp.1534-1545.
75. Rosset-Llobet, J., Pascual-Leone, A. and Fàbregas-Molas, S. (2012). Role of
female reproductive hormones in musicians’ dystonia, Med Probl Perform Art.,
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76.Rudzińska, M., Szubiga, M., Bik-Multanowski, M., Janik, P., Potulska-
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77. Sanger, T. D. and Merzenich, M. M. (2000). Computational model of the role
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78. Stacy, M. (2012). Handbook of dystonia. New York: Informa Healthcare.
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87. Waddy, H. M., Fletcher, N. A., Harding, A. E. and Marsden, C. D. (1991). A
genetic study of idiopathic focal dystonia’s, Annals of Neurology, 29(3), pp.
320–324. doi: 10.1002/ana.410290315
88. Zaremba, J., Mierzewska, H., Lysiak, Z., Kramer, P., Ozelius, L. and
Brashear, A. (2004). Rapid-onset dystonia-parkinsonism: A fourth family
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89. Zilber, N., Inzelberg, R., Kahana, E. and Korczyn, A. (1994). Natural Course
of Idiopathic Torsion Dystonia among Jews. Neuroepidemiology, 13(5),
pp.195-201.
90. Zlotogora, J. (2004). Autosomal recessive, DYT2-like primary torsion
dystonia: A new family. Neurology, 63(7), pp.1340-1340.
77
Appendix 1
RESEARCH ETHICS APPLICATION FORM (STAGE 1)
More information on ethics procedures and any documents detailed in bold can be found
at: www.anglia.ac.uk/researchethics. You must read the Question Specific Advice for
Stage 1 Research Ethics Approval form.
Please ensure you complete and sign this form on page 5. Before completing this form
please note:
78
All research carried out by students and staff at Anglia Ruskin University must comply with
Anglia Ruskin University Policy and Code of Practice for the Conduct of Research.
There is no distinction between undergraduate, taught masters, research degree students

and staff research.
All research projects, including pilot studies, must receive research ethical approval prior to
approaching participants and/or commencing data collection. Completion of this Stage 1
Research Ethics Application Form is mandatory for all research applications*. It should be
completed by the Principal Investigator in consultation with any co-researchers on the
project, or the student in consultation with his/her research project supervisor.
*For research only involving animals please complete the Animal Ethics Review Checklist
instead of this form.
All researchers should:

• Ensure they comply with any laws and associated Codes of Practice that may be
applicable to their area of research.
• Ensure their study meets with relevant Professional Codes of Conduct.
• Complete ethics training relevant to their research area.
• Refer to the Question Specific Advice for the Stage 1 Research Ethics Approval
form.
• Consult the Guidelines for Applying for Research Ethics Approval at Anglia Ruskin
University.
If you are still uncertain about the answer to any question please speak to your Dissertation
Supervisor/Supervisor, Faculty Research Ethics Panel (FREP) Chair or the Departmental
Research Ethics Panel (DREP) Chair.
Section 1: RESEARCHER AND PROJECT DETAILS
Researcher details:
Name(s): Jaundelle Dwyer
Department: Biomedical and Forensic Sciences
Faculty: Science & Technology
Anglia Ruskin email address: jaundelle.dwyer@student.anglia.ac.uk
Status:
Undergraduate Taught Postgraduate Staff
Postgraduate Research
If this is a student project:
SID: 1230045
Course title: BSc in Biomedical Sciences
Supervisor/tutor name Richard Jones
79
Project details:
Project title (not module title): Dystonia in musicians
Data collection start date: 05.04.2015
(note must be prospective)
Expected project completion 08.05.2015
date:
Is the project externally funded? No
Licence number (if applicable): N/A
CONFIRMATION STATEMENTS – please tick the box to confirm you understand these
requirements
The project has a direct benefit to society and/or improves knowledge and Yes
understanding.
All researchers involved have completed relevant training in research ethics, and Yes
consulted the Guidelines for Applying for Ethical Approval at Anglia Ruskin
University.
The risks participants, colleagues or the researchers may be exposed to have Yes
been considered and appropriate steps to reduce any risks identified taken (risk
assessment(s) must be completed if applicable, available at:
http://rm.anglia.ac.uk/extlogin.asp) or the equivalent for Associate Colleges.
My research will comply with the Data Protection Act (1998). Yes
Project summary (maximum 500 words):
Please outline rationale for the research, the project aim, the research questions,
research procedure and details of the participant population and how they will be
recruited.
Introduction
This research project concerns focal dystonia, which is a hand motor neurological
disorder. I will explore the causes (whether genetic or acquired), the physical problems
that can develop over time, and the effectiveness of treatments. Specifically, my aim is
to explore the causes, consequences and treatments of this condition for musicians.
The interview and the questions

I aim to incorporate a case study obtained by interviewing and potentially obtaining a
written journal from a participant I already know. The interview format will avoid
aggravating the participant’s dystonia by writing. I would analyse the data. The questions
I would like to ask are as follows:
1. How old are you?
2. What instrument do you play?
3. How many years have you known of your dystonia condition?
4. In what part of your body did your dystonia first appear?
5. What is your history of dystonia?
6. Deleted
7. Have you experienced any of the following? (Please answer “yes”, “no” or “prefer
not to answer” to each part i, ii and iii. Further details are not required.)
80
*
ii. Psychiatric condition (e.g. depression, anxiety, obsessive-compulsive
disorder)
iii. Repetitive strain injury
8. What do you think first triggered your dystonia?
9. What are your daily dystonia triggers?
10. What are your common dystonia symptoms?
11. When do you experience these dystonia symptoms?
12. How does your dystonia condition affect your lifestyle?
13. What examinations / investigations for dystonia have you had?
14. What treatments have been given to alleviate the symptoms of dystonia?
15. What doses do you take?
16. How often do you take medications for dystonia?
17. Have you / would you try an alternative therapy for dystonia?
18. Is there anything that temporarily eases the symptoms of dystonia?
19. Have you experienced any side effects (either long or short term) from these
treatments?
20. Does anyone else in your family have dystonia? (Please answer “yes”, “no” or
“prefer not to answer”. Further details are not required.)
21. Have you ever been treated for any other form of dystonia or muscle contraction
problem?
The questions will be posed in an interview and not by a questionnaire. The interviewer
(JD) will note down the answers. Only the questions listed above will be asked. The
participant will be told beforehand that they may state “prefer not to answer” to any
question.
*
Regarding Q7(ii), there is high comorbidity between dystonia and psychiatric disorders
especially anxiety, depression and obsessive compulsive disorder (please see Movement
Disorders Special Issue: Advances in Dystonia Volume 28, Issue 7, pages 914–920, 15
June 2013, http://onlinelibrary.wiley.com/doi/10.1002/mds.25501/abstract). Further,
these psychiatric disorders have high impact on the quality of life. Hence, a psychiatric
history would provide information relevant to the project.
Participant Information Sheet, Consent and Anonymity

The participant will first be provided with the participant information sheet and consent
form (below) that detail procedures to retain the anonymity of the participant to those
other than the two researchers (RJ and JD) in any verbal or written communications. The
participant will be referred to only as “Participant A” is JD’s notes, computer files,
dissertation and all other written and verbal communications. The researchers recognise
that the participant cannot be anonymous to the researchers because a face-to-face
interview is planned, signed consent will be provided, and the participant is personally
known to one of the researchers (JD). Once signed, JD will not copy the consent form
81
and will give the consent form to RJ. RJ will keep the consent form in a locked cabinet.
The data provided by the participant will be used in JD’s dissertation and could
potentially be used in a case study publication. Hence, confidentiality of the data is not
planned.
Risks to the research

The main risk to the research is if the participant either does not consent to an interview
or withdraws afterwards. This risk is managed by having a withdrawal deadline of 14
days after the date of consent and by the following “plan B”:-
RJ has already instructed JD in a meta-analysis of already published data (ethics approval
for this part of the project has already been obtained). This meta-analysis can form a
complete project (if the participant declines consent) or a supplement (if the participant
grants consent). This means that a project can still be completed by the deadline without
participation of the participant. This reduces the dependence upon participation by the
participant.
Risks to the Participant

Loss of time
The participant is informed in the PIS that the interview will take no more than one hour.
Tiredness through repeatedly answering questions

The participant is informed in the PIS that they may request a break at any time.
Discussing medical problems can be upsetting

JD will conduct the interview in a calm, friendly and professional manner. If the
participant becomes visibly upset, the interview will be terminated by JD. The participant
is informed in the PIS that he / she may terminate the interview at any point.
Invasion of privacy
This risk is managed by providing a clear rationale for the research in the PIS, by JD
asking only those questions listed above (i.e. no follow-up questions will be asked), and
by informing the participant beforehand that they may reply “prefer not to answer” to
any question(s) without reproach.
Participant Information Sheet (PIS)
Dystonia Case Study Interview
Researcher and Project Supervisor:

Dr Richard Jones
Senior Lecturer in Biomedical Science
Department of Biomedical and Forensic Sciences
82
Faculty of Science and Technology
Anglia Ruskin University
OPT 028, East Road
Cambridge CB1 1PT
Tel: 01223 363271 x2385
Email: richard.jones@anglia.ac.uk
Student Researcher
Miss Jaundelle Dwyer
Email: jaundelle.dwyer@student.anglia.ac.uk
Origin and Intended Use of this Project

This project originates from Anglia Ruskin University. Any relevant literature and / or
data arising from this study is intended to be used for the Student Researcher’s
dissertation (definitely) and a published case report (potentially) only.
Introduction
This research project concerns Focal Dystonia, which is a hand motor neurological
disorder. The literature component will explore the causes (whether genetic or
acquired), the physical problems that can develop over time, and the effectiveness of
treatments. Specifically, the aims are to explore the causes, consequences and
treatments of this condition for musicians.
The Case Study

We aim to incorporate a case study obtained by interviewing a participant and / or
reviewing a participant’s written journal.
Anonymity
The participant’s personal details (including name, address and date-of-birth) would not
be requested or revealed. The participant will be asked to provide his / her sex and age
only: these would be revealed in the dissertation. The participant cannot be anonymous
to the researchers because a face-to-face interview is planned, signed consent would be
required beforehand, and the participant is personally known to one of the researchers
(JD). However, the two researchers guarantee anonymity of the participant to those
other than the two researchers (listed above) in any verbal or written communications
(e.g. the Dissertation and any published case study report).
Your Decision
Please take some time to read through this form before making your decision to
participate or not.
The Procedure
83
An interview would be based upon a list of 20 pre-planned questions posed by the
Student Researcher. Anonymised notes of the answers would be taken. You may choose
to refuse to answer any question(s) asked without reproach. You could say “prefer not to
answer”. The interview will take no more than one hour. You may request a break at any
time. You may end the interview at any time.
Data Storage
The data provided and / or notes made of the interview may be kept in paper form (in a
notebook that will be used only for the interview) and / or on a password-protected
computer. The notebook or computer files (e.g. dissertation drafts) will neither contain
nor be linked specifically to any personal details that could reveal the identity of the
participant. Hence, the researcher’s copy of the completed consent form will be given to
RJ without being copied before the interview takes place. This will ensure that the
consent form will not be stored with the notebook or drafts of the dissertation.
Withdrawal from the Study

Even after giving consent, it will be possible for the participant to withdraw from the
study or request that specified details are omitted from computer files during a period of
14 days from the date of consent. After 14 days from the date of consent it will not be
possible to withdraw from the study because the information given will be included in
Dwyer’s dissertation.
Questions
Any questions you have at any time can be directed to the Student Researcher or to the
Project Supervisor. Contact details are at the top of this form.
Opportunity to Refuse Consent

You are under no obligation to participate in this project. If you do not wish to be
included in this study then please inform the Student Researcher who gave this form to
you.
Opportunity to Participate in this Project

If you agree to participate in this study then please read the consent form below, tick
one or more of the circles in question 2, and sign the consent form to confirm that you
understand and agree to the details outlined in this information sheet and the consent
form. One copy of these forms will be given to you to keep and a second identical form
will be retained by the researcher.
Section 2: RESEARCH ETHICS CHECKLIST - please answer YES or NO to ALL of the questions.
WILL YOUR RESEARCH STUDY? YES NO

1 Involve any external organisation for which separate research ethics N
clearance is required (e.g. NHS, Social Services, Ministry of Justice)?
84
2 Involve individuals aged 16 years of age and over who lack capacity N
to consent and will therefore fall under the Mental Capacity Act
(2005)?
3 Collect, use or store any human tissue/DNA including but not N
limited to serum, plasma, organs, saliva, urine, hairs and nails?
Contact Dr Matt Bristow.
4 Involve medical research with humans, including clinical trials? N
5 Administer drugs, placebos or other substances (e.g. food N
substances, vitamins) to human participants?
6 Cause (or could cause) pain, physical or psychological harm or N
negative consequences to human participants?
7 Involve the researchers and/or participants in the potential N
disclosure of any information relating to illegal activities; or
observation/handling/storage of material which may be illegal?
8 With respect to human participants or stakeholders, involve any N
deliberate deception, covert data collection or data collection
without informed consent?
9 Involve interventions with children under 18 years of age? N
10 Relate to military sites, equipment, weapons or the defense N
industry?
11 Risk damage or disturbance to culturally, spiritually or historically N
significant artefacts or places, or human remains?
12 Involve genetic modification, or use of genetically modified N
organisms?
13 Contain elements you (or members of your team) are not trained to N
conduct?
14 Potentially reveal incidental findings related to human participant N
health status?
15 Present a risk of compromising the anonymity or confidentiality of N
personal, sensitive or confidential information provided by human
participants and/or organisations?
16 Involve colleagues, students, employees, business contacts or other Y
individuals whose response may be influenced by your power or
relationship with them?
17 Require the co-operation of a gatekeeper for initial access to the N
human participants (e.g. pupils/students, self-help groups, nursing
home residents, business, charity, museum, government
department, international agency)?
18 Offer financial or other incentives to human participants? N
19 Take place outside of the country in which your campus is located, N
in full or in part?
20 Cause a negative impact on the environment (over and above that N
of normal daily activity)?
21 Involve direct and/or indirect contact with human participants? Y
85
22 Raise any other ethical concerns not covered in this checklist? N
Section 4: ETHICAL RISK (Risk category 2 projects only)
Management of Ethical Risk (Q14-22)

For each question 14-22 ticked ‘yes’, please outline how you will manage the ethical risk
posed by your study.
Regarding checklist items 16 and 21 (yes answers)

RJ will instruct JD in writing that it is the participant’s decision whether or not to
participate in this study, and that researchers cannot force the participant to participate
using any means (including e.g. intimidation, threats, pressure or implication that the
relationship between JD and the participant will deteriorate as a result of non-
participation).
RJ has already instructed JD in a meta-analysis of already published data (ethics approval

for this part of the project has already been obtained). This meta-analysis can form a
complete project (if the participant declines consent) or a supplement (if the participant
grants consent). This means that a project can still be completed by the deadline without
participation of the participant. This reduces the dependence upon participation by the
participant, and hence ethical risk.
Section 5: Declaration
*Student/Staff Declaration
By sending this form from My Anglia e-mail account I confirm that I will undertake this
project as detailed above. I understand that I must abide by the terms of this approval
and that I may not substantially amend the project without further approval.
**Supervisor Declaration
By sending this form from My Anglia e-mail account I confirm that I will undertake to
supervise this project as detailed above.
*Student’s to forward completed form to their Dissertation Supervisor/Supervisor.
** Dissertation Supervisor/Supervisor to forward the completed form to the relevant ethics
committee.
1 November, 2013
Version: 3.0
86
Appendix 2
Participant Information Sheet (PIS) – As the participant saw it
Dystonia Case Study Interview
Researcher and Project Supervisor:

Dr Richard Jones
87
OPT 028, East Road
Cambridge CB1 1PT
Tel: 01223 363271 x2385
Student Researcher
Origin and Intended Use of this Project

This project originates from Anglia Ruskin University. Any relevant literature and / or data
arising from this study is intended to be used for the Student Researcher’s dissertation
(definitely) and a published case report (potentially) only.
Introduction
This research project concerns Focal Dystonia, which is a hand motor neurological disorder.
The literature component will explore the causes (whether genetic or acquired), the physical
problems that can develop over time, and the effectiveness of treatments. Specifically, the
aims are to explore the causes, consequences and treatments of this condition for
musicians.
The Case Study

We aim to incorporate a case study obtained by interviewing a participant and / or
reviewing a participant’s written journal.
Anonymity
The participant’s personal details (including name, address and date-of-birth) would not be
requested or revealed. The participant will be asked to provide his / her sex and age only:
these would be revealed in the dissertation. The participant cannot be anonymous to the
researchers because a face-to-face interview is planned, signed consent would be required
beforehand, and the participant is personally known to one of the researchers (JD).
However, the two researchers guarantee anonymity of the participant to those other than
the two researchers (listed above) in any verbal or written communications (e.g. the
Dissertation and any published case study report).
Your Decision
Please take some time to read through this form before making your decision to participate
or not.
The Procedure
An interview would be based upon a list of 20 pre-planned questions posed by the Student
Researcher. Anonymised notes of the answers would be taken. You may choose to refuse to
88
answer any question(s) asked without reproach. You could say “prefer not to answer”. The
interview will take no more than one hour. You may request a break at any time. You may
end the interview at any time.
Data Storage
The data provided and / or notes made of the interview may be kept in paper form (in a
notebook that will be used only for the interview) and / or on a password-protected
computer. The notebook or computer files (e.g. dissertation drafts) will neither contain nor
be linked specifically to any personal details that could reveal the identity of the participant.
Hence, the researcher’s copy of the completed consent form will be given to RJ without
being copied before the interview takes place. This will ensure that the consent form will
not be stored with the notebook or drafts of the dissertation.
Withdrawal from the Study

Even after giving consent, it will be possible for the participant to withdraw from the study
or request that specified details are omitted from computer files during a period of 14 days
from the date of consent. After 14 days from the date of consent it will not be possible to
withdraw from the study because the information given will be included in Dwyer’s
dissertation.
Questions
Any questions you have at any time can be directed to the Student Researcher or to the
Project Supervisor. Contact details are at the top of this form.
Opportunity to Refuse Consent

You are under no obligation to participate in this project. If you do not wish to be included
in this study then please inform the Student Researcher who gave this form to you.
Opportunity to Participate in this Project

If you agree to participate in this study then please read the consent form below, tick one or
more of the circles in question 2, and sign the consent form to confirm that you understand
and agree to the details outlined in this information sheet and the consent form. One copy
of these forms will be given to you to keep and a second identical form will be retained by
the researcher.
PARTICIPANT CONSENT FORM – As the participant saw it
NAME OF PARTICIPANT:
89
Title of the project: Dystonia in musicians
Main investigator and contact details:

Dr Richard Jones
OPT 028
East Road
Cambridge CB1 1PT
Tel: 01223 363271 x2385
Members of the research team:

1. I agree to take part in the above research. I have read the Participant Information
Sheet for the study. I understand what my role will be in this research, and all my
questions have been answered to my satisfaction.
2. I agree to provide an:

o Interview
o Written journal
(Please tick those circles that you are willing to consent to. You may choose to not
tick one or all of the circles.)
3. I agree that the data I provide can be used in a dissertation (definitely planned) and a
case study report for publication (potentially) given that no data that could identify
me will be contained in either document.
4. I understand that I am free to withdraw from the research up to 14 days after the
date of consent, for any reason and without prejudice.
5. I have been informed that the anonymity to those other than the two researchers of
the information I provide will be safeguarded.
6. I am free to ask any questions at any time before and during the study.
7. I have been provided with a copy of this form and the Participant Information Sheet.
90
Data Protection: I agree to the University1 processing personal data which I have supplied.
I agree to the processing of such data for any purposes connected with the Research
Project as outlined to me*
Name of participant (print)………………………….Signed………………..….Date………………
YOU WILL BE GIVEN A COPY OF THIS FORM TO KEEP

------------------------------------------------------------------------------------------------------------------------
Even after giving consent, it will be possible for the participant to withdraw from the study
by signing or returning the form below, or request by email to RJ that specified details are
deleted from the notebook or computer files, during a period of 14 days from the date of
consent.
If you wish to withdraw from the research, please complete the form below and return to
the main investigator (RJ) named above.
Title of Project: Dystonia in musicians

I WISH TO WITHDRAW FROM THIS STUDY
Signed: __________________________________ Date: _____________________
“The University” includes Anglia Ruskin University and its partner colleges.
91
Appendix 3
92
************************************************************

************************************************************
1A-1 EGGLNSDYVHLFVATLHFPHASNITLYKDQLQLWIRGNVSACARSIFIFDEMDKMHAGLI 180

1A-2 EGGLNSDYVHLFVATLHFPHASNITLYKARMEVWNPFLDVIGFGVSLLWDEIWEFYVEMS 180
**************************** ::::* :::**: :::. :
1A-1 DAIKPFLDYYDLVDGVSYQKAMFIFLSNAGAERITDVALDFWRSGKQREDIKLKDIEHAL 240

1A-2 EPGKRFMSQFPLERC---------------------------RS---------------- 197
: * *:. : * **
1A-1 SVSVFNNKNSGFWHSSLIDRNLIDYFVPFLPLEYKHLKMCIRVEMQSRGYEIDEDIVSRV 300

1A-2 ------------------------------------------------------------ 197
1A-1 AEEMTFFPKEERVFSDKGCKTVFTKLDYYYDD 332

1A-2 -------------------------------- 197
Dystonia isoforms Code in Protein Number of
sequenc amino
e figures acids
Early-onset Torsin-1A isotope 1 O14656 TorsinA 332
generalised (UniProt
2015)
Early-onset Torsin-1A isotope 2 O14656- TorsinA 197
generalised 2 (UniProt
2015)
93
Comparisons of Amino Acid Sequence Sim-
ilarity of TOR1A-1 and TOR1A-2
100.00%
90.00%
80.00%
Identity 157/198
70.00%
60.00%
Percentage
50.00% Similarity 170/198

40.00%
30.00% Gaps 12/198
20.00%
10.00%
0.00%
TOR1A-1 TOR1A-2
Differences in TOR1A-1 and TOR1A-2
94
Frequencies of The of Amino Acids in TOR1A-1 and
TOR1A-2
16
14
12
10
Frequency
8
6
4
2
0
Ala Arg Asn Asp Cys Gln Glu Gly His Ile Leu Lys MetPhe Pro Ser Thr Trp Tyr Val Pyl Sec
Composition of Amino Acids
TOR1A TOR1B
95
3.3 Case Study – Interview Results
Researcher: “How old are you?”
Participant A: “45”
Researcher: “What instrument do you play?”
Participant A: “Piano”
Researcher: “How many years have you known of your dystonia condition?”
Participant A: “20 years”
Researcher: “In what part of your body did your dystonia first appear?”
Participant A: “Right hand”
Researcher: “What is your history of dystonia?”
Participant A: “1995 first happened as a copy typist. Working 7 hours of copy typing
a day, first noticed when copy typing the first index finger collapsed. First instinct was
to just ignore at first. Had a break and then tried to continue typing again but never
recovered. Then went to see a GP who put me on antibiotics and ibuprofen for a
month. The condition was still the same. Then was referred to National Hospital of
Neurology. Attended there ever since.”
96
Researcher: “Have you experienced any of the following? (Please answer “yes”,
“no” or “prefer not to answer” to each part i, ii and iii. Further details are not
required.)
ii. Psychiatric
*
condition (e.g. depression, anxiety, obsessive-compulsive
disorder)
iii. Repetitive strain injury”
Participant A: i. “Yes”
ii. “No”
iii. “Yes”
Researcher: “What do you think first triggered your dystonia?”
Participant A: “Repetitive strain in left hand taking cortisone injections for it so
overworking right which put stress on right hand.”
Researcher: “What are your daily dystonia triggers?”
Participant A: “Playing and writing”
Researcher: “What are your common dystonia symptoms?”
Participant A: “Arm contracts fingers also curl in.”
Researcher: “When do you experience these dystonia symptoms?”
Participant A: “When playing.”
97
Researcher: “How does your dystonia condition affect your lifestyle?”
Participant A: “As a musician it affects it a lot but in general not at all but it depends
on career choice and when writing sometimes.”
Researcher: “What examinations / investigations for dystonia have you had?”
Participant A: “Observed while played piano. Observation of holding a
pen.”
Researcher: “What treatments have been given to alleviate the symptoms of
dystonia?”
Participant A: “Botox”
Researcher: “What doses do you take?”
Participant A: “Vary dependent on how bad the contractions are each time.”
Researcher: “How often do you take medications for dystonia?”
Participant A: “Every 4 months.”
Researcher: “Have you / would you try an alternative therapy for dystonia?”
Participant A: “Yes if it would help but not open to surgery. Only tDCS by a student
specialist.”
Researcher: “Is there anything that temporarily eases the symptoms of dystonia?”
Participant A: “Only the Botox and zinc, green and yellow foods. Iron”
98
Researcher: “Have you experienced any side effects (either long or short term) from
these treatments?”
Participant A: “Weakness from Botox.”
Researcher: “Does anyone else in your family have dystonia? (Please answer
“yes”, “no” or “prefer not to answer”. Further details are not required.)”
Researcher: “Have you ever been treated for any other form of dystonia or muscle
contraction problem?”
99

(Reedited) The Effect of Focal Task Specific Dystonia in Pianists

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The Effect of Focal Task-Specific Dystonia on

Pianists: An Analysis of Literature and A Case Study

Dissertation submitted to the Faculty of Science and Technology at

Anglia Ruskin University Cambridge campus of the requirements for the

Degree Biomedical Sciences BSc

Table 1. Hypothesis of Research………………………………………………………….9

Table 2. Search Terms Used in Database……………………………………………...15

Table 3. Main Books Included…………………………………..………………………..18

Table 4. Summary of Amino Acids in TOR1A isotopes…………………………………

Table 5. Classifications of Dystonia’s by Age………………………………………..

Table 6. Classifications of Dystonia’s by Affected Body

associations and efficient treatments in pianists with focal task-specific dystonia.

based on relationships between genetics and treatments for focal task-specific

Dystonia in pianists. Case study was conducted in order to attain information in

relation to focal task-specific dystonia in pianists.

specific hand Dystonia at later stages in life.

Focal task-specific dystonia can be explained in relation to environmental and

Chapter one consists of a brief introduction and definition of focal-task specific

dystonia, aims, hypothesis and an overview of keys neurological concepts as well as

research of the definition of focal-task specific dystonia; considering the

in the chapter genetic association in focal-task specific dystonia is also evaluated as

includes a summary of key points and suggestions of further studies.

word tonos, meaning tension (Martin, 2010). Dystonia is a neurological movement

influenced by voluntary action; it is also associated with excess muscle activation

dystonia (FTSD) is characterised as the degradation or loss of voluntary control of

overlearned complex and skilled movement in a specific sensory-motor task

Research Question What is the Effect of Focal Task-

Null Hypothesis There is no significance link between

1. What is focal task-specific dystonia?

3. What causes FTSD?

4. What are the possible symptoms of FTSD?

5. What are the treatments for FTSD?

6. Does FTSD overlap with repetitive stress injury?

1.4 The Nervous System

results in the fight or flight response. The parasympathetic nervous system

body (Garett, 2015).

release neurotransmitters in order to communicate with an organ or muscle, or

produced (Garett, 2015).

1.6 Basal Ganglia

movements. The basal ganglia is characterised as a collection of motor nuclei within

VL/VA complex of the thalamus

anterior, intralaminar/parafascicular (pf), pedunculopontine nucleus (PPN) and

sensorimotor cortex in the parietal lobe. Abnormalities of the sensorimotor cortex is

assumed to lead to dysfunctions of movement (Ekman, 2007).

2.0 Methods and Techniques

2.1 Literature Search

brain, genetic, inherited, exercise, physiotherapy, treatment, electromyography, EMG

Cerebral palsy, selective peripheral denervation, and rhizotomy. Table 2 illustrates

Database First step First term Second Third term Additional

Figure 3: Science Direct database.

able to be saved to endnote online through Refworks as shown in figure 4. To obtain

Figure 4: Save to Refworks.

 Author, title, source

 Author, title, source, abstract

 Full record and cited references

Potentially relevant journals

Journals excluding based on

Articles that were assessed more

Article that did not match the

Potential articles scored

Figure 5: Flowchart of the literature search of articles.

are summarised in table 3.

Author, year of Title of Book Recommended