Polyglutamine Disorders

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Clévio Nóbrega Luís Pereira de Almeida
•

Editors

Polyglutamine Disorders

123
Editors
Clévio Nóbrega Luís Pereira de Almeida
Department of Biomedical Sciences and Center for Neuroscience and Cell Biology
Medicine, Centre for Biomedical and Faculty of Pharmacy
Research and Algarve Biomedical Center University of Coimbra
University of Algarve Coimbra
Faro Portugal
Portugal

ISSN 0065-2598 ISSN 2214-8019 (electronic)

Advances in Experimental Medicine and Biology
ISBN 978-3-319-71778-4 ISBN 978-3-319-71779-1 (eBook)
https://doi.org/10.1007/978-3-319-71779-1
Library of Congress Control Number: 2017960922

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Preface

On Polyglutamine Diseases

Polyglutamine (polyQ) diseases are a group of rare neurodegenerative disorders that

share a common genetic cause: they arise as a result of abnormal expansions of
CAG trinucleotide sequences occurring at particular genome loci. In contrast with
other repeat-related disorders, the repeat-bearing tracts associated with polyQ dis-
eases are present at the codifying region of genes, being translated as expanded
polyQ tracts in their respective protein products. Although these genes and proteins
are otherwise unrelated and share no significant homology outside the CAG/polyQ
tract, proteins carrying an abnormally expanded polyQ tract tend to aggregate,
forming insoluble protein aggregates that constitute a key neuropathological feature
of polyQ disorders. The group currently includes nine disorders: Huntington’s
disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar
muscular atrophy (SBMA), and six different types of spinocerebellar ataxia: SCA 1,
2, 3, 6, 7, and 17. PolyQ diseases are highly incapacitating and, to this date, no
therapy able to modify disease progression is available for any of them.
PolyQ disorders share several features. These include (a) the existence of a
positive correlation between the variable CAG repeat number and both the severity
and precocity of symptoms; (b) the generational instability in CAG repeat number
transmission; and (c) the aforementioned propensity for the protein products to
aggregate and to constitute large intracellular multiprotein inclusions that are
detected in patients’ neuronal tissue. Despite the genetic cause of polyQ disorders
being clearly identified, the molecular mechanisms involved in their pathogenesis
are not fully understood. Though it is frequently accepted that these disorders share
common pathogenic mechanisms, the symptoms and the regional patterns of neu-
rodegeneration are not shared among disorders. Taken together, the similarities and
differences existing in this group of disorders suggest that the search for disease
mechanisms and putative therapeutic strategies will benefit from an integrative view
that conjugates common factors and motifs with the particularities of each polyQ
disease.

v
vi Preface

For this book entitled Polyglutamine Disorders, we have gathered many of the
main experts around the world in the field, whom we would like to acknowledge for
their work and collaboration, providing a state-of-the-art revision about several
aspects of the different polyQ diseases. The book addresses the molecular mech-
anisms described to underlie disease pathogenesis, the animal models developed to
study these diseases and, importantly, the advanced therapeutic strategies being
investigated for these disorders.

Coimbra, Portugal Clévio Nóbrega

January 2018 Luís Pereira de Almeida
Contents

1 Clinical Features of Huntington’s Disease . . . . . . . . . . . . . . . . . . . . 1

Rhia Ghosh and Sarah J. Tabrizi
2 Genetic Rodent Models of Huntington Disease . . . . . . . . . . . . . . . . 29
J. Stricker-Shaver, A. Novati, L. Yu-Taeger and H. P. Nguyen
3 Mitochondrial Dysfunction in Huntington’s Disease . . . . . . . . . . . . 59
Catarina Carmo, Luana Naia, Carla Lopes and A. Cristina Rego
4 RNA Related Pathology in Huntington’s Disease . . . . . . . . . . . . . . 85
Andreas Neueder and Gillian P. Bates
5 X-Linked Spinal and Bulbar Muscular Atrophy: From Clinical
Genetic Features and Molecular Pathology to Mechanisms
Underlying Disease Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Constanza J. Cortes and Albert R. La Spada
6 Spinocerebellar Ataxia Type 1: Molecular Mechanisms of
Neurodegeneration and Preclinical Studies . . . . . . . . . . . . . . . . . . . 135
Judit M. Pérez Ortiz and Harry T. Orr
7 Spinocerebellum Ataxia Type 6: Molecular Mechanisms
and Calcium Channel Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Xiaofei Du and Christopher Manuel Gomez
8 Spinocerebellar Ataxia Type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Daniel R. Scoles and Stefan M. Pulst
9 Molecular Mechanisms and Therapeutic Strategies in
Spinocerebellar Ataxia Type 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Alice Karam and Yvon Trottier
10 Spinocerebellar Ataxia Type 17 (SCA17) . . . . . . . . . . . . . . . . . . . . 219
Yasuko Toyoshima and Hitoshi Takahashi

vii
viii Contents

11 The Neuropathology of Spinocerebellar Ataxia

Type 3/Machado-Joseph Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Arnulf H. Koeppen
12 Origins and Spread of Machado-Joseph Disease Ancestral
Mutations Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Sandra Martins and Jorge Sequeiros
13 Clinical Features of Machado-Joseph Disease . . . . . . . . . . . . . . . . . 255
Nuno Mendonça, Marcondes C. França, Jr.,
António Freire Gonçalves and Cristina Januário
14 Polyglutamine-Independent Features in Ataxin-3 Aggregation
and Pathogenesis of Machado-Joseph Disease . . . . . . . . . . . . . . . . . 275
Ana Luisa Carvalho, Alexandra Silva and Sandra Macedo-Ribeiro
15 Animal Models of Machado-Joseph Disease . . . . . . . . . . . . . . . . . . 289
Jana Schmidt and Thorsten Schmidt
16 Towards the Identification of Molecular Biomarkers of
Spinocerebellar Ataxia Type 3 (SCA3)/Machado-Joseph
Disease (MJD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Manuela Lima and Mafalda Raposo
17 Planning Future Clinical Trials for Machado-Joseph Disease . . . . . 321
Jonas Alex Morales Saute and Laura Bannach Jardim
18 Molecular Mechanisms and Cellular Pathways Implicated in
Machado-Joseph Disease Pathogenesis . . . . . . . . . . . . . . . . . . . . . . 349
Clévio Nóbrega, Ana Teresa Simões, Joana Duarte-Neves,
Sónia Duarte, Ana Vasconcelos-Ferreira, Janete Cunha-Santos,
Dina Pereira, Magda Santana, Cláudia Cavadas
and Luís Pereira de Almeida
19 Pharmacological Therapies for Machado-Joseph Disease . . . . . . . . 369
Sara Duarte-Silva and Patrícia Maciel
20 Gene Therapies for Polyglutamine Diseases . . . . . . . . . . . . . . . . . . 395
Carlos A. Matos, Vítor Carmona, Udaya-Geetha Vijayakumar,
Sara Lopes, Patrícia Albuquerque, Mariana Conceição,
Rui Jorge Nobre, Clévio Nóbrega and Luís Pereira de Almeida
21 Stem Cell-Based Therapies for Polyglutamine Diseases . . . . . . . . . . 439
Liliana S. Mendonça, Isabel Onofre, Catarina Oliveira Miranda,
Rita Perfeito, Clévio Nóbrega and Luís Pereira de Almeida
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Chapter 1
Clinical Features of Huntington’s Disease

Rhia Ghosh and Sarah J. Tabrizi

Abstract Huntington’s disease (HD) is the most common monogenic neurode-

generative disease and the commonest genetic dementia in the developed world.
With autosomal dominant inheritance, typically mid-life onset, and unrelenting
progressive motor, cognitive and psychiatric symptoms over 15–20 years, its
impact on patients and their families is devastating. The causative genetic mutation
is an expanded CAG trinucleotide repeat in the gene encoding the Huntingtin
protein, which leads to a prolonged polyglutamine stretch at the N-terminus of the
protein. Since the discovery of the gene over 20 years ago much progress has been
made in HD research, and although there are currently no disease-modifying
treatments available, there are a number of exciting potential therapeutic develop-
ments in the pipeline. In this chapter we discuss the epidemiology, genetics and
pathogenesis of HD as well as the clinical presentation and management of HD,
which is currently focused on symptomatic treatment. The principles of genetic
testing for HD are also explained. Recent developments in therapeutics research,
including gene silencing and targeted small molecule approaches are also discussed,
as well as the search for HD biomarkers that will assist the validation of these
potentially new treatments.

Keywords Huntington’s disease
Genetics
Symptoms
Management

Therapeutics Biomarkers

1.1 Introduction

Huntington’s disease (HD) is one of the most common causes of dominantly inherited
neurodegenerative disease [1]. There is typically adult onset, with irreversible pro-
gression of motor, psychiatric and cognitive symptoms over 15–20 years, followed

R. Ghosh
S. J. Tabrizi (&)

UCL Huntington’s Disease Centre, Department of Neurodegenerative Disease,
UCL Institute of Neurology, London WC1N 3BG, UK
e-mail: s.tabrizi@ucl.ac.uk

© Springer International Publishing AG 2018 1

C. Nóbrega and L. Pereira de Almeida (eds.), Polyglutamine Disorders,
Advances in Experimental Medicine and Biology 1049,
https://doi.org/10.1007/978-3-319-71779-1_1
2 R. Ghosh and S. J. Tabrizi

by death [2]. The condition was first described in the USA by George Huntingtin in
1872, himself a newly qualified doctor at the time, and his original descriptions of the
disease remain true today.
As yet there are still no disease modifying treatments available, but an intensive
international research effort is underway with many clinical trials currently
on-going. In this chapter we will first cover the epidemiology, genetics, and
pathogenesis of HD and then discuss clinical aspects of the disease and the latest
developments in HD therapeutics research.

1.2 Epidemiology

The prevalence of HD had been thought to be 4–10/100,000 in Western populations

[3], though a more recent study in the UK suggests a figure of 12.3/100,000 [4].
The true prevalence of HD may have been underestimated in the past due to the
stigma that has traditionally been attached to the diagnosis; in recent centuries,
sufferers have even been accused of witchcraft, pressuring families into hiding the
condition [5]. The wider availability of genetic testing may also have contributed to
an apparent increase in disease prevalence [6].
The disease is thought to have migrated from North-West Europe to other parts
of the world, and there is global variation in prevalence, with naturally low rates in
Japan, Hong Kong and Taiwan [7]. One of the highest rates of HD occurs in
Venezuela where communities living near the edge of Lake Maracaibo see a
prevalence of 700/100,000 people. It was in this population that genetic linkage
studies led to the discovery of the causative genetic mutation in HD [8, 9].

1.3 Genetics of Huntington’s Disease

HD is a single-gene disorder with autosomal dominant transmission and so the

presence of the mutation on either allele leads to the disease. Therefore an affected
parent has a 50% chance of passing it on to their child. The mutation is an expanded
CAG triplet repeat near the start of exon 1 of the Huntingtin gene (HTT), which lies
on the short arm of chromosome 4. On translation, this leads to the presence of a
polyglutamine (polyQ) stretch at the N-terminus of Huntingtin protein (HTT).
The wild-type gene carries 10–35 CAG repeats, with a mean value of 18 CAG
repeats across the population (although this mean value is greater in populations
with higher disease prevalence) [7, 10]. The mutation is fully penetrant at 40 or
more repeats. Between 36 and 39 repeats there is reduced penetrance; carriers may
develop HD symptoms in later life or not at all [11]. HTT with 27–35 CAG repeats
is referred to as an “intermediate allele”.
Intermediate alleles in the general population are thought to arise from stepwise
expansion of the CAG repeat over many generations. People who inherit
1 Clinical Features of Huntington’s Disease 3

intermediate length alleles have long been thought to be unaffected, but a beha-
vioural phenotype has now been identified in this group [12]. During meiosis it is
possible for intermediate alleles to expand further, leading to offspring who may
carry a disease gene with 36 or more repeats. The risk of this is as high as 21% for
those with 35 CAG repeats [13].
This intrinsic instability of the CAG repeat during meiosis especially affects the
disease gene, leading to expansions (and sometimes contractions) in repeat length
inherited by successive generations [14]. As longer CAG repeat length correlates
with earlier age of onset, symptoms may develop at progressively younger ages as
the condition is passed down the family tree. This is known as anticipation. Due to
differences between spermatogenesis and oogenesis this is more likely to occur
when transmission occurs through the paternal bloodline [15]. In rare cases large
increases in CAG repeat length above 55 can occur, leading to Juvenile HD (JHD),
when the age of onset is less than 20 years old. 90% of JHD cases result from
paternal inheritance [16, 17].
As with all genetic conditions a detailed family history is essential to help make
a correct diagnosis. However 6–8% of patients with newly diagnosed HD have no
family history [18]. As mentioned above, de novo mutations may arise from
intermediate length alleles, leading to sporadic cases. Seemingly sporadic cases may
occur following non-paternity, misdiagnosis in prior generations, or when deaths of
family members occur from other causes before development of neurological
symptoms thus masking the presence of the HD gene.

1.3.1 Effect of CAG Repeat Length on Disease Phenotype

Disease onset is defined clinically as the presence of unequivocal extrapyramidal

motor signs suggestive of HD. In typical mid-life onset HD with CAG repeat 40–55,
the length of the CAG repeat accounts for *56% of the variability in age at motor
onset [19]. A recent genome-wide association (GWA) study has identified genes
involved in DNA handling and repair mechanisms, including MLH1, as contributing
to further variation in the age of disease onset [20]. Remaining variation is likely
determined by other genetic and environmental modifiers [21].
Taking into account the CAG repeat length as well as the number of disease free
years already lived, a conditional probability model was developed by Langbehn
et al. which is able to estimate the chance of on-going disease free survival over a
number of years [22, 23]. However, models based on population data cannot be
applied in a one-to-one clinical setting and it is not possible to accurately predict an
individual’s age of onset of disease from their CAG repeat length.
Patients often experience psychiatric and cognitive symptoms, as well as very
subtle motor disturbances for many years before their official disease onset. CAG
repeat length correlates much less strongly with age of onset of psychiatric symp-
toms, but does show some correlation with rate of disease progression [24, 25]. The
duration of disease from diagnosis to death is independent of CAG repeat length.
4 R. Ghosh and S. J. Tabrizi

1.4 Pathogenesis of Huntington’s Disease

Huntingtin is a large 350 kDa protein comprised of multiple repeated units of 50

amino acids, termed HEAT repeats, which assemble into a superhelical structure
with a hydrophobic core. Compared to the wild-type protein, the mutant protein
contains an expanded polyglutamine stretch starting at residue 18 [26]. This triggers
a pathogenic cascade, with both cell autonomous and non-cell autonomous
mechanisms involved which are summarised in Table 1.1.

Table 1.1 Pathogenic mechanisms in Huntington’s disease

Mechanism Role of mutant Huntingtin
Proteolysis and generation of Multiple lines of evidence support the “toxic fragment
mHTT fragments hypothesis” that proteolytic cleavage of mutant HTT liberates
toxic N-terminal fragments containing the expanded polyQ
tract, which contribute to cell death through accumulation and
additional activation of further proteolytic caspases [27]. HTT
is cleaved by multiple proteases including caspases, calpains,
cathepsins and matrix metalloproteases (MMPs), and mutant
HTT fragments have been detected in many animal models
[28]. Recent evidence also raises the possibility that these
short N-terminal fragments may arise from alternative splicing
of exon 1 of HTT [29], and mHTT exon 1 fragments cause
neurodegeneration in HD model systems [30, 31]
Inclusion formation Intranuclear inclusions of mutant HTT are a pathognomic
feature of HD. Inclusions also form in the cytoplasm,
dendrites and axon terminals, though to a lesser extent.
Inclusions are heterogeneous population comprising different
forms of mHTT [32], and their definitive role (whether toxic
or protective) has not yet been established [33]
Post-translational modification HTT undergoes extensive post-translational modification at
of mHTT multiple sites through phosphorylation, SUMOylation,
acetylation, ubiquitination and palmitoylation. All these
modifications can exert an effect on mHTT pathogenicity, but
their full significance, interdependence and exact role in any
pathogenic mechanism remains largely unknown [28]
Loss of neurotrophin (BDNF) There is loss of brain-derived neurotrophic factor (BDNF)
support support from cortico-striatal projections, as mHTT is known
to interfere with both the expression and trafficking of BDNF
that promotes survival of striatal neurons [34]
Transcriptional dysregulation Transcriptional dysregulation occurs before symptom onset in
HD, and affects a large number of different transcription
factors and regulatory DNA target sequences (e.g. the
CREB-binding protein (CBP) [35] and repressor element 1
transcription factor (REST) [36]). This has been confirmed by
DNA microarray studies [37]. Mutant HTT has also been
shown to inhibit histone acetyltransferase activity, thus leading
to the condensation of chromatin and a downregulation of gene
transcription. This paves the way for histone deacetylase
(HDAC) inhibitors as a potential therapy [38]
(continued)
1 Clinical Features of Huntington’s Disease 5

Table 1.1 (continued)

Mechanism Role of mutant Huntingtin
Inflammation Microglial activation has been demonstrated in HD patients,
both in manifest [39] and premanifest disease [40]. Recent
evidence suggests that this is at least in part a cell-autonomous
effect, as microglia that express mHTT have been shown to
have enhanced transcription of pro-inflammatory factors [41].
A peripheral inflammatory response has also been shown with
raised levels of pro-inflammatory cytokines found in blood
samples of manifest and premanifest HD patients [42]
Trans-neuronal spread Recently evidence for the non-cell autonomous,
trans-neuronal spread of mHTT has come to light. mHTT was
shown to spread to wild-type human neurons within an HD
mouse model. This was blocked by botulinum neurotoxins,
suggesting the involvement of synaptic machinery [43].
Furthermore, post-mortem studies of HD patients who have
received experimental treatment with neural stem cell
transplantation have revealed the presence of huntingtin
inclusions in the grafted donor tissue [44]
Cytoskeleton signalling and Through its interactions with huntingtin-associated protein 1
vesicular trafficking (HAP1), huntingtin-associated protein of 40 kDa (HAP40)
and dynein, HTT regulates vesicle transport and recycling
[45]. Expression of mHTT disrupts this transport, including
vesicular trafficking of BDNF [46, 47]. mHTT aggregates can
also physically obstruct subcellular transport due to their large
size [48]
Mitochondrial dysfunction Mutant HTT affects the axonal transport of mitochondria and
also has a direct effect on mitochondrial function.
Mitochondrial calcium handling is impaired, and transcription
of nuclear genes responsible for the proper functioning of this
organelle is affected, leading to impaired respiration [49]. An
increase in mitochondrial DNA mutations has also been found
in neurons from the cortex of HD patients [50]
Excitotoxicity Injection of quinolinic acid (an NMDA receptor agonist) into
the striatum of mouse models recapitulates many aspects of
the HD phenotype [51]. In addition it has now been shown
that alterations in glutamatergic signalling occur through
changes in glutamate release [52], overactivity of glutamate
receptors [53], decreased levels of glutamate transporters and
reduced glutamate uptake [54]. Increased MSN excitability
has also been shown to result from decreased potassium
channel expression in mHTT expressing astrocytes [55]
Clearance of mHTT Two major cellular pathways for degradation of misfolded
proteins are the ubiquitin-proteasome system (UPS) and
autophagy. Impairment of the UPS has been noted in HD
mouse models and human post-mortem brain tissue [56]. In
addition, mHTT can interfere with target recognition and
impair autophagic clearance [57, 58]
Somatic instability of CAG CAG repeat expansion in germline cells has already been
repeat described, and can result in cases of juvenile HD. Somatic
expansion has also been shown to occur in the human striatum
[59] and is associated with younger onset, thus may contribute
to disease pathogenesis [60]. Impairment of DNA repair
pathways has been implicated in this [61]
6 R. Ghosh and S. J. Tabrizi

Ultimately there is massive striatal degeneration in the patient brain, as revealed

by post-mortem studies. Up to 95% of the GABAergic medium spiny neurons
(MSNs) that project to the globus pallidus and substantia nigra are lost, and there is
atrophy (though less so) of the cerebral cortex, subcortical white matter, thalamus
and hypothalamic nuclei [27].

1.5 Clinical Aspects of Huntington’s Disease

Huntington’s disease is characterized by a triad of progressive motor, cognitive and

psychiatric symptoms. The average age of onset is 45 years and the disease is fatal
after 15–20 years [62].

1.5.1 Natural History and Disease Progression

As mentioned above, onset of “manifest” HD is said to occur when patients develop

definitive motor signs suggestive of HD, which have no other explanation.
However prior to this, patients may have a “prodromal” phase of HD for many
years, during which subtle motor signs, psychiatric or cognitive symptoms may be
present. The TRACK-HD study found differences in speeded tapping (a fine motor
task) over 36 months between control and premanifest patients who were predi-
cated to be over 10.8 years from disease onset. During this time a corresponding
change in neurobiology, with loss of corticostriatal connectivity and striatal atro-
phy, is seen (Fig. 1.1).
Prior to development of manifest HD, patients who carry the HD gene mutation
are referred to as “premanifest”. Around 10–15 years before disease onset, pre-
manifest individuals are indistinguishable from controls. However as disease onset
approaches, patients are no longer completely asymptomatic and so the term “pe-
rimanifest” disease is used by clinicians to describe patients who are suffering from
prodromal HD symptoms, and are thought to likely develop the concrete motor
signs of manifest HD in the near future (Fig. 1.2).

1.5.1.1 Rating Scales and Disease Progression

The Unified HD Rating Scale (UHDRS) is comprised of motor, cognitive, beha-

vioural, emotional and functional components and is the most common rating scale
for HD [65]. It is widely utilised in HD research, and some of its component parts
are also useful in a clinical setting. The total motor score (TMS) subscale is helpful
in diagnosing disease onset; based on the score and their overall clinical impression,
the clinician assigns a diagnostic confidence score (DCS) between 0 and 4, which
reflects their belief that the motor signs are representative of HD.
1 Clinical Features of Huntington’s Disease 7

Fig. 1.1 Parametric maps showing regions with statistically significant atrophy in grey and white
matter at baseline, 12- and 24 months (from left to right in each frame). PreHD-A and preHD-B
are premanifest Huntington’s disease gene carriers with estimated time to clinical disease onset
greater than and less than 10.8 years, respectively. HD1 and HD2 are patients with early manifest
disease who have no functional impairment and mild functional impairment, respectively. The
striatum is affected early on, with more widespread atrophy at later stages. Adapted from Tabrizi
et al. [63] from Elsevier publishing group

Premanifest Motor diagnosis Manifest

100
Functional Motor impairment
abilities
Signs and symptoms (%)

Cognitive impairment
Function (%)

and/or dementia

Chorea

0
Presymptomatic Prodromal Early Moderate Advanced
Clinical stages
Age (years)
45
Typical adult onset

Fig. 1.2 Natural history of clinical Huntington’s disease. Adapted from Ross et al. [64] from
Nature Publishing Group
8 R. Ghosh and S. J. Tabrizi

Table 1.2 The Shoulson-Fahn Staging system

Stage Engagement Capacity to Capacity to Capacity to Care can be
of in handle manage domestic perform activities provided
disease occupation financial responsibilities of daily living at…
affairs
I Usual level Full Full Full Home
II Lower level Requires Full Full Home
slight
assistance
III Marginal Requires Impaired Mildly impaired Home
major
assistance
IV Unable Unable Unable Moderately Home or
impaired extended
care facility
V Unable Unable Unable Severely Total care
impaired facility

Diagnosis of disease onset can be a difficult and emotional time for patients and
their families, as they are faced with the prospect of inevitable decline, and will
have often witnessed other family members suffering the same fate. There are also
implications for patients in terms of their employment, insurance and driving, the
exact rules of which will vary between countries.
Following disease onset, there is progression through five disease stages, orig-
inally described by Shoulson and Fahn (Table 1.2). These stages also correspond to
Total Functional Capacity (TFC) subscale score of the UHDRS, which is based on
the same functional domains. In a clinical setting, the more general terms of early,
moderate and advanced disease are used (Table 1.3).

1.5.2 Clinical Presentation

HD displays much clinical heterogeneity, even within families, in terms of the

balance of motor, cognitive and psychiatric features that predominate.
Motor symptoms are comprised of both involuntary movements, seen in
early-moderate stage typical adult onset disease, and impaired voluntary movement
seen in more advanced stages. Chorea is one of the most striking features, and is

Table 1.3 The Total Total Functional Capacity (TFC) Stage

Functional Capacity
(TFC) score and its Early 11–13 I
relationship to Shoulson-Fahn 7–10 II
stages and clinical descriptors Moderate or mid 4–6 III
Advanced or late 1–3 IV
0 V