PBL #3: Genetics Module

Like My Father

Day 1

Chief Complaint: Marty Ramakrishna is a 41-year-old man who presents to his physician
because of restlessness and anxiety for several months.

History of the Present Illness: Marty developed depression about 2 years ago and has been
treated with psychotherapy and sertraline. In the past several months, he has noted that it
takes longer than before to complete tasks at work. He has noted involuntary movements in
his arms and moves his legs while sitting more than others; colleagues have called him
“fidgety.” He has felt insecure driving and stopped driving about a month ago.

Past Medical History: unremarkable

Past Surgical History: none

Medications: Sertraline 100 mg daily

Allergies: no known drug allergies
Supplements: none

Social History: He grew up in Raleigh, NC and works as a chef in Manhattan. He was in the U.S.
Army from 1995-98, serving in Germany and Haiti. He is married and lives with his wife and 2
teenage daughters in northern New Jersey.

Habits:
Tobacco: none
Alcohol: none
Recreational drugs: none

Family History:
Mother: alive and well, age 65
MGM: alive, diabetes
 MGF: alive, hypertension

Father: depression; died age 53 in motor vehicle accident

PGM: depression; movement disorder attributed to psychiatric medications
PGF: alive, hyperlipidemia

Siblings: none
Daughter 1: alive and well, age 19
Daughter 2: alive and well, age 14

Review of Systems: unremarkable except as above

Physical Examination:
A well-appearing man in no apparent distress but frequently stretching his neck and changing
his position

Vital signs: Temperature 36.8 C

̊ . BP 120/78, HR 72, RR 10, Oxygen saturation 98%.

HEENT: clear
Neck: supple
Nodes: normal
Chest: clear
Cardiac: no jugular venous distension. Apical impulse normal. Regular rate and rhythm.
Normal S1 and S2 without murmur, gallop or rub. [normal exam]
Abdomen: Normal abdominal bowel sounds. Soft, nontender, without hepatosplenomegaly.
[normal exam]
Extremities: normal
Psychiatric: depressed, anxious mood; reduced range of affect
Neurologic:
Mental status: alert, appears depressed
Orientation to person, place and time: normal
Recent memory: recalls 3/3 objects at 5 minutes with 2 prompts
Remote memory: normal
Attention and concentration: repeats 7-digit number forwards; backwards with
one error
Language: reduced word choice
Fund of knowledge: normal
Cranial nerves: darting tongue movements, otherwise normal
Motor exam: normal strength, reduced muscle tone
fingers writhe involuntarily when the arms are outstretched
Sensory: normal
Deep tendon reflexes: increased (hyperreactive)
Gait: normal
What is your differential diagnosis for Marty’s presentation?

Basic blood tests

(Complete blood count, biochemistry profile, thyroid stimulating hormone, vitamin B12,
syphilis serology)

MRI brain:

(see images on CANVAS)

What is your presumptive diagnosis?

 Day 2

After discussing the risks, benefits and alternatives with his physician, Marty is referred for
genetic testing for Huntington’s disease. He has 60 CAG repeats in HTT, which is the gene that
causes Huntington’s disease (HD). This confirms his diagnosis of HD.

Marty comes back with his wife and children to discuss what they can do to assess their risk
factors. How would you advise the family if you were their genetic counselor regarding their
recurrence risks and prognosis of the disorder in their case?
Are there practical reasons to want to have this information? What are the drawbacks? What
are the therapeutic options that can be offered to the family? At present? In future?

Youtube video: http://www.youtube.com/watch?v=Nc3qo4HU-_o

Youtube video: https://www.youtube.com/watch?v=i_EDkmOZVus
Youtube video: http://www.youtube.com/watch?v=KP7DaxZy7FY

See the following for a comprehensive review of HD:

https://www.ncbi.nlm.nih.gov/books/NBK1305/
Learning Objectives:

1. The student will be able to describe in detail what is known about an inheritance
pattern from the case history:
a. Mendelian modes of inheritance and how the pattern is established from family
history
b. Importance of age of onset
c. How gender provides a clue

2. The student will be able to recognize some of the disease types associated with
trinucleotide repeat disorders.

3. The student will be able to describe the nature of the risk for Huntington’s disease
conferred by these mutations, including describing the magnitude of risk associated
with numbers of triplet repeats and the concept of repeat expansion during meiosis.

4. The student will be familiar with and able to describe the process whereby genetic
testing for an adult onset disease may be appropriate, including:
a. Describing the patients in whom such testing may be indicated.
b. The implications to the lives of patients and implications for other family
members.
c. The process of counseling that is required for interpretation of results.

5. The student will be able to describe the process of shared decision making that is
involved in the interpretation of genetic testing results and in subsequent patient
management, and demonstrate an appreciation for the complex decisions that patients
with these mutations must make.
https://huntingtonsdiseasenews.com/crispr-cas9-system/

CRISPR/Cas9 System
Huntington’s disease is a heritable genetic disorder characterized by chorea (tremors), psychiatric
problems, and loss of thinking ability.

CRISPR/Cas9 is a new gene editing technique that could potentially treat Huntington’s disease. The
approach is currently in preclinical testing, but early results are promising.

How the CRISPR/Cas9 system works in Huntington’s disease

Huntington’s disease is caused by mutations, which introduce long repeating CAG nucleotide sequences in
the huntingtin (HTT) gene. When the gene is transcribed, a messenger RNA molecule is made, which
serves as the template for cells to make HTT protein.

Because of the CAG repeat expansion, a faulty protein is made, which is then degraded by cells. This leads
to the formation of toxic protein fragments, which stick together and accumulate inside cells, leading to
neurodegeneration. The length of the CAG repeat region seems to correlate with the severity and age of
onset of Huntington’s disease.

CRISPR/Cas9 is a revolutionary gene editing technology, which could permit the “silencing” of the
mutated HTT gene and prevent the formation of faulty protein.

Cas9 is an enzyme that cuts DNA very precisely and accurately by using a guide RNA complementary to a
specific gene sequence — in this case, the mutated region of the HTT gene. The guide RNAs are designed
to target either side of the CAG repeat region in the HTT gene.

Once cut, the DNA strands should be reconnected by the DNA repair machinery of the cell, without the
CAG repeats, permanently removing the mutation from the genome of every cell that is edited. The name
“CRISPR” comes from the bacterial system in which Cas9 was first identified and characterized.

CRISPR/Cas9 research in Huntington’s disease

In a recent study published in Frontiers in Neuroscience, researchers successfully edited out the faulty
region of the HTT gene in cells derived from patient samples using the CRISPR/Cas9 system. Even in
samples from patients with differing lengths of CAG repeat regions in their genome, the CRISPR/Cas9
system was able to greatly reduce the amount of faulty HTT protein produced.

This technique could be tested in clinical trials by pharmaceutical companies, both in Huntington’s disease
and other neurodegenerative disorders.

Other information
Although very promising, the CRISPR/Cas9 system is still a new technology. It is not clear what the
potential side effects of the approach will be, and a major concern is the potential, however slight, of Cas9
to edit the genome in unpredictable ways.

***

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Huntington’s Disease News is strictly a news and information website about the disease. It does not
provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for
professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other
qualified health provider with any questions you may have regarding a medical condition. Never disregard
professional medical advice or delay in seeking it because of something you have read on this website.

CRISPR takes on Huntington’s disease.

By Michael Eisenstein, Nature 30th May 2018

https://www.nature.com/articles/d41586-018-05177-y

Gene editing offers the prospect of curing the inherited neurodegenerative

condition in a single dose.

Beverly Davidson and Alex Monteys are using gene editing to inactivate the mutated
gene huntingtin.Credit: Children’s Hospital of Philadelphia

Beverly Davidson is well insulated from the hype of gene therapy, having spent decades
working in the field. During that time, she has grappled with the harsh realities of turning
flashy and potentially transformational technologies into clinical applications. But when
she heard about the genome-editing technology CRISPR, she was instantly intrigued. “As
soon as those first papers came out, we started playing with it,” says Davidson, a
specialist in neurodegenerative disease at the Children’s Hospital of Philadelphia in
Pennsylvania.

Like most other neurological disorders, Huntington’s disease has proved to be a costly
and frustrating target for drug developers. But it also has distinctive features that make it
a good match for treatments that target genes. It arises from a mutation in a single gene
that encodes the protein huntingtin, and a disease-causing copy of the gene can be readily
distinguished from a normal copy by the presence of an overlong stretch of a repeated
triplet of nucleotides, CAG. Before turning to CRISPR, Davidson and her colleagues had
some success in treating animal models of Huntington’s disease with RNA interference
(RNAi), which uses synthetic molecules of RNA to prevent the production of mutant
huntingtin — although it took them a considerable amount of time to get there. “We’ve
focused the last 17 years on RNAi-based approaches,” says Davidson. However, both this
and a promising related treatment for Huntington’s disease that involves antisense
oligonucleotides will probably require long-term, repeated administration to provide
sustained benefits.

By contrast, CRISPR could achieve the same benefits through a single dose that
permanently inactivates the defective gene with remarkable efficiency, as Davidson’s
team demonstrated last year1, both in cells from people with Huntington’s disease and in
mouse models of the condition. “I was surprised how easy it was — I think that’s the
beauty of the system,” she says. In the past five years, several teams of researchers have
independently shown that genome editing can reliably eliminate the gene that encodes

2
mutant huntingtin, thereby halting the production of the toxic protein and its
accumulation into clumps in experimental models.

But clearing protein clumps in mice is of questionable value when researchers often
struggle to translate such findings into treatments for people — in general, potential
therapies for brain disorders have a long history of failure and disappointment in clinical
trials. Accordingly, the early adopters of CRISPR are trying to obtain clearer evidence of
its probable clinical benefits while grappling with thorny questions related to its safety,
efficacy and delivery that it is crucial to answer before trials in people can take place. “I
believe we can now seriously consider clinical strategies to edit huntingtin,” says Nicole
Déglon, a neurologist at the Lausanne University Hospital in Switzerland, “but I would
say we are still at the very beginning of the story.”

To the letter

The targeted DNA-snipping capabilities of CRISPR evolved in bacteria as a defence

against viruses that shoehorn their genomic material into their microbial hosts. The
system uses a short sequence of RNA known as a guide RNA, which can pair with a
complementary DNA sequence. Researchers have learnt how to target almost any
genomic sequence by engineering an appropriate guide RNA. They couple it with an
enzyme called Cas9, which can then cut both strands of a DNA sequence of interest at a
specific site. Because the DNA-repair mechanism of cells is sloppy, it typically produces
insertions or deletions that inactivate the affected gene.

One of the first decisions that would-be editors have to make is whether to eliminate the
gene that encodes huntingtin altogether, or to selectively target the repeat-laden mutated
copy. Although the function of huntingtin remains poorly understood, it is crucial for
early development. “If you knock out huntingtin in mice, they die in the womb,” says
Jong-Min Lee, a neurogeneticist at Massachusetts General Hospital in Boston. However,
Xiao-Jiang Li and colleagues at Emory University School of Medicine in Atlanta,
Georgia, have obtained evidence from mouse studies2 that the depletion of huntingtin in
the brain might not be detrimental when it occurs in adulthood. His team subsequently
demonstrated3 that a CRISPR–Cas9 approach that eliminates huntingtin can clear clumps
of the protein from the brain with no apparent adverse effects in a mouse model of
Huntington’s disease (see ‘Cutting down on huntingtin’), although he is cautious about
drawing too firm a conclusion. “We didn’t find any obvious phenotype or
neuropathology, but we still don’t know whether there was some sort of functional
impact,” says Li.

Cutting down on huntingtin

The mutant protein huntingtin (green fluorescence) is abundant in brain tissue gathered
from a mouse model of Huntington’s disease (top), but a CRISPR-based intervention that
targets the gene encoding huntingtin greatly reduces production of the toxic protein
(bottom).

3
 4
Most researchers are therefore erring on the side of caution by designing guide RNAs that
recognize sequences found only in the mutated gene. This was the approach that
Davidson’s team pursued, and Lee and colleagues also showed that they could make edits
with remarkable accuracy in cells that were collected from a person with Huntington’s
disease, by designing guide RNAs that recognize sequence variations found only on the
chromosome that contains the mutated gene4. “The specificity is excellent,” says Lee,
noting that the chromosome that bears the normal copy of the gene is consistently
unaffected in treated cells. Achieving this in a clinical setting would require a level of
personalization, but Lee has collected genomic data from more than 4,000 people with
Huntington’s disease and identified some informative patterns of sequence variation that
are strongly associated with mutated copies of the gene that encodes huntingtin. “With
just a couple of CRISPR designs, you could easily target more than 50% of patients,” he
says.

Another concern is off-target editing, in which genes other than the target are modified
inadvertently — with potentially disastrous consequences. Software can be used to
predict probable off-target edits and to help researchers pick distinctive guide RNAs with
reasonable confidence. But clinical researchers do need to consider the effects that
CRISPR might have when used over the longer term. “We should not apply this to
humans if we have permanent expression of Cas9 in the brain,” says Déglon.
Unfortunately, most systems for getting the CRISPR machinery into the brain rely on its
delivery by viral vector, which could lead to Cas9 being produced indefinitely. Over
time, the enzyme might wreak irreparable genomic damage on healthy neurons. A
possible solution entails using synthetic nanoparticles to facilitate the one-time delivery
of the enzyme and guide RNA, although this work is still at an early stage.

Déglon’s team has devised a promising alternative to CRISPR called KamiCas9, which
includes a self-destruct button for Cas9. It uses two guide RNAs — one to target the gene
encoding huntingtin, and another to target the gene encoding Cas9. This means that, after
a brief flurry of activity by Cas9, production of the DNA-dicing enzyme is inactivated
permanently, which dramatically reduces the risk of collateral damage. She notes that
several weeks after conventional CRISPR–Cas9 was applied to neural cells derived from
people with Huntington’s disease, low levels of off-target editing were detected —
roughly 2% of modified cells received unwanted edits at a site that is particularly
susceptible to off-target editing5. By using KamiCas9, her team was able to reduce that
effect dramatically — only 0.5% of such modified cells had off-target edits. “We did not
see any difference in terms of efficacy, which is really good news,” says Déglon.

Burden of proof. Such concerns are of little relevance unless editing with CRISPR
can be shown to change the course of a disease — something that is difficult to
demonstrate through experiments with mice. Li’s team has been able to alter
Huntington’s disease at the molecular level3 by sharply reducing the production of mutant
huntingtin, which forms the toxic clumps that drive the progression of the condition. “We
have shown that, in an injected area of the mouse brain, probably more than 90% of cells
do not contain huntingtin aggregates,” says Li. This effect was accompanied by modest
yet measurable improvements in motor function. However, as with many animal models

5
developed for other diseases, the mouse models that researchers use to investigate
Huntington’s disease are poor surrogates for what happens in people with the condition.
“Our model has mild motor phenotypes that show up later in life,” says Davidson. “It
doesn’t have any overt, robust neurodegeneration like you would see in a human patient.”

To some extent, this issue reflects the lifespan of mice — one or two years is not enough
time in which to accurately map a degenerative disease that normally unfolds over
decades. And there are also fundamental differences in the function and organization of
rodent brains compared with those of larger mammals. However, Li’s team has
developed a promising pig model6 of the condition that reflects the neurodegeneration
and the motor and behavioral defects observed in people more closely than any mouse
model so far. “Small animals and large animals exhibit very different pathological
changes and behavioural changes,” says Li.

These improved models will also help researchers to get a handle on how many brain
cells must undergo gene editing to obtain clinical gains — useful information given the
impracticality and undesirability of bathing the brain in CRISPR-laden viral vectors. The
striatum, a brain structure that governs both movement and cognition, is a prominent
casualty of Huntington’s disease, and work with antisense oligonucleotides and RNAi
suggests that efficient targeting with CRISPR could help to prevent the death of neurons
in the area. Davidson thinks that cutting the production of mutant huntingtin in the
striatum by half might be sufficient to halt disease progression or even prevent its onset.

For those already in the grip of Huntington’s disease, there are hints that genomic repair
could provide a partial rebound. “Neurons may have a lot of capacity to get rid of mutant
protein if you break the continuous formation of new aggregates,” says Li. A preventive
approach, however, could one day enable individuals to avert their genetic destiny, long
before the onset of disease. Indeed, Huntington’s disease is among the few disorders that
can be confidently predicted using a genetic red flag. But even if CRISPR-based
treatment amasses a strong body of preclinical data to support its use in Huntington’s
disease, initial clinical testing will almost certainly focus on people with symptoms, for
whom improvements in motor and cognitive function can be measured in a reasonable
timeframe. “Then, based on the results of the first trials showing the absence of potential
side effects, they might consider early-stage or even presymptomatic patients,” says
Déglon.

The brain will not be the first clinical proving ground for CRISPR. Instead, initial forays
will probably be aimed at conditions such as haemophilia, which can be treated with cells
that have already been genetically manipulated in the laboratory. The brain remains a
daunting target because of its biological complexity, relative inaccessibility and
irreplaceable function. But the parallel surge in the clinical development of gene therapy
and oligonucleotide-based interventions has cleared a path for testing the potential of
CRISPR in treating Huntington’s disease. Even at this early stage, Davidson is optimistic.
She is collaborating with Intellia Therapeutics in Cambridge, Massachusetts, which was
co-founded by CRISPR pioneer Jennifer Doudna, to address the technical challenges that
are involved in moving her research into the clinic. “I hate to say this, because I probably

6
gave these sorts of numbers for RNAi, but with further advances in delivery, I could
envision doing clinical testing within five years,” says Davidson. “I don’t think it’s
particularly far off.”

Nature 557, S42-S43 (2018)

doi: https://doi.org/10.1038/d41586-018-05177-y

References
1. 1.

Monteys, A. M., Ebanks, S. A, Keiser, M. S. & Davidson, B. L. Mol. Ther. 25, 12–23 (2017).

PubMed Article Google Scholar

2. 2.

Wang, G., Liu, X., Gaertig, M. A., Li, S. & Li, X. J. Proc. Natl Acad. Sci. USA 113, 3359–3364
(2016).

PubMed Article Google Scholar

3. 3.

Yang, S. et al. J. Clin. Invest. 127, 2719–2724 (2017).

PubMed Article Google Scholar

4. 4.

Shin, J. W. et al. Hum. Mol. Genet. 25, 4566–4576 (2016).

PubMed Google Scholar

5. 5.

Merienne, N. et al. Cell Rep. 20, 2980–2991 (2017).

PubMed Article Google Scholar

6. 6.

Yan, S. et al. Cell 173, 989–1002 (2018).

PubMed Article Google Scholar

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Roos Orphanet Journal of Rare Diseases 2010, 5:40
http://www.ojrd.com/content/5/1/40

REVIEW Open Access

Huntington’s disease: a clinical review

Raymund AC Roos

Abstract
Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by
unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the
Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some
cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school
(Juvenile Huntington’s disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All
psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline.
HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the
short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of
disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an
individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should
only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they
carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders
or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed.
Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro
fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based
on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking
or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required.
The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-
time care, and finally death. The most common cause of death is pneumonia, followed by suicide.

Introduction actual premanifest diagnoses could be made and as

The first description by Waters, of a patient with what
we now call Huntington’s chorea, dates from 1842. But
it was not until 1872, after the lecture and description
of the disease by George Huntington, that it became
known as Huntington’s chorea. It is a neurodegenerative
disorder passing within families from generation to gen-
eration with onset in middle age and characterized by
unwanted choreatic movements, behavioral and psychia-
tric disturbances and dementia [1] For many decades its
name remained unchanged, until the nineteen-eighties
when, fully aware of the extensive non-motor symptoms
and signs, the name was changed to Huntington’s dis-
ease (HD). In 1983, a linkage on chromosome 4 was
established and in 1993 the gene for HD was found [2].
That period marked a tremendous increase in interest
in HD and neurogenetic disorders. For the first time,
Correspondence: r.a.c.roos@lumc.nl
Department of Neurology K5Q112, LUMC PO Box 9600, 2300RC Leiden The
Netherlands
more diseases involving trinucleotide repeats of CAG
were found, HD served as a model for many studies in
medicine. CAG (cytosine (C), adenine (A), and guanine
(G)), is a trinucleotide, the building stone of DNA. CAG
is the codon for the amino acid glutamic. Finding the
gene opened new research lines, new models and for
the first time a real rationale on the way to treat this
devastating disease. Many symptomatic treatments are
now available, but there is a need for better, modifying
drugs.
Epidemiology
Huntington’s disease is a rare neuropsychiatric disorder
with a prevalence of 5-10 per 100,000 in the Caucasian
population. In Japan, a much lower prevalence of about
one-tenth of prevalence of the Caucasion population is
described [3]. Recently, several phenocopies have been
described, all of which have an even lower prevalence
(see paragraph on differential diagnosis).

© 2010 Roos; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Roos Orphanet Journal of Rare Diseases 2010, 5:40
http://www.ojrd.com/content/5/1/40
Clinical description
The nuclear symptoms and signs of Huntington’s disease
(HD) consist of motor, cognitive and psychiatric distur-
bances. Other less well-known, but prevalent and often
debilitating features of HD include unintended weight
loss, sleep- and circadian rhythm disturbances and auto-
nomic nervous system dysfunction. The mean age at
onset is between 30 and 50 years, with a range of 2 to 85
years. The mean duration of the disease is 17-20 years.
The progression of the disease leads to more dependency
in daily life and finally death. The most common cause of
death is pneumonia, followed by suicide.
The motor symptoms and signs
The characteristic motor changes are involuntary,
unwanted movements. Initially, the movements often
occur in the distal extremities such as fingers and toes,
but also in small facial muscles. For bystanders these
muscle twitches are often invisible or can be explained
as nervousness. In daily life, walking becomes unstable
and the person can look as if he/she is slightly drunk.
Gradually the unwanted movements spread to all other
muscles from distal to more proximal and axial. Chorea-
tic movements are present all the time the patient is
awake. No single pattern exists, but facial choreatic
movements can lead to a continuous movement of facial
muscles where for instance an eyebrow is lifted, an eye
closed, the head is bent or turned while the tongue is
protruded with the lips pouting. The most prominent
are the extension movements of the long back muscles.
Talking and swallowing gradually become more proble-
matic leading to choking at any time in some patients.
In later stages the patient even becomes mute. Dysar-
thria and dysphagia become very prominent during the
course of the disease. All patients develop hypokinesia,
akinesia, and rigidity leading to a slower pace of all
activities (bradykinesia: slowness of movement) and a
severe hesitation in embarking on a movement (akinesia:
difficulty in starting movemevents)). The balance
between chorea and hypokinesia is determined individu-
ally. The extremes are on the one hand the younger
patient with an overwhelming rigidity (Westphal variant)
and on the other hand the very old patient severely
affected in the last stage of the disease with a long dura-
tion of illness, bed-bound with rigidity and flexion con-
tractures in the extremities. Dystonia is characterized by
slower movements with an increased muscle tone lead-
ing to abnormal posture, for instance torticollis, but also
rotation of the trunk or limbs. Dystonia (for instance
torticollis) can be the first motor sign in Huntington’s
disease. Other unwanted movements include tics, com-
parable to the ones seen in Tourette syndrome, but
these are fairly rare. Cerebellar signs can appear sporadi-
cally, similar to the presence of hypo- and hypermetria.
Page 2 of 8
Walking is often described as ‘drunk’ or ‘cerebellar
ataxia’-like. Distinguishing between choreatic and ataxic
walking is very difficult. Pyramidal signs (Babinski sign)
are present incidentally.
The influence of motor disturbance on activities of
daily life progresses over time. The presence of hyperki-
nesia and hypokinesia results in difficulties in walking
and standing, and frequently leads to an ataxic gait and
frequent falls. Furthermore, daily activities such as get-
ting out of bed, taking a shower, dressing, toileting,
cleaning the house, cooking and eating become more
and more difficult. Depending on the kind of work the
patient does, motor signs will sooner or later interfere
with performance, even if psychiatric and cognitive
changes are still in the background.
Behaviour and psychiatric symptoms and signs
Psychiatric symptoms are very frequently present in the
early stage of the disease, often prior to the onset of
motor symptoms. The percentage of patients with psy-
chiatric signs varies between 33% and 76% depending on
the methodology of the study [4]. Because of their impact
on daily life, these symptoms and signs usually have a
highly negative impact on functioning and on the family
[5]. The most frequently occurring sign is depression.
The diagnosis is difficult because weight loss, apathy and
inactivity also occur in HD. Usually there is low self-
esteem, feelings of guilt and anxiety. Apathy is related to
disease stage, whereas anxiety and depression are not.
Suicide occurs more frequently in early symptomatic
individuals and also in premanifest gene carriers. Around
the time of the gene test and the stage when indepen-
dence diminishes are the most risky periods for suicide.
Anxiety also occurs frequently (34-61%), sometimes in
relation to uncertainty about the start and or the course
of the disease. Obsessions and compulsions can disturb
the patient’s life and also lead to irritability and aggres-
sion. Irritability is often the very first sign, in retrospect,
but in fact occurs during all stages of the disease [4]. The
way irritability is expressed varies enormously from ser-
ious disputes to physical aggression. A loss of interest
and increasing passive behaviour are seen as part of the
apathy syndrome. It can be difficult to discriminate
apathy from depression. Pychosis may appear, mainly in
the later stages of the disease. In most cases this goes
together with cognitive decline. The complete clinical
picture is comparable to schizophrenia with paranoid
and acoustic hallucinations. In the early stages, hyper-
sexuality can cause considerable problems in a relation-
ship. In the later stages hypo-sexuality is the rule.
Dementia
Cognitive decline is the other main sign of HD and can
be present long before the first motor symptoms appear,
Roos Orphanet Journal of Rare Diseases 2010, 5:40
http://www.ojrd.com/content/5/1/40
but can also be very mild in far advanced stages of the
disease. The cognitive changes are particularly in rela-
tion to executive functions. In normal conditions, cogni-
tive and motor behaviour is goal-directed and planned.
Normally individuals are able to distinguish what is rele-
vant and what can be ignored, but patients with HD
lose this capability. The patients are no longer able to
organise their life or to plan things which in the past
were simple. They lose flexibility of mind, and can no
longer make mental adjustments. Misjudgements lead to
complicated situations, with patients no longer reacting
as they did in the past or in a way that the environment
expects. Language is relatively spared. Memory certainly
becomes impaired, although the semantic memory can
be spared to a certain extent. All psychomotor processes
become severely retarded [3].
Secondary symptoms and signs
From early on, an unintended weight loss has been
reported in all patients. As more attention is now paid to
this phenomenon, the loss seems to be a little less severe,
the cause being diverse. Although it seems logical to
think that chorea should play the main role in weight
loss, it has been shown that there is no relation between
weight loss and chorea or other movement disorders. A
relation with the length of the CAG repeat has been
described [6]. More practical issues, such as slower func-
tioning, decreased appetite, difficulty handling food and
swallowing certainly play a role. But hypothalamic neuro-
nal loss is also a causative factor [7,8].
Attention has only recently been focused on sleep-
and circadian rhythm disturbances of patients with HD
[9]. Autonomic disturbances can result in attacks of pro-
fuse sweating.
Juvenile Huntington’s disease
If the first symptoms and signs start before the age of 20
years, the disease is called Juvenile Huntington’s disease
(JHD). Behaviour disturbances and learning difficulties
at school are often the first signs. Motor behaviour is
often hypokinetic and bradykinetic with dystonic com-
ponents. Chorea is seldom seen in the first decade and
only appears in the second decade. Epileptic fits are fre-
quently seen. The CAG repeat length is over 55 in most
cases. In 75% of the juveniles the father is the affected
parent [10].
Development of the disease
The course of the life of a person with one parent with
Huntington’s disease can be divided into an at-risk, a
preclinical (A) and a clinical (B) stage. The at-risk stage
comes to an end when it is determined whether the per-
son carries the increased CAG repeat on chromosome 4.
If he does carry the gene, then he will go through the
preclinical and clinical stages until the end.
Page 3 of 8
The clinical course is roughly divided into three parts
(Table 1), indicating a decrease in independence and
increase in the need for care. The clinical stage with
clear manifest signs is preceded by the premanifest gene
positive stage, and the transition or phenoconversion
phase, when more and more doubt about manifestations
of signs emerges. During periods of stress, irrespective
of whether this is physical or psychological, it is not
uncommon for clinical symptoms or signs to become
manifest. These signs can fade away temporarily when
the circumstances normalize. In the past, the first symp-
tom was always a motor sign. Dependent on the family’s
and the doctor’s experience with the disease, a diagnosis
was suggested. However, over the last 20 years it has
become clear [11,12] that psychiatric as well as cognitive
changes can be the first signs, many years before motor
signs become visible. If the non-motor signs are less
specific, it can be very difficult to make a diagnosis. In
retrospect, many patients mention a gradual change in
behaviour and performance at work. They stayed home
for some time with a ‘burn-out’ or a ‘depression’. These
signs are rather non-specific and often have a plausible
explanation. With improved knowledge about the
genetic status and the course of the disease it has
become clear that these signs can be the first manifesta-
tion of Huntington’s disease.
Assessments
The clinical assessment of the symptoms and signs of
HD is important for patient, family and care-givers. To
follow the patient systematically, mainly for research
purposes, several scales have been developed. The best
known are the Shoulson and Fahn capability scale [13]
and the Unified Huntington Disease Rating Scale
(UHDRS) [14,15]. The UHDRS consists of a motor,
behaviour, cognitive and functional part, preceded by a
history and medication scheme. For the behaviour signs
a new scale was developed by Craufurd: the Problem
Behaviour Scale (PBS) [16]. Other scales, for instance
for the quality of life, are also in use. In the European
Network for Huntington disease (EHDN: website [17]) a
whole set of assessment scales has been devised, which
are now in use for over 6,000 patients in Europe.
Aetiology
Huntington’s disease is an autosomal dominantly inher-
ited disease caused by an elongated CAG repeat on the
short arm of chromosome 4p16.3 in the Huntingtine
gene [2]. This gene codes for the huntingtin protein and,
on exon 1, contains the CAG tract. The wild-type con-
tains a CAG repeat, coding for a polyglutamine stretch in
the protein at that site in the range 6 to 26. Huntington’s
disease is associated with 36 repeats or more. Definite
clinical manifestation will occur if the number of repeats
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Table 1 Stages during the life of a Huntington’s disease patient

A. Preclinical stage
A1. At-risk stage (50%), one affected parent - Anxiousness for the future
- Uncertainty about carriership
- Care for affected parent

A2.Gene carrier, premanifest stage - Certainty about carriership

- New position in the family
- Renewed uncertainty about onset
- Care for affected parent and own family

A3. Transition phase - Strong feelings about changes in cognition

- Changes in behaviour
- Changes in motor activity
- Uncertainty remains

B. Clinical stage
B1. Clinical stage I - Presentation first symptoms: neurological, cognitive or psychiatric
- Chorea most prominent symptom
- Independent in ADL
- Burden for the family mainly psychological
- Rare death, unless suicide

B2 Clinical stage II - Motor disturbance more generalised

- Physical dependence starts
- Burden for family psychological and physical
- Death by other cause, suicide, euthanasia

B3. Clinical stage III - Severe generalised motor disturbance

- Almost complete physical dependence
- Patient completely dependent on care
- Burden for family mainly physical
- Death

exceeds 40. The range 36-39 leads to an incomplete
penetrance of the disease or to a very late onset. The
range between 29 and 35, the so-called intermediate
alleles, is unstable, which means that these alleles are
prone to changes during reproduction. Copying the gene
may lead to mistakes and very often leads to elongation
and seldom to shortening. This phenomenon is mainly
seen in the male line of reproduction [18].
An inverse correlation has been described between the
length of the repeat and the age at onset, determined by
the first motor manifestation. The longer the CAG
repeat, the earlier the onset. When the disease starts
before the age of 20 years, so-called juvenile Hunting-
ton’s disease (JHD), the repeat often exceeds 55 [5]. The
length of the repeat determines about 70% of the var-
iance in age at onset and gives no indication at all about
the initial symptom, the course, or the duration of ill-
ness. The only correlation now described is the faster
weight loss associated with a longer CAG repeat [6].
Anticipation phenomenon is seen in Huntington
families in the paternal line of inheritance.
The normal wild-type Huntingtin protein plays a role
in synaptic function, is necessary in the post-embryonic
period, possibly has an anti-apoptotic function and is
possibly protective against the toxic mutant, huntingtin
[19]. There is evidence that the mutant form leads to a
gain of function as well as to a loss of function. The
role of the mutation has been studied in many models:
cells, fibroblasts, C. Elegans, drosophila, mice, rat, sheep
and monkey. Mice models (more than 10 available) are
most commonly used. As neuronal intranuclear and
intracytoplasmic inclusions are found, it is still not clear
Roos Orphanet Journal of Rare Diseases 2010, 5:40
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what role they play. Are the inclusions pathogenic in
themselves or are they only a side-product of other
mechanisms? The inclusions are present in many areas
of the brain. The overall pathology, brain atrophy, parti-
cularly in the striatum with extensive neuronal loss, is
well known [20,21].
Diagnosis
The diagnosis is based on the clinical symptoms and
signs in a person with a parent with proven HD. First, it
is obligatory to take a precise history from the person
with symptoms followed by a detailed family history.
When all information has been obtained the diagnosis is
not very difficult, although non-specific clinical pictures
can be misleading. Also when the parent is not known
or has died due to another cause at a young age, the
clinical picture can be difficult to recognise. It is often
necessary to request old information in the form of
medical records and autopsy reports. The current gold
standard is DNA determination, showing a CAG-repeat
of at least 36 on the huntingtin gene on chromosome 4.
Before 1993, a family history with clinical and morpho-
logical verification in at least one of the parents or
grandparents was obligatory.
The clinical criteria currently necessary are still motor
changes with or without psychiatric or cognitive
changes. However, in most cases a combination of the
three main signs is present. The combination with the
family history is sufficient for diagnosis. No imaging,
general blood tests or other diagnostic tools are helpful.
For all diagnostic tests, it is necessary to obtain
informed consent from the patient. This is important
because if that person is given a diagnosis of Hunting-
ton’s disease, then probably many more individuals
around the patient will be confronted with an increased
risk of Huntington’s disease. Extensive studies are
underway to detect biomarkers (clinical, blood, MRI)
and hence the transition determining parameters [22].
Several studies are now focussing on changes in func-
tion and changes in brain imaging (MRI) before clinical
overt manifestation is present. It seems that brain
volume and brain connections show changes several
years before any clinical manifestation is present [23].
Differential Diagnosis
When chorea is the presenting and most prominent
sign, taking a history is the first and most valuable step.
The frequently occurring differential diagnoses for
motor sign chorea are given in Table 2. In many cases
the underlying cause is another general internal disorder
or an iatrogenic disorder. Only very few genetically
determined disorders are responsible for choreatic syn-
dromes. In about 1% of the cases clinically diagnosed as
HD by the clinician, the genetic test does not confirm
Page 5 of 8
Table 2 Differential Diagnosis for chorea
Hereditary - Huntington’s disease
- Benign hereditary chorea
- Neuroacanthocytosis
- DentatoRubroPallidoLuysianAtrophy (DRPLA)
- Wilson disease
Rheumatic disorders - Sydenham chorea
- Chorea gravidarum
Drug-induced - Neuroleptic drugs
- Oral anticonceptive drugs
- Phenytoine
- Levo-dopa
- Cocaine
Systemic disorders - Systemic Lupus Erythematodes (SLE)
- Thyrotoxicosis
- Polycythemia vera
- Hyperglycemia
- AIDS
- Paraneoplastic
the diagnosis. These are the so-called phenocopies [24].
Phenocopies are defined by a clinical diagnosis of HD
with chorea, psychiatric and or cognitive signs and an
autosomal dominant pattern of inheritance or family
history. In the last few years, several have been
described (Table 3)
Genetic Counselling
When the gene was localised on chromosome 4 in 1983
[25], premanifest diagnosis became available for the first
time using linkage analysis. Linkage analysis provided
the applicant with results, initially with a certainty of
93% and later with a certainty of about 98%. When in
1993 the CAG repeat on chromosome 4 was described,
real premanifest diagnosis could be given to those at
risk of HD. It was the first disease in which this techni-
que became practically available, functioning as an
example of how to cope with new questions and pro-
blems. A manifest was written by the HD community, a
collaboration of scientists, doctors and lay people [26].
The standard procedure was the following: step 1, con-
sultation with a clinical geneticist and preferably in
combination with a psychologist and a neurologist.
After 4-6 weeks a second consultation (step 2) takes
place including blood sampling. After a period of 6-
8 weeks a consultation (step 3) with disclosure is
planned. Exclusion criteria for the procedure are: age
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Table 3 Phenocopy of Huntington’s disease (OMIM) [32]
Mutation
1. HDL1 octapeptiderepeatexpansion PRNP-gen
2. HDL2 CTG/CAG-expansion JPH3-gen
3. HDL3 Not known
4. SCA17 (HDL4) CAG/CAA-expansion TBP-gen
5. SCA1/2/3 CAG-expansion ATXN1/2/3-gen
6. DRPLA CAG-expansion ATN1-gen
7. Chorea-acanthocytosis mutation VPS13A-gen
8. McLeod syndrome mutation XK-gen
9. NBIA2 mutation PLA2G6-gen
10. NBIA1/PKAN mutation PANK2-gen
11. Friedreich ataxia GAA-expansion FXN-gen
HDL = Huntington Disease-Like; SCA = Spinocerebellar ataxia; DRPLA = DentatoRubroPallidoLuysian Atrophy; NBIA = Neurodegeneration with Brain Iron
Accumulation; PKAN = Pantothenate-Kinase-Associated-Neurodegeneration.
below 18 years, severe psychiatric illness, and external
pressure for the applicant. Long discussions took place
concerning applicants with a 25% risk at the time of the
request. The procedure was extended with the rule that
maximal efforts must be taken by the applicant to get a
result from the parent with a 50% risk of HD. Finally
the 25% at risk applicant can get his test [27].
Prenatal diagnosis
As the test can be performed on any cell with a nucleus
containing DNA, antenatal diagnosis is also possible.
Between the 10th and 12th weeks of pregnancy, chorio-
nic villus sampling and between the 15th and 17th weeks
amniocentesis can be performed and DNA-testing car-
ried out. The procedure is only initiated if the parents
already know their own genetic status to prevent
unwanted disclosure for two individuals at the same
time. The procedure is embarked on with the intention
of ending the pregnancy if the HD gene is found in the
embryo. The mother cannot be forced to agree with this
conclusion.
If the parents have not yet been genotyped, one can
opt for an exclusion test by comparing the genetic status
of the embryo with that of the grandparents. In this
situation the result is either 0% risk for the foetus, and
so the parent keeps his or her 50% status, or 50% risk
for the foetus. The foetus has received a chromosome
from the affected grandparent, but it is not known to
which chromosome the HD gen is coupled. In this case
the foetus has a 50% risk, comparable to the parent, and
the parents can decide to abort a 50% at risk baby.
During the last decade, preimplantation diagnostics
has also been offered in several countries. The proce-
dure starts with in vitro fertilisation. When the embryo
is in its eight-cell stage, one cell is removed for DNA
testing. The embryo without the elongated CAG repeat
Page 6 of 8
Locus
20pter.p12
16q24.3
4p15.3
6q27
6p23, 12q24, 14q24-q31
12p13
9q
Xp21.2-21.1
22q13.1
20p13-12.3
9q13; 9p23-p11
is placed in the mother’s womb to allow a normal preg-
nancy to develop. Before starting this procedure, the
genetic status of the parent must be known, although
not all countries follow this line of thinking [28].
Management including treatment
Despite the fact that the pathogenesis of HD has still
not been resolved and a cure is not available, many
therapeutic options are available for treating symptoms
and signs with a view to improving quality of life.
Although many signs and symptoms can be treated, it is
not always necessary to do so. The patient’s limitations
in daily life determine whether or not drugs are
required. Very little evidence is available about the drug
or the dosage to prescribe for any signs and symptoms.
Drug treatment is, therefore, individualized and based
on expert opinion and daily practice.
Treatment consists of drug prescription and non-med-
ication advice. Surgical treatment does not play an
important role in HD and will be addressed only briefly.
Motor signs
Hyperkinesia, or chorea, is treated with dopamine recep-
tor blocking or depleting agents. Most commonly used
drugs for chorea (Table 4) are typical or atypical neuro-
leptics (dopamine receptor blocking) and tetrabenazine
(dopamine depleting). The drugs prescribed differ per
country. An extensive review of all medication is given
by Bonelli [29,30]. The most commonly used drugs for
depression and aggression are listed in Table 5. Cloza-
pine and olanzapine are atypical neuroleptics. Both have
an antichoreatic effect. Clozapine requires white cell
control in the blood and is, therefore, less practical,
making olanzapine the preferred drug. The most fre-
quently reported side effects are weight increase and
anti-depressive effects. From small case studies some
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Table 4 Drug treatment for chorea
Tiapride max 600 mg
Olanzapine max 20 mg
Tetrabenazine* max 200 mg
Pimozide max 6 mg
Risperidone max 16 mg
Fluphenazine max 10 mg
*When tetrabenazine is officially approved per country, this drug
will probably become the drug of first choice based on the
literature.
Hypokinesia None
(drug dosages vary individually; here maximal dosages are given; these are
seldom necessary in practice)
support can be found for prescribing quetiapine, zote-
pine, ziprasidone, and risperidon. However, only tetrabe-
nazine, a dopamine depleting drug, has been shown in a
controlled trial to significantly reduce chorea [31]. The
most common side-effects are depression and sedation.
There is a long list of drugs without or with only a very
limited result, mostly in open case studies: a-tocopherol
amantadine, baclofen, cannabidiol, chlordiazepoxide,
choline, clonazepam, creatine, deanol, dextromethor-
phan, fluoxetine, idebenone, ketamine, lamotrigine, leva-
tiracetam, milacemide, minocycline, muscimol, OPC
14117, PUFA, remacemide, riluzole.
Drug treatment for hypokinesia has been tried using
antiparkinsonian drugs, but almost always with very dis-
appointing results. In practice, therefore, dopaminergic
drug are not prescribed.
To date, despite several claims, no drug is available
with any neuroprotective or disease-delaying effect. Dis-
ease modifying drugs are developed, but not available.
Also embryonic cell implants, still under study, are not
proven treatment options at the moment.
Surgical intervention to treat chorea has been
described in a few cases. Deep brain stimulation has a
place in other movement disorders such as Parkinson
disease.
In Alzheimer’s disease, anticholinesterase drugs are in
use. In Huntington’s disease no clinical trials with Rivas-
tigmine or Donepezil are available. In short-term, open
studies, no effect was found.
Psychiatric signs
As depression and aggressive behaviour are the most
devastating to family life, the majority of drugs are pre-
scribed for these signs. All advice is based on open stu-
dies and expert opinion. (Table 5)
Besides medication, many other care measures are
available. It is important to find the right therapy for
the right person at the right time. Non-medical inter-
ventions available are: physiotherapy, occupational
Page 7 of 8
Table 5 Drug Treatment for depression (A) and
aggression (B)
A. Depression B. Aggression
Citalopram max 60 mg Citalopram max 60 mg
Fluoxetine max 60 mg Sertraline max 200 mg
Mirtazapine max 45 mgr Olanzapine max 20 mg
Valproinezuur max 2000 mg Dipiperon max 360 mg
Carbamazepine max 1600 mg Haloperidol max 10 mg
(drug dosages vary individually; here maximal dosages are given; these are
seldom necessary in practice)
therapy, speech therapy, dietician, psychologist, social
worker, and nurse.
During the course of the disease, the patient requires
more care, which can also help his/her partner, for
example by having a nurse at home to help with show-
ering. The burden for the caregiver can become too
heavy and so help must be found in day-care institu-
tions, usually connected to nursing home facilities. In
the period that follows the patient moves into a transi-
tion phase and eventually a 24-hour care situation.
Throughout the whole process of increasing depen-
dency, psychological help is often needed for the care-
giver, who has to deal with increasing responsibilities
while losing contact with his or her former partner.
Partner groups can be very useful. In general, lay organi-
zations play an enormous role in educating caregivers,
patients and families.
Medical and non-medical treatment must be individu-
ally tailored, as the symptoms and signs differ by person
and over time tremendously. Ideally treatment of
patients and their families should be organised by a
multidisciplinary team. Treatment is intended to
improve quality of life. To date, no cure is available
unfortunately.
Future perspectives
Huntington’s disease is a physically, psychologically and
socially devastating disorder. Knowledge about the dis-
ease and care for patients has increased enormously
over the last two decades. As the mean duration of ill-
ness is more than 17 years, one tends to forget the
many years prior to the onset of symptoms during the
at-risk and the preclinical periods, or the premanifest
period. Huntington’s disease is a lifelong disease for
both the individual and the family. From the moment
the gene was localised in 1983, and particularly after
1993, attention has focussed on the pathophysiological
pathway with the aim of developing a therapy. It was
the first autosomal dominant disease where premanifest
diagnosis became possible and it was the first trinucleo-
tide disease to be described. Consequently, since 1993
many researchers have developed an interest in this
Roos Orphanet Journal of Rare Diseases 2010, 5:40
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disorder. The number of publications has increased
enormously.
What is the current perspective? The basic studies
mainly focus on the pathophysiology and the search for
biomarkers. A better understanding of the pathophysiol-
ogy will surely lead to drug development to interfere in
the pathological process. Drugs that can slow down,
delay, or stop the onset of the disease are being sought.
The second issue is the search for reliable, early to
detect and clinically relevant markers for onset of the
end course of the disease. In the search for biomarkers,
a very well organised study is underway: TRACK-HD, a
multinational study with 366 participants. This will end
in 2011 [22]. The Registry study, the main project of the
European Huntington Disease Network, also aims to
prepare the field for larger studies when drugs become
available for human testing.
In parallel with the rational pathway to find solutions
to treat this disorder, attention is being paid to finding
the best care for all patients and at-risk persons at this
point in time. The developments are promising, but one
thing is certain: the road to a solution is a long one.
Competing interests
The author declares that he has no competing interests.
Received: 21 October 2009 Accepted: 20 December 2010
Published: 20 December 2010
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doi:10.1186/1750-1172-5-40
Cite this article as: Roos: Huntington’s disease: a clinical review.
Orphanet Journal of Rare Diseases 2010 5:40.
 Case 4-
Like my dad
Group 3
September 14, 2021
Objectives
✗ Huntington’s disease- Latifa Mahmoud
✗ Inheritance of Huntington's disease- Deema Al-Abdulla
✗ Who gets it?- Sara Joseph
✗ Testing for Huntington’s disease- Haya Al-Ansari
✗ “Potential treatments” for Huntington’s Disease- Fatema Falamrz
✗ Diseases Associated with Trinucleotide Repeats - Noor Al-Qatabri
✗ Case Presentation- Beshr Mushannan, Isa Al-Mannai & Mohammed
Khalid

2
1
Huntington disease
Latifa Mahmoud
Discovery
✗ By George Huntington in 1972
✗ Incurable
✗ Adult-onset
✗ Progressive neurodegenerative
disorder

https://en.wikipedia.org/wiki/George_Huntington 4
Pathological Process

https://www.gene.com/stories/understanding-h 5
untingtons-disease
Pathophysiology

https://www.gene.com/stories/unders
tanding-huntingtons-disease
6
Clinical Presentation

Motor Behavior Cognitive

7
STAGES OF HUNTINGTON’S DISEASE

Pre-symptomatic Prodromal Manifest

8
References
✗ Huntington G. On chorea. Med Surg Report. 1872. 26:320
✗ Huntington's Disease Clinical Research Center, UC San Diego School of Medicine. For physicians:
stages of HD progression.
https://medschool.ucsd.edu/som/neurosciences/centers/huntingtons-disease/professionals/Pa
ges/stages-of-progression.aspx
✗ Huntington's Disease Society of America. Overview of HD.
https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/.
✗ Kirkwood SC, Su JL, Conneally PM. Progression of symptoms in the early and middle stages of
Huntington disease. Arch Neurol. 2001. 58(2):273-278.
✗ Quintanilla RA, Johnson GV. Role of mitochondrial dysfunction in the pathogenesis of Huntington's
disease. Brain Res Bull. 2009 Oct 28. 80(4-5):242-7
✗ Roos et al. Huntington's disease: a clinical review. Orphanet Journal of Rare Diseases. 2010. 5:40

9
 2
Inheritance of Huntington's disease
Deema Al-Abdulla
Huntington Disease (HD) and causes
● Huntington disease is a progressive neurological disorder that causes motor
impairment, cognitive decline and psychiatric manifestations.
● It is caused by mutations in the HTT gene, which codes for the huntingtin
protein.
● The HTT mutation involves the expansion of CAG trinucleotide repeats
within a DNA segment. Normally, the CAG segment is repeated 10 to 35
times.
● People with 36 to 39 CAG repeats may or may not develop symptoms of
Huntington's disease, while people with 40 or more repeats almost always
develop the disorder.
● The increase in the size of the CAG segment leads to the production of an
abnormally elongated version of the huntingtin protein which aggregate to
form toxic fragments in neurons, ultimately leading to nerve cell death.

11
Huntington Disease (HD) and causes
Length of CAG repeat allele has
been reported to influence age of
onset.
● People with the adult-onset form
of Huntington disease typically
have 40 to 50 CAG repeats in the
HTT gene.
● People with the juvenile form of
the disorder tend to have more
than 60 CAG repeats.

12
 inheritance
Depression,

● This condition is inherited in an movement

disorder

autosomal dominant pattern;

I
therefore, an affected parent has a
50% chance of having an affected
Depression
child because one copy of the II (53)

altered gene in each cell is sufficient

to cause the disorder.
III
● In rare cases, an individual with
Huntington disease does not have a
parent with the disorder.
IV

13
Anticipation
● As the altered HTT gene is passed from one
generation to the next, the CAG trinucleotide
repeat increases in size.
● A larger number of repeats is associated with an
earlier onset of signs and symptoms. This
phenomenon is called anticipation.
● Individuals with 27 to 35 CAG repeats in the HTT
gene do not develop Huntington disease;
however, they are at risk of having children who
could develop the disorder because the size of the
CAG trinucleotide repeat may lengthen into the
range associated with Huntington’s disease.

14
3
Who Gets It?
Sara Joseph
CHROMOSOME

https://www.news-medical.net/health/Chromosome-4-Related-Diseases.aspx

16
HOW?

https://medlineplus.gov/genetics/condition/huntington-disease/
https://www.cusabio.com/c-20774.html

17
Repeat Number Vs. Age

Onset age = 54.87 − 0.81*CAG

+ 0.51*(Parent’s onset age)
Aylward et al.

https://www.researchgate.net/figure/CAG-repeat-number-and-age-of-motor
-onset-in-HD-Reprinted-with-permission-from-Holmans-et_fig1_337937961

18
Repeats vs. Risk

https://en.hdbuzz.net/027

19
FREQUENCY

https://www.nature.com/articles/s41398-017-0042
-1

20
 References
✗ Gardiner, S.L., van Belzen, M.J., Boogaard, M.W. et al. Huntingtin gene repeat size variations affect risk of lifetime
depression. Transl Psychiatry 7, 1277 (2017). https://doi.org/10.1038/s41398-017-0042-1

✗ Möncke-Buchner, E., Reich, S., Mücke, M., Reuter, M., Messer, W., Wanker, E. E., & Krüger, D. H. (2002). Counting CAG
repeats in the Huntington's disease gene by restriction endonuclease EcoP15I cleavage. Nucleic acids research, 30(16),
e83. https://doi.org/10.1093/nar/gnf082

✗ Niemelä, Valter. (2019). Mapping the Huntington's disease process using cerebrospinal fluid analysis.

✗ Shabir, Osman. (2019, July 19). Chromosome 4 Related Diseases. News-Medical. Retrieved on September 13, 2021 from
https://www.news-medical.net/health/Chromosome-4-Related-Diseases.aspx.

✗ Langbehn, D. R., Hayden, M. R., Paulsen, J. S., & and the PREDICT-HD Investigators of the Huntington Study Group
(2010). CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical
approaches. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the
International Society of Psychiatric Genetics, 153B(2), 397–408. https://doi.org/10.1002/ajmg.b.30992

21
4 Testing for huntington’s
disease
Haya Al-Ansari
testing
To diagnose Huntington disease, a physician may inquire about the person’s detailed family
history and symptoms throughout the years. In addition, a physical exam will be done by a
neurologist as they will look for twitches and jerking as well as problems with your balance,
reflexes and coordination.

Imaging tests (MRI & CT scan) can be performed to look for signs of the disease and genetic
testing can be done to determine if the person has the abnormal gene.

Usually using a blood sample, genetic testing analyzes DNA for the HD mutation by counting
the number of CAG repeats in the Huntingtin gene.
✗ Individuals who do not have HD usually have 28 or fewer repeats.
✗ Individuals with HD usually have 40 or more repeats.

23
Some who are at risk choose not to take the test. They choose to live with the uncertainty of
being at risk and to forgo the emotional consequences of a positive result, as well as possible
losses of insurance and employment.

Prospective parents consider prenatal testing when one parent has been diagnosed with
Huntington's disease or has been found to carry the gene. Prenatal testing can show whether
the child will inherit the defective gene. To test the fetus, DNA is extracted from fetal cells via
CVS (chorionic villi sampling) or amniocentesis. If the fetus tests positive, parents can make
decisions about whether to terminate the pregnancy.

24
References
“Huntington's Disease: Genetics, Juvenile Cases & CHOREA.” Cleveland Clinic,
my.clevelandclinic.org/health/diseases/14369-huntingtons-disease.

“About Huntington's Disease.” Genome.gov,

www.genome.gov/Genetic-Disorders/Huntingtons-Disease.

“Huntington Disease.” Lab Tests Online, 31 Aug. 2021,

labtestsonline.org/conditions/huntington-disease.

25
5
“Possible tREAtments” for
Huntington's disease
Fatema Falamrz
Pharmacological Intervention
✗ Not enough evidence for long term symptomatic treatment for HD

✗ However, Tetrabenazine (TBZ) showed clear efficacy for the control of chorea in HD
✗ TBZ lowers the amount of dopamine
✗ TBZ is the only FDA approved drug for treatment of chorea associated with HD
✗ Side effects include: drowsiness, insomnia, depressed mood, agitation
A placebo controlled trial on patients with HD supported that when an optimal dosage of
TBZ was given there was no differences between TBZ and placebo

✗ Because TBZ can worsen depression patients should be monitored

✗ Some studies included a variety of drugs such as dopamine antagonists, neuroleptics,
benzodiazepines. However, some showed no efficacy or poor efficacy

27
Non pharmacological intervention
Non pharmacological interventions are being evaluated and being used without supporting
evidence:
- Low cost and risk
- Easily accessible
- Music therapy, exercise, dance or video game playing
- Examining their effect on gait (pattern of walking) and balance

Therapy: Occupational and speech therapy

28
Crispr/cas9 and hd
✗ Crispr/ Cas9 is a gene editing technology which could allow the silencing of the mutant
HTT gene and prevent formation of the faulty protein.
✗ Cas9 cuts the DNA with the help of the guideRNA which targets the CAG repeat
region in the HTT gene.
✗ Faulty regions of the HTT gene in patient samples were reduced with the help of
CRISPR/ Cas9 system.
✗ CRISPR/Cas9 system on mouse models of HD cleared clumps of the protein with no
adverse effects.
✗ However, scientists cannot depend on mice as their system works differently than
humans. Scientists are using pig models instead of mice to demonstrate the CRISPR
system on large mammals instead of small ones.
✗ More studies should be done with the CRISPR/ Cas9 system in order to find the
potential side effects before implementing them on humans

29
 CRISPR intervention showed reduced number
Brain tissue with mutant Huntingtin protein
of mutant proteins

30
REFERENCES
Eisenstein, M. (2018). CRISPR takes on huntington's disease. Nature (London), 557(7707), S42-S43.

doi:10.1038/d41586-018-05177-y

Frank, S. Treatment of Huntington’s Disease. Neurotherapeutics 11, 153–160 (2014).

https://doi.org/10.1007/s13311-013-0244-z

Pidgeon, C., & Rickards, H. (2013). The pathophysiology and pharmacological treatment of huntington

disease. Behavioural Neurology, 26(4), 245-253. doi:10.3233/BEN-2012-120267

Roos, R. A. C. (2010). Huntington’s disease: A clinical review. Orphanet Journal of Rare Diseases, 5(1), 40.

doi:10.1186/1750-1172-5-40

31
6 Diseases Associated with
Trinucleotide Repeats
Noor Al-Qatabri
Huntington Disease (HD)
● Caused genetically (inherited or new mutation).
● Triplet repeat sequence is CAG.
● Normal Range is 10-35 repeats.
● Pathological Range 36-120 repeats.

33
Dentatorubral-pallidoluysian atrophy (DRPLA)
● Rare autosomal dominant disorder.
● Triplet repeat sequence is CAG.
● Normal Range is 6-35 repeats.
● Pathological Range 48-93 repeats.

34
Kennedy's disease
● Spinal and Bulbar Muscular Atrophy (SBMA).
● Triplet repeat sequence is CAG.
● Normal Range is 11-35 repeats.
● Pathological Range 40-62 repeats.

35
Myotonic dystrophy
● Genetic disorder (autosomal-dominant).
● Triplet repeat sequence is CTG.
● Normal Range is 5-37 repeats.
● Pathological Range 60-100 repeats.

36
Fragile X syndrome
● Genetic disorder (X-linked recessive).
● Triplet repeat sequence is CGG.
● Normal Range is 5-44 repeats.
● Pathological Range >200 repeats.

37
References:
Everett, C. M. (2004). Trinucleotide repeats and neurodegenerative disease. Brain, 127(11), 2385-2405.
doi:10.1093/brain/awh278

Timchenko, L. T., Tapscott, S. J., Cooper, T. A., & Monckton, D. G. (2002). Myotonic Dystrophy: Discussion of Molecular Basis.
Triple Repeat Diseases of the Nervous Systems Advances in Experimental Medicine and Biology, 27-45.
doi:10.1007/978-1-4615-0117-6_2

Hunter JE, Berry-Kravis E, Hipp H, et al. FMR1 Disorders. 1998 Jun 16 [Updated 2019 Nov 21]. In: Adam MP, Ardinger HH,
Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK1384/

Huntington disease - Genetics Home Reference - NIH. (n.d.). Retrieved September 14, 2020, from
https://ghr.nlm.nih.gov/condition/huntington-disease

Veneziano L, Frontali M. DRPLA. 1999 Aug 6 [Updated 2016 Jun 9]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK1491/

List of Rare Disease Information. (2019, January 31). Retrieved September 14, 2020, from
https://rarediseases.org/for-patients-and-families/information-resources/rare-disease-information/

Myotonic dystrophy - Genetics Home Reference - NIH. (n.d.). Retrieved September 14, 2020, from
https://ghr.nlm.nih.gov/condition/myotonic-dystrophy

What is Fragile X Syndrome (FXS)? (2020, July 15). Retrieved September 14, 2020, from
https://www.cdc.gov/ncbddd/fxs/facts.html

38
7
Case Presentation
Beshr Mushannen, Isa Al-Mannai &
Mohammed Khalid
1. HTT gene is located on the short arm of chromosome 4 at 4p16.3.
(EXPLAIN FIGURE)

2. HTT contains a sequence of three DNA bases—cytosine-adenine-

guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...),
known as a trinucleotide repeat. CAG is the three-letter genetic
code (codon) for the amino acidglutamine, so a series of them results
in the production of a chain of glutamine known as a polyglutamine
tract (or polyQ tract), and the repeated part of the gene, the polyQ
region.

3. The equation

4. If both copies of a person’s HD gene contain 26 or fewer repeats,

they will not develop HD, and nor will any of their children.

repeat length between 27 and 39 CAGs - often described as the ‘gray

area’.

Although people with intermediate alleles (27 to 35 repeats) will

never experience HD symptoms themselves, the repeat inherited
by their children can be longer than their own. Their children are at
risk of inheriting a reduced penetrance or full penetrance gene

People with an HD gene containing between 36 and 39 repeats are in

the ‘incomplete penetrance’ range. Some people in this range will
develop symptoms of the disease, while others won’t.

HTT alleles containing 40 or more CAG repeats lead invariably to HD.

If one copy of an person’s HD gene has 40 or more repeats,
they will develop HD in their lifetime, and each of their children will
have a 50% risk of inheriting the expanded HD gene because of full
penetrance gene that means the person will definitely develop HD in
their life

5. odds ratio tells us how much higher the odds of exposure are among
case-patients than among controls. An odds ratio of • 1.0 (or close to
1.0) indicates that the odds of exposure among case-patients are the
same as, or similar to, the odds of exposure among controls. The
exposure is not associated with the disease. Odds ratios between 0
and 0.99 indicate a lower risk, between 1 and infinity indicate a higher
risk, and equal to 1 indicate no relationship between two variables.