Huntington between CAG repeats with onset and severity of

Disease – A Comprehensive Review

ABSTRACT : A gradual
progressive loss of function and number of neurons is called as
neurodegeneration. Huntington disease is an autosomal dominant  neurodegenerative disease which is a very
rare disease with prevalence of about 2-5 cases per 50,000 found worldwide.. Main
genetic cause is high number of repeats  of CAG codon (poly glutamine) present on the 4th
chromosome. Due to  autosomal dominant
nature, an individual has 50 % chances of inheriting the mutant gene from
infected parent. Severity of the disease is directly related to the number of
repeats. Higher the number of repeats, earlier and severe the onset of
symptoms. Symptoms starts showing at an age of 30-40 years (15 years in case of
juvenile Huntington disease (JHD) and develops progressively over a course of
15-20 years. Up to date, no cure or treatment is available for the disease. However
with the aid of transgenic animal models of disease, scientists have been able
to have an insight look into mechanical causes and potential treatment of the

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Historical records of Huntington disease dates back to 1374 when an outbreak of
HD was seen. However until the late 1600s, it was misunderstood as “dancing
disorder” due to lack of medical knowledge. Parcelus was first to use term
“chorea” for this due to its characteristic feature of involuntary muscle
twitches suggesting CNS origin. It was not until 1872 when George Huntington, a
professional doctor in USA,  first time
described about Huntington disease in his paper called :On Chorea” published in
the Medical and Surgical Reporter of Philadelphia (volume 26, no. 15, April 13,
1872) Bruyn . Since then disease was named as Huntington’s chorea. In 1993,
scientists found that HD is associated with CAG repeats present on the 4th
chr named it as Huntington’s disease. Hunington. A wild-type htt gene carries
6-26 CAG repeats at N-terinal region. While a mutant gene having more than
thirty six repeats is associated with absolute occurrence of disease. Fig 1.
Shows relationship between CAG repeats with onset and severity of disease. Fig
2. shows relationship between genotype with onset and severity of disease



1. Relationship between CAG repeats and Huntington disease




type gene. No mutation. No disease.


alleles. Unstability due  to high no of
CAG repeats. Are prone to mutation during reproduction. Children have a
higher risk.


penetrance of disease. Very late onset of disease. Symptoms appear at very
late age.


penetrance of disease. Symtoms start appearing at age of 30-40 years.


penetrance of disease. Symptoms start appearing at an early age of about
15-20 years.



2. Relationship between genotype and Huntington disease





mutant gene
wild type gene

severe phenotype symptoms. Wild type gene counter balances toxic effects of
mutant gene


mutant allele

severe phenotype symptoms. Both mutant allele contributes to toxic effects


mutant allele
type knockout



disease is an autosomal dominant disease associated with progressive loss of
neuron functions and number with progressively behavioral, physical and mental
abnormalities occurrence in due course of time until death. In countries of
Europe, Africa, Central and South Asia, a relatively high prevalence (2-5 per
50,000) of disease i.e. is found .In Japan and Finland, disease is very rarely


of disease can be in any age between 2-80 years. Brain damage starts at an
early age at onset of puberty. About 40% of neurons are lost and  20%  of
brain weight loss also called as atropia is seen till severe stage of disease.
first symptom appear at age of 30-40 years and develop slowly through a period of
15-20 years with chronic condition till death of the patient.


:Genetic cause of HD is codon sequensce (CAG)n where n is any number
from 36-60 present on first coding region i.e exon of “IT15 (interesting
transcript) ” present on chr number 4th as a result of mutation. On
translation, results in poly glutamine residues on N-terminal region of  a large 350 kDa protein named as
huntingtin(htt)” Hunington. A wild-type htt gene carries 6-26 CAG repeats at
N-terinal region. As a result, protein is unable to fold properly which
interferes with normal functioning of protein. Protein forms aggregates in
brain which are proportional to no of repeats4. Caspases 2-, 3-, and 6- play
a major role in this aggregation process. 
Ubiquitin degradation system is overloaded with aggregates and hence
cannot get rid of unfolded protein. Furthermore, htt also aggregates with other
proteins such as CERB and impairs functioning of a lot of other proteins as



main feature of huntingtin gene as following :

v  Poly
Q sequence : starts
from the 18th position and consists of thirty-five poly glutamine
residues in normal individual. Presence in number greater than 35 results in
onset of disease. In higher vertebrates (sp. Mammals), Poly Q sequence is
followed by a stretch of proline amino acids which seems to function as
protein-protein interaction domain as well as maintaining stability of Poly Q

repeats : These
are present downstream of poly Q sequence, are approximate forty a.a. long and
present in multiple numbers. These repeats are suggested to be involved in
physiological function of htt gene8-10.

v  Consensus
sequences : htt

§  consensus
cleavage sites for caspases 2-, 3-, 6-, calpain and aspartyl proteases11-14.

§  Presence
of nuclear localization signal (NLS) at N-terminal and nuclear export signal at
C-terminal suggest its role in transport mechanism15-17.

§  Post
translational modification – Presence of 
phosphorylation sites for enzyme PKB and cdK-5 helps in reduction of
caspase-mediated cleavage and hence reduced toxic activity of protein19-20.


gene plays an important part in gastrulation, neural tube formation and
maturation of adult brain and also acts as an anti-apoptopic protein.
Huntington protein helps in production of BDNF which is a neurotrophin
necessary for striated neurons survival. Huntington also plays an important
role in vesicle transport.


SIGNS OF HD : Patients
suffers with cognitive and motor disability. Start of  Involuntary muscle movements  is early sign of disease. With due time of
course, continuous choreatic movements are seen like difficulty in walking,
swallowing, talking (Dysarthria and dysphagia) , movements
dispairments like bradykinesia, akinesia and dystonia, continued tongue
protruding from mouth, increased muscle tones, bending of limbs etc. at the
later stages of disease, patients may become mute, completely bed-ridden due to
high rigidity levels, severe weight loss due to inability to eat, impaired
sleeping and circadian rhythm25  and 24
hour presence of care taker is a must21,22.


Table 3. symptoms and signs of HD



Cognitive impairment

Confusion about
time and place
 Loss of reasoning
 memory loss
Personality changes


 Facial movements
 Head turning to shift eye position Jerking movements

Slow, uncontrolled
movements   Speech problems
 Swallowing problems
 Unsteady gait (walking pattern)



Signs of
depression, weight loss, apathy, low self esteem, irratibility and aggression
are common among patients of HD. Risk of suicide is highest when patient is in
early stages of  loss of dependency.
Suicide is the second most common cause of death among HD patients23-24.

Patients lose ability to reason, unable
to differentiate between what is relevant or what is not, unable to carry on
daily activities like reading, taking a bath, cleaning, cooking etc.


(JHD) : If
symptoms of disease starts appearing IN 20s or 30s we call it as adult
Huntington disease. First symtoms to appear at the involuntary muscle
movements. Choreatic, Bradykinetic and hypokinetic movements occur with
appearance of dystonia. Length of CAG repeats in JHD is between 36-54.

If symptoms of disease starts appearing
before age of 20 years, we call it as juvenile Huntington disease. First
symtoms to appear at the school level is difficuty in learning. Bradykinetic
and hypokinetic movements occur with appearance of dystonia. No choreatic
movements. Fraternal type of inheritance is seen in 75% of cases  i.e. individual has inherited dominant mutant
gene from affected father. Length of CAG repeats in JHD is between 55-60.

DIAGNOSIS : diagnosis of huntington
disease is related to visible motor movemevents impairment and individual must
have at least one affected parent. A detailed family clinical history of the
patient is observed to know the penetrance of the disease in family. However
this information may not be always available in cases if parents are already
dead or a person with mutant HD gene died early before the onset of disease due
to some other cause such as an accident, fatal injury or any other disease. Current
criteria of diagnosis includes GAG number repeats greater than 36 with
visible  clinical symptons in any one of
the parents or grandparents.

Clinical symptoms may refer to
any abnormal involuntary movements along with behavioral and mental impairment.
In some cases all three are present. However a combination of any two is also
applicable. A consent from patient’s parents is mandatory in all kinds of
diagnostic  tests since if the person is
found HD+, it can have a major affect family members and other family members
can be at a greater risk of being affected with HD26.

Brain scan :We know that
brain cells start deteriorating many years before the onset of first symptom.
Scientists are now focusing on imaging procedures like  computerised
tomography (CT scan) or a magnetic resonance imaging (MRI) scan. An MRI scan is
more detailed and is more sensitive at picking up changes in the brain that can
give us proper brain imaging detailing about brain volume and interconnections27.

Genetic testing gives 98%
accuracy and can be done at your nearby genetic clinic. However age of individual
opting for test must be greater than eighteen years. First, doctor provide you
medical counseling and then one week later, blood is collected for testing

: If both parent are well aware of their genotype and have an possibility of
transferring the disease, they can check the genotype of their unkown child
either through Chorionic Villus Sampling or through amniocentesis after tenth
and twelveth week of pregnancy and 
between the fifteeenth and seventeenth weeks.


Table.3 an
overview of various diagnostic tests for huntington’s disease



Adult Diagnosis

Prenatal Diagnosis

Tomography (CT)

Villus Sampling

 Magnetic Resonance Imaging (MRI)



Diagnosis Through Invitro Fetilization


TREATMENT : Present treatment of Huntington
disease does not cure the patient but deals with the symptoms implicated in
progressive onset of disease. Mainly drugs are used for this and surgical
treatment do not have anyimpact on disease. Slow movement difficulties and chorea
is treated with drugs as shown in table no.4 and drugs for treatment of
psychotic behavious is shown in table no. 5.

Table.4 drugs
used for HD chorea





Dopamine – modifying

between nerve cells

tetrabenazine (TBZ)







between nerve cells


Blood problems
Accumulation of
fluid in the lungs
Heart problems  Hypersensitivity

Other drugs


coenzyme Q10

moderate side




moderate side




moderate side










Table.3 Drug Treatment for HD Psychotic behavior

Type of drug

Name of drug

Any side



Drowsiness and
Low blood pressure




Antipsychotic drugs


Violent outbursts


with drugs, other care measures should also be taken. Like patient must be
provided with talk therapy by psychiatrist to help overcome behavioral
problems. Proper physiotherapy must be given to patient so that by appropriate
exercising, patient could learn better coordination of movement and can
maintain motility ability as long as possible. Speaking ability also can be
improved with the help of a speech therapist.

CONCLUSION AND DISCUSSION : Even after two centuries, since
discovery of HD, no cure or treatment is available up to date. Treatment
currently in use only concerns with symptoms of the disease but plays no role
in elimination of disease. We can imagine complications related to this disease
by the fact that over 2000 research papers have been published since discovery
of this disease and yet scientists have not been able to fully understand
biochemical mechanism completely and have not succeed in finding a cure. It is
not a very rare disease so a significant portion of worldwide population
suffers from HD. And we cannot even imagine what kind of mental torture and
pressure patient including their family members have to go through, considering
the multilevel dysfunctioning of body systems. Also it is very costly and
difficult to keep patients for 24 hr watch under a medical practitioner.
Although through study of animal models of HD, we can better understand
cellular processes of diseases and use different potential treatment approaches
to treat it.

FUTURE PERSPECTIVE : Finding a cure for HD is still in
its baby steps. We are still trying to understand cellular processes of poly Q
sequence and its role in a cell which leads to mass cellular destruction at
neural level. Poly Q sequence is also associated with many other
neurodegenerative disorder are Dentatorubropallidoluysian
atrophy, Spinal and bulbar
muscular atrophy
and Spinocerebellar
ataxia Type
1,2, 3, , 7 and 17 etc. If we can find a cure or completely understand
molecular  mechanism of disease, it will
also come handy in treating of finding cure of 
other diseases as well associated with this CAG repeats. Techniques like
CT and MRI still in initial stages. If we can diagnose disease at an early
stage by brain scan with help of these imaging techniques then treating them
would possibly be pretty easy. There is also a scope in studying
microsatellites and and their functioning in the cell. Overall CAG expansion
seems to have greater scope in reference to research prospects.



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