 INTRODUCTION

What's Huntington's disease?

• Huntington's disease is a rare inherited disorder that affects the brains
of 5 to 8 out of every 1,00,000 people, vary geographically. Its a
devastating, degenerative brain disorder. HD slowly diminishes the
affected individual’s ability to walk, think, talk and reason i.e change
in personality and mental ability. Eventually, the person with HD
becomes totally dependent upon others for his or her care.
Huntington’s Disease profoundly affects the lives of entire families:
emotionally, socially and economically.
• Huntington's results from genetically programmed degeneration of
nerve cells, called neurons, in certain areas of the brain. Symptoms
most commonly begin between the ages of 30-50, although onset can
occur in young and old people. If the age of onset is below20 years
then it is known as Juvenile HD. Symptoms can then develop over a
period of up to 20 years but the illness invariably causes premature
death .Huntington's disease affects three main areas of function:
motor, mood, and cognition.
• Around 4800 people in the UK are living with Huntington's disease. It
is also called Huntington's chorea. Chorea means jerky, involuntary
movements - a main symptom of the condition.

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HISTORY AND BACKGROUND

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History
• 1872 George Huntington was one of three generations of medical
practitioners in Long Island. With their combined experience of
several generations of a family with the same symptoms, he realised
their conditions were linked and set about describing it. A year after
leaving medical school , in 1872, he presented his accurate definition
of the disease to a medical society in Middleport, Ohio.
• c1923 Smith Ely Jelliffe (1866-1945) and Frederick Tilney (1875-
1938) began analyzing the history of Huntington's sufferers in New
England.
• 1932 P. R. Vessie expanded Jelliffe and Tilney's work, tracing about a
thousand people with Huntington's back to two brothers and their
families who left Bures in Essex for Suffolk bound for Boston in
1630.

• 1979 The U.S-Venezuela Huntington's Disease Collaborative

Research Project began an extensive study which gave the basis for
the gene to be discovered. This was conducted in the small and
isolated Venezuelan fishing village of Barranquitas. Families there
have a high presence of the disease, which has proved invaluable in
the research of the disease.
• 1983 Professor Wexler, James Gusella, David Housman, P. Michael
Conneally and their colleagues find the general location of the gene,
using DNA marking methods for the first time - an important first step
toward the Human Genome Project.
• 1993 The Huntington's Disease Collaborative Research Group isolates
the precise gene at 4p16.3.
• 1996 A transgenic mouse was created that could be made to exhibit
HD greatly advancing how much experimentation can be achieved.
• 1997 Researchers discovered that the mutant huntingtin protein
bunches up (mis folds) to form nuclear inclusions.
• 2001 Christopher Ross and his team at Johns Hopkins University
described how the HD gene causes the death of cells through a flawed
form of the huntingtin protein.

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George Huntington

George Huntington

George Sumner Huntington (April 9, 1850 - March 3, 1916) was an

American physician.

Huntington's disease bears his name because he described it in the first of

only two academic papers he ever wrote. He wrote this paper when he was
22, one year after getting his medical degree at Columbia University in New
York City. Initially he read the paper before the Meigs and Mason Academy
of Medicine at Middleport, Ohio on February 15, 1872. It was later
published in the Medical and Surgical Reporter of Philadelphia, on April 13,
1872.

His father, George Lee Huntington 1811-1881) and grandfather, Dr. Abel
Huntington (1778-1858), were also physicians in the same family practice.
Their observations combined with his own were invaluable in precisely
describing this disease, which afflicted several generations of a family in
East Hampton on Long Island.

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Frequency:
• In the US: Several epidemiological studies in the United States,
conducted from 1945-1980, show consistent statistics stating that
approximately 30,000 people have HD.

• Internationally: The worldwide prevalence of HD is 5-10 cases

per 100,000 persons. In North America and Europe, HD has a
prevalence of 0.5-9.95 cases per 100,000 individuals. In a particular
study by Walker et al in South Wales, a prevalence of 7.61 cases per
100,000 persons was reported. This study was reanalyzed in 1988 and
showed the prevalence to be higher (8.85 cases per 100,000 persons),
indicating a slight rise over the years.

Race:
• No significant differences exist among national and ethnic groups in
the number of CAG repeats; however, the higher frequency of HD
among white persons and its lower prevalence in other populations,
including black persons and Japanese persons, has led to the
hypothesis that the mutation responsible for the disease was carried to
different parts of the world by immigrant European settlers.

• This theory is further supported by the suggestion that the mutation

rate in the HD gene is exceedingly low, perhaps the lowest such rate
for any human genetic disease. The fact that the mutation rate for HD
is higher than previously estimated and that new mutations may
account for as many as 3% of the cases is now apparent; therefore,
new mutations, in addition to European migration, may account for
the disease's presence in many different and sometimes isolated
communities.

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CAUSES AND MECHANISM

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 Causes

Huntington's disease is inherited in an autosomal dominant fashion. That is,

a recipient of the gene only needs one allele from one parent, to inherit the
disease. More often, genetic diseases are autosomal recessive, meaning that
they need two alleles, one from each parent, to inherit the disease. The
dominant nature of Huntington's disease increases the chance of the disease
occurring in offspring. A parent who has the disorder has a 50% chance of
passing on the gene to each child.

The gene involved in Huntington's disease, HD was identified in 1993 and is

located on the short arm of chromosome 4 . The end of the HD gene has a
sequence of 3 DNA bases, cytosine-adenine-guanosine (CAG), coding for
the amino acid glutamine, that is repeated multiple times. This region is
called a trinucleotide repeat.

The product of this gene is a 348 kDa cytoplasmic protein called huntingtin.
Huntingtin has a characteristic sequence of fewer than 40 glutamine amino
acid residues (encoded by CAG trinucleotide repeats) in the normal form,
more than this and a mutated form of huntingtin that causes the disease is
produced. The severity of the disease is generally proportional to the number
of extra residues.

If the gene is inherited from the mother the count is usually similar, but
tends to increase if inherited from the father. Because of the progressive
increase in length of the repeats, the disease tends to increase in severity and
have an earlier onset in successive generations. This is known as anticipation

 PROTIEN AGGREGATES

The continuous aggregation of this huntingtin molecules i.e the huntingtin

protein in people with HD tends to break into pieces, which then clump
together in nucleus of cells giving rise to structure called inclusion
body.CLUMPING due to excessive chain of glutamine alters the way
huntingtin interacts with other proteins inside the brain cell. The neuron first
becomes dysfunctional then undergoes progressive degeneration and die in

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selected regions of the brain. Certain neurons appear to be more vulnerable
in HD.

 Free radicals

Lipid peroxidation is defined as the process whereby free radicals “steal”

electrons from the lipids in our cell membranes, resulting in cell damage and
increased production of free radicals. Lipids include molecules such as fatty
acids, cholesterol, and other related compounds.

 Apoptosis
Another theory to explain the death of nerve cells postulates that the cells
actually kill themselves in response to chemical changes caused by HD. The
theory proposes that HD triggers the early death of neurons by accelerating a
normal process called apoptosis, or “programmed cell death.”

 Overaccumulation of excitory chemicals

One theory proposes that neurons die in HD because of an over-
accumulation of normal excitatory chemicals involved in nerve impulses.
Excitatory chemicals are important, and they are normally present in the
brain. However, if they are released in excessive amounts or if brain cells are
weak, these excitatory chemicals can cause cell damage and become
chemicals known as “excitotoxins.” One of the neurotransmitters released by
the basal ganglia is called glutamate, which acts as an excitatory
neurotransmitter in the brain.

 Overactivation of glutamate receptors

In HD cells, the overactivation of the glutamate receptors results in

overactivation of the messenger cascades and consequently, increased
calcium release. High amounts of calcium in the nerve cells are known to

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cause cell death, which is one possible explanation of how HD nerve cells
die.

Mechanism

 Formation of protein aggregates

Mutant huntingtin may react with other proteins & by cross-linking of
huntingtin with these protiens results in aggregates and change their
function. The huntingtin protein interacts with two proteins: huntingtin’s
interactor protein (HIP-1) and huntingtin’s associated protein (HAP-1).
These two proteins are present only in the brain . Most likely, however,
fragments of this abnormal protein homodimerize or heterodimerize to form
large, insoluble aggregates of protein within the nucleus, intranuclear

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inclusions.The continuous aggregation of the abnormal huntingtin molecules
in neuronal cells causes cell death, especially in the frontal lobes and the
basal ganglia (mainly in the caudate nucleus).Huntingtin aggregates form
through a nucleation dependent polymerization.

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 Effect of huntington disease on brain
HD affects the basal ganglia, large masses of gray matter located deep
within the cerebral hemispheres that regulate and coordinate cortically
originated movement. The corpus striatum includes the globus pallidus and
the striatum, which contains the caudate nucleus and the putamen.

Degeneration of the striatum (a part of the brain consisting of the caudate

nucleus and the putamen) can be found. There is also neuronal loss and
astrogliosis, as well as loss of medium spiny neurons, a GABAergic (the
chief inhibitory neurotransmitter in the vertebrate central nervous system)
result. Intranuclear inclusions that stain for ubiquitin and huntingtin can be
seen, as well as huntingtin in cortical neurites.

In HD, binding at serotonin and muscarinic cholinergic receptors reduces by

50% in the caudate putamen, but is normal in the cerebral cortex. Atrophy of
the striatum is due to degeneration of its medium-sized spiny neurons and

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causes problems with voluntary movement. Neurons that project to the
lateral globus pallidus are preferentially lost. Although the lateral portion of
the globus pallidus is more severely affected than the medial portion during
the early and middle phases of HD, all areas of the striatum are depleted in
advanced stages. The cannabinoid receptors of striatal nerve terminals in
lateral GP are lost more than those of the medial GP. These abnormalities
produce the clinical manifestations of HD.

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1. Corona radiata 2. Sagittal stratum 3. Head of caudate nucleus 4. Body of caudate
nucleus 5. Tail of caudate nucleus 6. Connecting piece between lentiform nucleus
and taiI of caudate nucleus 7. Amygdaloid body 8. Anterior commissure 9. Stria
terminalis 10. Internal capsule 11. Cut surface of basis pedunculi

1. Corona radiata 2. Putamen 3. Bridges of gray matter between putamen and

caudate nucleus 4. Sagittal stratum 5. Anterior commissure

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1. Corona radiata 2. Internal capsule 3. Globus pallidus 4. Sagittal stratum 5.Olfactory
bulb 6. Olfactory tract 7. Straight gyrus 8. Anterior (rostral) commissure 9. Optic chiasma
10. Optic nerve Figure 4: The left hemisphere from the lateral aspect

 Defect in the power plant of the cell, called

mitochondria, where energy is produced.
It is suspected that the cross-linking of huntingtin results in aggregates
which are toxic, and can lead to dysfunction of the proteasome system. This
mitochondrial dysfunction can lead to excitotoxicity and oxidative stress.

The exact link between CAG repeats (huntingtin) and mitochondrial failure
is that aggregates may trap critical enzymes that are involved in energy
metabolism. Some think that the cause of cell death is the splitting of the
lysosome so that the hydrolytic enzymes within it are released. This will
cause the cell membrane to split and the cell to die.

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DIAGNOSIS

DIAGNOSIS

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 Genetic Testing
With the discovery of the gene a simple and accurate genetic test became
available. The HD gene test usually requires a blood sample, but can be
performed on other tissues, such as skin, amniocytes or chorionic villus
cells, or autopsy material. The test requires special moleculardiagnostic
facilities.
Genetic testing for HD is potentially useful in three clinical situations:
diagnostic or confirmatory testing; predictive or presymptomatic testing; and
prenatal testing.

• Confirmatory testing
Confirmatory testing should be performed in a patient who appears to have
HD if no other affected family members have previously had a gene test, to
be sure that the “family disease” is really HD and not some other condition.
A small blood sample is taken, and DNA from it is analyzed to determine the
CAG repeat number. A person with a repeat number of 30 or below will not
develop Huntington's disease. A person with a repeat number between 35
and 40 may not develop the disease within their normal lifespan. A person
with a very high number of repeats (70 or above) is likely to develop the
juvenile-onset form.

• Predictive testing

Predictive testing refers to the use of an HD gene test in a person who

has no symptoms but wants to know whether or not he carries the
expanded gene. Predictive testing of healthy individuals requires a
different clinical approach than the one to which physicians and
patients are most accustomed. There are no direct medical indications
for or benefits from a predictive test. There are also potential
psychosocial risks to predictive testing, including adverse effects on
the individual’s mood, on relationships with friends and family and on
insurability and employability. Predictive testing should be reserved

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for competent adults who have participated in a careful discussion of
their genetic risks and the potential risks and benefits of the test itself.

• Prenatal testing

Prenatal testing for HD is possible, and should be performed in

conjunction with detailed genetic counseling. Affected or at-risk
individuals or couples should be informed of all of their reproductive
options with the understanding that different options are appropriate
or desirable for different people. For those who desire prenatal testing,
the best time to make arrangements is prior to the pregnancy .Herein it
examines the pattern of DNA near the gene in both parent and fetus,
but does not analyze for the triple repeat itself. If the DNA patterns do
not match, the fetus can be assumed not to have inherited the HD
gene, even if present in the parent A pattern match indicates the fetus
probably has the same genetic makeup of the at-risk parent It does not
indicate whether the parent (or fetus) actually has the defective gene.
Chorionic villus sampling can be performed very early, at 8-10 weeks,
and a non-disclosing prenatal test, which determines only whether the
fetus received a chromosome from the affected grandparent or the
unaffected grandparent.

 NEUROIMAGING STUDIES

Computed tomography (CT) scans and magnetic resonance imaging (MRI)

Figure 6: Magnetic resonance imaging of a patient with Huntingdon's disease.

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Figure 7: Positron emission tomography image of a patient with Huntingdon's
disease

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SIGNS AND SYMPTOMS

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 Congnitive Disorder

Introduction
The cognitive disorder in HD is considered a “sub-cortical” syndrome. The
most prominent cognitive impairments in HD involve the so-called
“executive functions”- abilities such as organization, regulation and
perception. These fundamental abilities can affect performance in many
cognitive areas, including speed, reasoning, planning, judgement, decision
making, emotional engagement, perseveration, impulse control, temper
control, perception, awareness, attention, language, learning, memory and
timing.

• Disorganization

Difficulties in planning, organization, sequencing and prioritizing. Daily

tasks, such as attempts to follow a recipe, to maintain a daily planner, to
complete a list of household errands, to develop a meeting agenda, or to
apply for social security benefits, become daunting. There are several ways
to compensate for poor organization. Routines should be established at work
or in the home so that the environment can provide structure and
organization. Activities should be organized so that each day is basically the
same. For example, 7:00 shower, 7:30breakfast, 8:00 take bus to work,
8:30check mail, 9:30 dictate letters, 10:00 coffee,10:30 staff meeting, 12:00
lunch,1:00 return phone calls, 2:30 review accounting, 4:00 open meeting to
schedule with customers, 5:00 take bus home, 6:00 dinner, 7:00 family time
with kids, 8:30 time with spouse, 9:30 read, 10:00 lights out. A central
location could be established for posting a daily schedule. Persons who
never before used daily planners or computer calendars may need to start. A
centralized message center can be used to make lists and organize tasks to be
accomplished each day.

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• Lack of Initiation

Some family members complain that the person with HD “just sits around
all day and won’t do anything”. A lack of initiation is often misinterpreted as
laziness, apathy or lack of interest, and may be a reason for poor
performance at work. Once started, persons with HD may be able to execute
the behaviors adequately (i.e., compute taxes, calculate sales, administrate
employees, teach school), but may be unable to organize and initiate the
behaviors at the appropriate time.
External initiation often helps the person with HD remain active and
participate in both social and work activities. Keeping a daily routine can
minimize the need for internal initiation. Maintaining the desired behavior is
usually less of a problem for persons with HD.

• Perseveration
Perseveration or being fixed on a specific thought or action can occur when
behaviors are inadequately regulated by the brain. Patients become
behaviorally rigid, and tend to get stuck on an idea or task. Established
routines and gentle reminders of changing tasks can help avoid problems.

• Impulsivity

Some persons with HD experience difficulties with impulse control and may
develop problem behaviors such as irritability, temper outbursts, sexual
promiscuity and acting without thinking. Some degree of impulsivity and
dysregulation of behaviors is quite common in HD. Some strategies to help
family members and caregivers cope with impulsivity are addressed below.

COPING STRATEGIES FOR IMPULSIVITY

 Since the person with HD cannot control their responses, a predictable daily
schedule can reduce confusion, fear and, as a result, outbursts.
 Stay calm. In addition, staying calm may help the person calm down and able
the person to think .
 Medications may be helpful for outbursts and sexually inappropriate
behavior.

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• Irritability and Temper Outbursts

One of the most typical complaints we hear from HD families is concern

about irritability and temper outbursts. These signs can be present for a
couple of reasons.
First, it is important to assess for depression when increased irritability is
reported. Oftentimes, irritability and temper outbursts diminish when a
mood disorder is treated. Many times, however, irritability or outbursts
remain even in the absence of a mood disorder.
Examination of the underlying causes of irritability and temper outbursts is
helpful in diminishing the frequency and severity of these behaviors. Close
attention should be paid to the signals, verbal or nonverbal, that the patient is
upset or wanting something, so that they do not get to the stage of exploding
before they receive attention.
It may be possible to identify situations which trigger frustration and either
avoid them or provide diversional activities .The person with HD should be
encouraged to do things for himself and to participate in primary decision-
making as long as possible, except perhaps in situations where safety is an
issue (i.e. driving or cooking). Family members should be responsible for
providing a safe environment so that no person is ever in danger. Remove
dangerous implements, such as guns, from the house and have emergency
numbers near the telephone.
Speak with the person in low and soft voice.

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 Physical Movement Disorder

Introduction
There are two parts to the movement disorder associated with
Huntington’s disease: the presence of involuntary movements, and the
impairment of voluntary movements.
The involuntary movements are called chorea and consist of irregular
jerking or writhing movements referred to as Huntington’s chorea.
Abnormal eye movements ,movements of neck ,lips etc.

• Chorea

Chorea, like most forms of involuntary movement, is worsened by stress,

anxiety, or depression, is decreased during sleep, and often varies with
posture or positioning. Treatment of underlying mood and anxiety disorders
and providing a calm, predictable environment are a first step.
Various assistive devices may be helpful as padded, reclining chairs, padding
for the bed, and wrist and ankle weights to reduce the amplitude of the
chorea.
Medications will not alter the progression of the underlying illness . In fact,
drug-related side effects such as sedation and rigidity may increase the risk
of falls and decrease the intelligibility of speech.

• Rigidity, Spasticity and Dystonia

Rigidity and spasticity tend to emerge later in the course of Huntington’s

disease, except incases of childhood onset, in which they are often present
from the beginning. They can impair gait, lead to falls, and necessitate the
use of a wheelchair. Dystonia may include twisting, tilting or turning of the
neck (torticollis), involuntary arching of the back (opisthotonos) and arching
of the feet. It may be a symptom of HD, or a side effect of neuroleptic
therapy.

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A variety of medications have been used to treat rigidity, spasticity, and
dystonia, all with modest success at best.
Consultation with a physiotherapist or physiatrist to design a program to
mobilize the patient and prevent contractures may be an important
component to the management of rigidity and spasticity. Botulinum toxin
injections have been used rarely, but might be beneficial if severe rigidity
of a small muscle or group of muscles is disturbing function.

• Myoclonus, Tics, and Epilepsy

Myoclonus, sudden brief jerks involving groups of muscles, is more

common in juvenile-onsetHD, where it may be mistaken for a seizure.
necessary. Tics are brief, intermittent stereotyped movements such as
blinking, nose twitching, head jerking, or transient abnormal postures. Tics
which involve the respiratory and vocal apparatus may result in sounds
including sniffs, snorts, grunts, coughs, and sucking sounds. Patients may be
unaware of vocal tics, but family members may find the incessant noises
grating. They should be helped to understand that the tics are not under
voluntary control. Tics generally do not by themselves require treatment, but
may respond to neuroleptics, benzodiazepines.
Epilepsy is uncommon, though not unheard of, in adults with HD, but is
said to be present in 30% of individuals with juvenile-onset HD.. In the
juvenile HD patient, myoclonic epilepsy or other generalized seizures may
suggest divalproex sodium as a first treatment choice.

Swallowing Difficulties

Dysphagia is, directly or indirectly, the most common cause of death in

people with late stage HD, whether through choking, aspiration, or
malnutrition. Dysphagia results from impaired voluntary control of the
mouth and tongue, impaired respiratory control due to chorea, and impaired
judgement resulting in eating too rapidly, or taking overly large bites of food
and gulps of liquid. No medications are known to improve swallowing
directly. Devices such as enlarged grips for silverware and non-slip plates
with raised edges to prevent spilling may prolong independent eating. HD
affected individuals should be instructed early in the disease, before the
onset of dysphagia to eat slowly and deliberately, to sit in an upright position

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during and after meals, to take small bites, and to clear the mouth of food
after each bite by taking sips of liquid.
Drinking fluid through a straw may be easier than drinking directly from a
cup, and the use of a covered cup or mug, like a “sippy cup” used by young
children ,may prevent spillage due to chorea. Grainy items, such as ground
beef or rice, may irritate the pharynx and cause choking. Foods such as
steak, which are hard to chew, should also be avoided.Patients may have
difficulty adjusting to different textures of food, and may do better if they
finish each item on the plate in turn.
Self-feeding may be prolonged by having the patient eat more frequent, but
smaller meals,and by using“finger foods”. The transition to assisted feeding
does not have to be all or nothing, as patients may still be able to eat
unassisted at certain times and be fed at other times.
Choking may decrease once self-feeding is stopped, because the caregiver
will have greater controlover the size and frequency of the bites. The
caregiver should still promote eating slowly, and not talkingwhile eating,
and should make sure the mouth is empty before each bite. With supervision,
mostpatients are able to assist with feeding and to take adequate amounts of
food by mouth quite far into the illness. However, before dysphagia and
communication difficulties become severe, the issue of feeding tubes should
be discussed with the patient and family, to ensure that appropriate nutrition
can be maintained throughout the illness. A gastrostomy tube can clearly
improve nutritional status in a debilitated person with severe dysphagia, and
may prolong life. However, patients and families may not desire this
intervention late in thecourse of HD.

Nutrition

W eight loss is a common problem in Huntington’s disease. This is probably

due in part to diminished food intake because of dysphagia, fatigue, and
depression. However many HD patients also require a large caloric intake to
maintain their body weight. This may be simply due to the expenditure of
energy through involuntary movements, but there may be other metabolic
reasons not fully understood. Two strategies can be employed to increase the
caloric intake of someone with HD: increase the number of meals, or
increase the calorie content of the food. The first goal can be achieved by
eating five small meals a day or by adding high calorie snacks such as
milkshakes. The caloric content of the food can be increased by measures

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such as adding oil to soups, drinking cream instead of skim milk, adding
margarine liberally as a condiment, and focusing on easily eaten, high-
calorie foods such as pasta with cream based sauce.

Dysarthria

Dysarthria, a difficulty with the physical production of speech, results

largely from impairment ofvoluntary movement. Speech becomes slurred,
dysrhythmic, variable in volume due to inconsistentbreath support, and
increasingly difficult to understand. Furthermore, just as patients donot
always appreciate the presence or degree of chorea, some patients do not
seem to be aware of distortions in their speech. For others, articulation is a
constant source of frustration. No medications are known to be helpful, and
dysarthria may be worsened by agents.
Dysarthria may be compounded by cognitive problems found in HD, such
as word-finding difficulty, difficulty initiating speech, or difficulty
completing a sentence.

Falls

Falls are common in persons with HD, and can be a source of significant
morbidity. Usually seen more in the moderate to advanced stages,often result
from combination of spasticity, rigidity, chorea, and loss of balance.
Pharmacotherapy to prevent falls could includetreatment of chorea, rigidity,
spasticity and dystonia, while minimizing the use of drugs such as
neurolepticsand benzodiazepines, whose side effects include sedation,
ataxia, or parkinsonism. Installing handrails in key locations and minimizing
the use of stairs can help to reduce falls.Some families convert a ground
floor office or den into a bedroom. Furniture such as tables and desks,
particularly items with sharp corners, should be arrayed along the periphery
of the room, where they will present less of an obstacle. Floors should be
carpeted to lessen the impact when falls do occur. Patients who fall out of
bed may have a mattress placed beside the bed at night, or may sleep on a
mattress placed directly on the floor.

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 Psychiatric Disorder

Introduction
Patients with Huntington’s disease who have psychiatric disorders suffer
from conditions such as Major Depression, Bipolar Disorder or Obsessive-
Compulsive Disorder which are specific well-described syndromes, found in
all sorts of patients. Most of these psychiatric problems are believed to be
related directly to the central nervous system injury caused by HD.

Specific Psychiatric Disorder

• Depression
Because depression in HD appears directly related to the brain disease,
pharmacotherapy is usually indicated.
Major Depression is a clinical syndrome, a constellation of signs and
symptoms which, taken together, suggest the diagnosis. Use of diagnostic
criteria helps to distinguish major depression from demoralization, transient
changes in mood caused by negative life events, such as bereavement, and
from some of the symptoms of HD itself, such as weight loss, trouble with
concentration, and apathy. Patients with Major Depression have a sustained
low mood, often accompanied by changes in self-attitude, such as feelings of
worthlessness or guilt, a loss of interest or pleasure in activities, changes in
sleep, particularly early morning awakening, and appetite, loss of energy,
and hopelessness. Depressed patients often feel worse in the morning than in
the afternoon.
A specific complaint of depressed mood is not necessary to make the
diagnosis if the patient has the other symptoms. In fact patients with HD
often have trouble identifying or describing their emotional state. Depression
in such a patient may be characterized by changes in sleep or appetite
patterns, agitation, tearfulness, or a drop-off in functional abilities. In such
circumstances the diagnosis should be considered.
In evaluating an HD patient with depression the physician also needs to
consider whether some physical problem, other than HD, might be the cause.
The patient’s medical history should be reviewed for conditions such as

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hypothyroidism, stroke, or exposure to certain drugs associated with mood
changes, such as steroids, reserpine, beta-blockers, and particularly alcohol.

Suicide

Depressed patients should always be asked about suicide, and this should be
regularly reassessed.
If the patient acknowledges these feelings, the clinician needs to ask more
questions to evaluate their severity and decide on the best course of action.
Some patients, although having suicidal thoughts, may be at low risk if they
have a good relationship with their doctor, have family support, and have no
specific plans. Others may be so dangerous to themselves that they require
emergency hospitalization.
A physician should listen supportively to these concerns, realizing that most
patients will be able to adapt if they are not suffering from depression.

Mania

While depression is the most common psychiatric problem in HD, a smaller

number of patients will become manic, displaying elevated or irritable
mood, overactivity, decreased need for sleep, impulsiveness, and grandiosity.
Some may alternate between spells of depression and spells of mania with
times of normal mood in between, a condition known as bipolar disorder.
Patients with these conditions are usually treated with a mood stabilizer.
Lithium is probably still the most popular mood stabilizer for people with
idiopathic bipolar disorder, but we have not found it to be as helpful in
patients with HD

Obsessive-Compulsive Disorders

Obsessions are recurrent, intrusive thoughts or impulses which are

experienced as being senseless, at least initially. A compulsion is a repetitive
performance of the same activity, a stereotyped routine which must be
followed, often in response to an obsession, such as handwashing because of
an obsessive concern with germs. Obsessions are usually a source of anxiety

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and the patient may struggle to put them aside, whereas the acting out of
compulsions generally relieves anxiety and may not be as strongly resisted.
Serotonergic antidepressants are used to treat OCD and may ameliorate
obsessions and compulsions in HD patients that do not meet the criteria for
the full syndrome.

Schizophrenia-Like Disorders

Schizophrenia and schizophrenia-like conditions are much less common

than affective disorder in HD. The new onset of delusions and hallucinations
should prompt a search for specific causes or precipitating factors, including
mood disorders, delirium related to metabolic or neurologic derangements
and intoxication with or withdrawal from illicit or prescription drugs.
Caregivers should be encouraged to respond diplomatically, to
appreciate that the delusions are symptoms of a disease, and to avoid direct
confrontation if the issue is not crucial.

Delirium

Delirium, an abnormal change in a patient’s level of consciousness, may

result from a variety of
toxic, structural or metabolic causes. Delirious patients consciousness, may
be agitated or lethargic, and frequently have disturbed sleep. Patients in the
later stages of HD, are particularly vulnerable to delirium. Common causes
of delirium in HD include prescription medications, particularly
benzodiazepines and anticholinergic agents, alcohol or illicit drugs, and
medical problems such as dehydration and respiratory or urinary tract
infections. For
example, a dehydrated patient may no longer be able to tolerate his usual
medication regimen.
Delirium can also be mistaken for a number of other conditions in HD. As
mentioned previously, it may be accompanied by hallucinations or paranoia.

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Psychiatric Symptoms not Belonging
to a Specific Disorder

Apathy
Apathy is common in HD and is probably related to frontal lobe
dysfunction. Apathetic patients become unmotivated and uninterested in
their surroundings. They lose enthusiasm and spontaneity. Performance at
work or school becomes sluggish. While apathetic patients have trouble
initiating actions, they will often participate if someone else suggests an
activity and works along with them to sustain energy and attention. For
example, a man with HD had always loved fishing, but when his brother
came to take him fishing for his birthday he wanted to stay home in front of
the television. The brother insisted, and when they left the house, he had a
good time fishing all day. When he returned, he immediately turned the
television back on.

Anxiety

Patients with HD are vulnerable to anxiety because of life circumstances, but

also because of physical changes in the brain. Patients may develop a social
phobia related to embarrassment about visible symptoms. As thought
processes become less flexible, patients may be made anxious by trivial
departures from the usual routine . Patients may worry for days in advance
about what to wear when going to the hairdresser or whetherto attend a
family function.
Some patients will not improve with counseling and environmental
interventions and will require pharmacotherapy. Panic attacks usually last
only fifteen or twenty minutes, may begin during sleep, and may result in
syncope. Suspected panic attacks require a good medical work-up, because
most of the other possible explanations for the symptoms represent highly
dangerous conditions.
Once these other causes have been ruled out, the usual treatment consists of
SSRIs, sometimes temporarily supplemented with benzodiazepines. SSRIs
are usually mildly stimulating and may need to start at a lower dose than that
used for depression.

31
DRUGS FOR TREATMENT

32
 Drugs for treating huntington disease.

 Ginkgo Biloba(Mechanism: Free Radical Damage)

Ginkgo biloba has been shown to have antioxidant and anti-inflammatory

properties. Because free radicals and inflammation are believed to be factors
involved in the progression of HD, Ginkgo biloba may help in alleviating
the symptoms of HD
The principal constituents of Ginkgo biloba extract include flavonoids,
terpenoids (ginkgolides and bilobalide) and different organic acids.

• Flavonoids
The flavonoids contribute to Ginkgo’s antioxidant properties. They have
been found to reduce the levels of free radicals(hydrogen peroxide), which
are highly reactive molecules with unpaired electrons. One way by which
flavonoids protect the cell is by reducing cell membrane lipid peroxidation.
Lipid peroxidation is defined as the process whereby free radicals “steal”
electrons from the lipids in our cell membranes, resulting in cell damage and
increased production of free radicals. Lipids include molecules such as fatty
acids, cholesterol, and other related compounds. As antioxidants, the
flavonoids neutralize the free radicals in our cell, lowering the levels of free
radicals available for lipid peroxidation.

. Terpenoids
The terpenoids include bilobalide and the ginkgolides A, B, C, M, and J.
Bilobalides have been proposed to have protective effects on nerve cells and
on the nervous tissue through their role in motor nerve cell regeneration.

 Geldanamycin (Mechanism: Protein Aggregation)

Geldanamycin (GA) is a naturally-occurring drug produced by

microorganisms to protect themselves from disease-causing substances. GA

33
binds to a special kind of protein called a heat shock protein. All cells
produce a common set of heat shock proteins (Hsp’s) in response to a variety
of stresses, including heat, exposure to toxic compounds, or other conditions
that cells normally do not experience.
Most, but not all, heat shock proteins play the role of “molecular
chaperones.” Molecular chaperones are substances inside the cell that bind
and stabilize proteins at intermediate stages of folding, assembly, movement
across membranes, and degradation.
When GA is absent in cells, Hsp 90 and HSF 1(Heat Shock Factor 1).
commonly bind together and perform various functions as a unit. When GA
is added to cells, it binds to Hsp 90, making Hsp 90 unable to associate with
HSF 1. The free HSF 1 is then able to enter the cell nucleus where it initiates
the production of other heat shock proteins, specifically Hsp 70 and Hsp 40.
Once Hsp 70 and Hsp 40 are produced, they associate with the misfolded
huntingtin protein and prevent its aggregation.
In summary, recent research suggests that GA works against huntingtin
aggregations by triggering the following chain of events: (1) GA binds to the
heat stress protein Hsp 90, creating free HSF 1 within HD neurons; (2) the
free HSF 1 triggers increased production of Hsp 70 and Hsp 40 within the
cells; and (3) high levels of Hsp 70 and Hsp 40 then prevent the aggregation
of mutant huntingtin.

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 Cystamine (Mechanism: Protein Aggregation)

Cystamine inhibits the activity of transglutaminase (TGase), an enzyme

involved in the formation of of huntingtin of protein aggregates. Treating
mouse models of HD with cystamine in several studies has resulted in
improvements in physical symptoms and decreased nerve cell death.
Aggregates are formed through the linking action of the enzyme TGase. By
hooking proteins together into aggregates, TGase contributes to the
formation of NIs.
TGase normally helps link the pieces of huntingtin protein together to form
protein aggregates. In this case, the huntingtin protein is the substrate, or
target, of TGase. Cystamine prevents TGase from doing its job by acting as
a competitive inhibitor. Cystamine competes with huntingtin for TGase’s
active site, distracting TGase from doing its normal job. Theoretically, with
cystamine blocking TGase’s active site, TGase will not be able to link
huntingtin proteins together and aggregates should not form.

 Rapamycin (Mechanism: Protein Aggregation)

35
Rapamycin, also known as sirolimus, is an FDA-approved antibiotic and
immunosuppressant.
Rapamycin inhibits the activity of a protein called mTOR which, among its
other functions, inhibits a process called autophagy. Autophagy is the
process by which a cell breaks down its own molecules and other
components that are no longer needed. Since mTOR functions to inhibit
autophagy, by inhibiting mTOR, rapamycin promotes autophagy, allowing
for the breakdown of unnecessary components of the cell.
The part of the cell that is to be degraded is first engulfed by a double
membrane to separate it from the rest of the cell; the resulting membrane-
enclosed bubble of cytosol (and the proteins it contains) becomes what is
called the autophagosome. The autophagosome eventually fuses with a
cellular organelle called a lysosome, a much larger membrane-enclosed
bubble that contains a variety of enzymes that can break down all sorts of
cellular components (which is why lysosomes are sometimes referred to as
the “garbage disposals” of the cell). In order to protect the rest of the cell
from being degraded, these enzymes only work in a very acidic
environment, so the pH inside lysosomes is much lower than the neutral pH
in the rest of the cell.

In this process, the proteins are gathered up and transported to the lysosome,
where they are broken down and their component amino acids recycled.
Studies of nerve cells have shown that huntingtin can often be found in
autophagosomes, the membrane-bound sacs that carry cell parts to the
lysosome for degradation

36
 Minocycline (Mechanism: Inflammation)

Inhibit the activation of cells involved in inflammation as well as decrease

the production of free radicals.
The anti-inflammatory effects of minocycline include inhibition of
microglial activation. Microglia are cells found in the brain that are involved
in the immune response. By inhibiting the activation of microglia,
minocycline inhibits inflammation.
Minocycline decreases free radical formation by inhibiting the production of
inducible nitric oxide synthetase (iNOS), an enzyme responsible for the
formation of nitric oxide (NO), which acts as a free radical in the cell.
Minocycline also inhibits the production of caspases, a family of enzymes
involved in HD progression. Caspases are activated in the brains of humans
with HD .Once activated, caspases cleave the altered huntingtin protein.
Studies have shown that the cleaved huntingtin fragments easily aggregate to
form aggregations called neuronal inclusions (NIs) that are toxic to the cell.

37
 Creatine (Mechanism: Abnormalities in Energy
Metabolism)

• Creatine’s role in stabilizing membranes

Creatine can potentially prevent tissue damage by stabilizing biological
membranes, particularly the membranes that form the outer boundary of
nerve cells. Inside such cells, the protein mtCK (mitochondrial creatine
kinase) exists in two different forms. When activated, it exists in a form that
binds to certain molecules in the cell membrane, making the membrane
more stable. But mtCk is inactivated by various toxic substances called free
radicals. (For more information of free radicals, click here.) Once mtCk is
inactivated, it transforms into a less stable form that does not bind to
membrane molecules, leaving the membrane less stable. Decreased stability
of the membrane allows essential molecules to pass through, leaving the cell
susceptible to the loss of important substances. Furthermore, the unstable
membrane can allow the entrance of foreign substances that are toxic to the
cell. Cr and PCr have been found to delay the inactivation of mtCk, thus
stabilizing the membranes of cells.
• Other neuroprotective effects
Researchers speculate that glutamate, an excitatory neurotransmitter, exerts
toxic effects on nerve cells due to increased sensitivity of the nerve cells to
glutamate. (Click here for background on the neurobiology of HD.)
Experiments have shown that PCr has the ability to stimulate the removal of
glutamate from the site of neurotransmitter release, thereby reducing the
amount of glutamate in cells.

 Riluzole

In HD cells, the overactivation of the glutamate receptors results in

overactivation of the messenger cascades and consequently, increased
calcium release. High amounts of calcium in the nerve cells are known to
cause cell death, which is one possible explanation of how HD nerve cells
die.
Riluzole may disrupt glutamate activity by interfering with the activity of
certain proteins involved in the messenger cascade. Once the cascade is
inhibited, changes induced by glutamate such as calcium release and the

38
associated cell death might eventually be delayed.

 HDAC inhibitors

HDAC inhibitors interfere with the regulation of gene expression by

inhibiting the activity of enzymes known as histone deacetylases.
NIs trap coactivators and transcription factors by which HD progresses is
through the loss of transcription of several key genes essential for cell
survival
The altered huntingtin protein forms NIs that trap coactivators such as CBP.
Loss of CBP results in the loss of histone acetylation, which in turn results in
the inability of the transcription factor p53 to bind to DNA. Drugs such as
HDAC inhibitors that could compensate for the loss of the coactivator CBP
be possible treatments for HD.

39
 OTHER DRUGS
Medical care:
Drugs used to manage psychosis and agitation in patients with dementia are
intended to decrease psychotic symptoms (eg, paranoia, delusions,
hallucinations) and associated or independent agitation, screaming,
combativeness, or violence. The therapeutic goal is increased comfort and
safety of patients, families, and caregivers.

Drug category: Antipsychotics (neuroleptics)

Drug name Adult Pediatric Adverse effects
Dose dose

Haloperidol 0.5-2 mg >3 years: Sedation, parkinsonism , dystonia

(Haldol) 0.5 mg ,akathisia , hypotension,
constipation, dry mouth, weight gain.
.

Risperidone 0.5-2 mg - hypersensitivity, extrapyramidal reactions,

40
(Risperdal not to hypotension, tachycardia, and arrhythmias
exceed 16
mg/d

Drug category: Benzodiazepines

Drug name Adult dose Pediatric Adverse effects
dose
Lorazepam 0.5-2 mg 0.02-0.05 renal or hepatic impairment,
(Ativan) mg/kg myasthenia gravis, organic
brain syndrome, or PD; drug or
alcohol abuse; suicidal
tendencies, sedation, ataxia,
apathy, withdrawal seizures .
Diazepam 1.25mg/da 20mg/day same
y

Drug category: Anticonvulsants

Drug name Adult Dose Pediatric Adverse effects
dose

Carbamaz 100 mg
epine not to <1 year: Drowsiness, dizziness, and blurred vision;
(Tegretol) exceed 100-200 caution while driving or performing other
1200 mg qd mg/d tasks requiring alertness; history of
1-5 years: cardiac, hepatic, renal, or hematopoietic
200-400 dysfunction .
mg/d
6-10 years:
400-600
mg/d
11-15

41
 years: 600-
1000 mg/d

Zonisamide 100 mg/d - Drowsiness, weight loss, ataxia, nausea,

(Zonegran) not to and slowing of mental
exceed 400 activity,hypersensitivity.
mg/d

Drug category: Antidepressants

Drug name Adult Dose Pediatric Adverse effects
dose

Sertraline 50 mg/d - Caution in preexisting seizure disorders

(Zoloft) not to and recent myocardial infarction, unstable
exceed 200 heart disease, and hepatic or renal
mg/d impairment; monitor for mania or
hypomania; suicidal tendencies

Venlafaxine IR: 75 mg/d - Hypertension; fatal reaction may occur if

(Effexor) to 225-375 taken concurrently with an MAOI;
mg/d exercise caution in patients with
ER: 75 cardiovascular disorders
mg/d to 225
mg/d

• Combine drug therapy

Low doses of each single drug, but together their combined effects all
converge on a single disease process. This minimizes toxic side effects while
maximizing benefit.

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PROGNOSIS

43
 PROGNOSIS

 Gene knockdown
A gene knockdown is either a genetically modified organism that carries one
or more genes in its chromosomes that has been made less active or had its
"expression" reduced or is the use of a reagent such as a short DNA or RNA
(oligonucleotide) with seqeuence complementary to an active gene or its
mRNA transcript. This oligonucleotide will bind to this active gene (or its
transcripts) to decrease expression of a specific gene, copying the effects of
such a genetic modification. So far such organisms have been engineered
chiefly for research purposes. Also known as knockdown organisms or
simply knockdowns, their most direct use is for learning about a gene that
has been sequenced, but has an unknown or incompletely known function,
an experimental approach known as reverse genetics. Researchers draw
inferences from how the knockdown differs from individuals in which the
gene of interest has not been made inoperative. Knockdown includes the
processes of modifying an organism or of using a reagent to suppress gene
expression, as in "knocking down a gene."

44
Popular reagent-based methods of knocking down the expression of a gene
include suppression of translation using small interfering RNA (siRNA) or
Morpholino oligos.

RNAi has recently been applied as an experimental technique to study the

function of genes in model organisms. Double-stranded RNA for a gene of
interest is introduced into a cell or organism, where it through RNAi causes
an often drastic decrease in production of the protein the gene codes for.
Studying the effects of this decrease can yield insights into the protein's role
and function. Since RNAi may not totally abolish expression of the gene,
this technique is sometimes referred as a "knockdown", to distinguish it
from "knockout" procedures in which expression of a gene is entirely
eliminated by removing or destroying its DNA sequence.

Most functional genomics applications of RNAi have used the nematode

Caenorhabditis elegans and the fruit fly Drosophila melanogaster, both
commonly used model organisms in genetics research.[12] C. elegans is
particularly useful for RNAi research because the effects of the gene
silencing are generally heritable and because delivery of the dsRNA is
exceptionally easy. Via a mechanism whose details are poorly understood,
bacteria such as E coli that carry the desired dsRNA can be fed to the worms
and will transfer their RNA payload to the worm via the intestinal tract. This
"delivery by feeding" yields essentially the same magnitude of gene
silencing as do more costly and time-consuming traditional delivery
methods, such as soaking the worms in dsRNA solution and injecting
dsRNA into the gonads.

 Gene silencing
Gene silencing is a general term describing epigenetic processes of gene
regulation. The term gene silencing is generally used to describe the
"switching off" of a gene by a mechanism other than genetic mutation. That
is, a gene which would be expressed (turned on) under normal circumstances
is switched off by machinery in the cell.Genes are regulated at either the
transcriptional or post-transcriptional level.

45
Transcriptional gene silencing is the result of histone modifications, creating
an environment of heterochromatin around a gene that makes it inaccessible
to transcriptional machinery (RNA polymerase, transcription factors, etc.).

Post-transcriptional gene silencing is the result of mRNA of a particular

gene being destroyed. The destruction of the mRNA prevents translation to
form an active gene product (in most cases, a protein). A common
mechanism of post-transcriptional gene silencing is RNAi.

Both transcriptional and post-transcriptional gene silencing are used to

regulate endogenous genes. Mechanisms of gene silencing also protect the
organism's genome from transposons and viruses. Gene silencing thus may
be part of an ancient immune system protecting from such infectious DNA
elements.

RNA interference (RNAi) is a mechanism in molecular biology where the

presence of certain fragments of double-stranded RNA (dsRNA) interferes
with the expression of a particular gene which shares a homologous
sequence with the dsRNA. RNAi is distinct from other gene silencing
phenomena in that silencing can spread from cell to cell and generate
heritable phenotypes in first generation progeny when used in
Caenorhabditis elegans.

Before RNAi was well characterized, it was called by other names, including
post transcriptional gene silencing and transgene silencing. Only after these
phenomena were characterized at the molecular level was it obvious that
they were the same phenomenon

Cellular mechanism

RNAi is a gene silencing process that requires active participation of cellular

machinery. Although the specific mechanism is poorly understood, it is
known that the ribonuclease enzyme Dicer binds to and cleaves short
double-stranded RNA molecules (dsRNA) to produce double-stranded
fragments of 21-23 base pairs with two-base single-stranded overhangs on
each end. The short double-stranded fragments produced by Dicer, called
small interfering RNAs (siRNAs), are then separated, presumably by an
enzyme with helicase activity, and integrated into a multiprotein complex
called the RNA-induced silencing complex (RISC).[1]

46
The native cellular purpose of the RNA interference machinery is not well
characterized, but it is known to be involved in microRNA (miRNAs)
processing and the resulting translational repression. MicroRNAs, which are
encoded in the genome and have a role in gene regulation, typically have
incomplete base pairing and only inhibit the translation of the target mRNA;
by contrast, RNA interference as used in the laboratory typically involves
perfectly base-paired dsRNA molecules that induce mRNA cleavage. After
integration into the RISC, siRNAs base pair to their target mRNA and
induce the RISC component protein argonaute to cleave the mRNA, thereby
preventing it from being used as a translation template.

Organisms vary in their cells' ability to take up foreign dsRNA and use it in
the RNAi pathway. The effects of RNA interference are both systemic and
heritable in plants and in C. elegans, although not in Drosophila or mammals
due to the absence of RNA replicase in these organisms. In plants, RNAi is
thought to propagate through cells via the transfer of siRNAs through
plasmodesmata.

47
STEM CELLS
Stem cells are the primitive cells that are responsible for creating

48
 the various tissues of the body. There are skin stem cells, blood
stem cells and, most recently discovered, brain and spinal cord
stem cells.

When taken out of the brain of an embryonic or adult mouse and

grown in incubators, these stem cells respond to protein growth
factors (one is called epidermal growth factor) and they can make
many brain cells. One of the brain cell types that they make is a
neuron that produces gamma-aminobutyric acid. It is this type of
neuron that is principally lost in HD.

Studies have shown that the brain stem cells in adult mice and
monkeys are usually making new neurons that participate in
olfaction (the ability to smell) and memory. So, it seems as though
the stem cells in mammals are regenerating two principal functions
- the ability to smell odour and to remember things - which may
tell us that these are the most important functions for our species.

Stem cells are making new neurons for controlling movement,

these are being made in very small numbers. A recent study,
however, found that when a mouse was made to have a small
stroke, the brain stem cells sent new neurons to repair the damage.
This very exciting result suggests that stem cells may respond to an
injury with an attempt to repair. It further suggests that if we can
learn how to "hyperstimulate" the stem cells, they may be able to
repair a larger injury or degeneration that results from a chronic
disease, such as HD.

Embryonic stem cells (the ones that are present in newly-fertilized

embryos) can be grown in incubators and turned into brain stem
cells.

 REFERENCES

1. FOYE’S Principle of medicinal chemistry By David A. William and

Thomas L. Lemke 5Edition Pg .nos 395 to 397, 408 to 429,492.

49
2.WLISON & GISVOLD’S Textbook of Oganic Medicinal & Pharmaceutical
Chemistry By John H Block & John M Beale Jr Pg .nos 496 to 508,
514 to 520.

3. Herbal Tech VOL-2 Issue 6 April 2006.

4. Pharmaceutical Chemistry Organic By G.R.CHATWAL Vol-2 2Edition

pg nos 162 to 174.

5. www.wikipedia.com

6. www.stanford.edu/grp/hopes/causes html

7. depts.washington.edu/mucholab/research.html

8. http--www_tcd_ie-tsmj-2003-images-hoseyfig3_gif.htm

9. A Physicians Guide To Management Of Huntington Disease 2Edition

by Adam Rosenblatt, M.D
Neal G. Ranen, M.D
Martha A Nance, M.D
Jane S. Paulsen, Ph.d

10. http://www.stat.washington.edu/www/seminars/

11. www.dnaftb.org/ygyh/index.html

12. www.hdac.org/hd causes.html

13. http://www.mdvu.org/library/disease/hd/hd_sym.html

14.http://www.disability.vic.gov.au/bhcv2/bhcsubmit.nsf/maxsearch?openagen
t&c=top&v=1&j=.2702187&jz=.8787732&tx=huntington_disease

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51