Huntington's Disease: An Overview

Jai Kumar Tripathi

Huntington's disease is a
rare inherited disorder involving the progressive loss of selected nerve cells
in the brain. This results in dementia of gradually increasing severity, and
eventually requires full nursing care. In over 90 per cent of cases, the
disease symptoms appear between the ages of 30 and 50. Although there is no
cure for the disease, early symptoms can be managed with drugs and other forms
of therapy to improve quality of life.

American physician George Huntington
documented the disorder in 1872. The name "chorea" comes from the
Greek word for "dance" and refers to the incessant quick, jerky,
involuntary movements that are characteristic of this condition.

Huntington's disease is an inherited
disease. Signs and symptoms usually develop in middle age, and men and women
are equally likely to develop the condition. Younger people with Huntington's
disease often have a more severe case, and their symptoms may progress more
quickly. Rarely, children may develop this condition.

Medications are available to help manage
the signs and symptoms of Huntington's disease, but treatments can't prevent
the physical and mental decline associated with this condition.

Causes

Huntington's disease is caused by a faulty
gene and runs in families.Most genes in the body are present in two copies, one
from the mother and one from the father. The gene (which is called
"huntingtin") that causes Huntington's disease is dominant. This
means that if a person inherits one copy of this gene from either parent, they
will go on to develop the disease at some point in their life.

A person who has one parent with Huntington's
disease has a 50% chance of inheriting the faulty gene. This risk is 50% for
each child and is not altered by gender or whether brothers and sisters are
affected. Only people who have the faulty gene are capable of passing it on to
their own children.

Very occasionally some people can develop
the condition even though there is no family history of it. This is usually
because previous generations were not diagnosed as a result of early death from
other causes, or loss of contact through adoption.

Huntington's disease causes damage to brain
cells in the areas of the brain involved in the control of movement, planning
and motivation.

Genetics

Huntington's disease is a
single gene disorder caused by a malfunctioning gene on chromosome 4. It is an
autosomal dominant disease, which means that only one copy of the gene needs to
be defective. Indeed, unlike many dominant diseases, the possession of one
defective copy of the gene results in disease symptoms that are every bit as
bad as those caused by two defective copies.

The occurrence of the disease
is about one in 15 000 across much of the world, although the incidence is
higher in some specific populations, such as the

Lake

Maracaibo

region of

Venezuela

.

The disease gene is named HD
(for Huntington's disease) and the protein is called huntingtin. The exact
function of the huntingtin protein is unclear, but it is known to be associated
with microtubules and synaptic vesicles, suggesting a role in the transport of
substances or cell components along the microtubules to the synapses (the
structures which facilitate communication between neurons). There is also some
evidence that huntingtin is involved with apoptosis (deliberately programmed
cell death).

The mutation causing the
disease is a pathogenic trinucleotide repeat expansion. There is a series of
repeats (in this case the sequence CAG) within the coding region of the gene
that can expand or contract from generation to generation. This produces
huntingtin proteins with variable numbers of glutamine residues. Once the
number of repeats exceeds 35, it becomes unstable and can increase rapidly in
subsequent generations. The greater the number of repeats, the earlier the
onset of the disease and the more severe the symptoms.

Symptoms

People usually have symptoms for up to 10
years before they find out they have Huntington's disease. Most people are
diagnosed between the ages of 30 and 50, although this can happen much earlier
or later. Symptoms are often overlooked, as they are mild and commonly experienced
by well people. They include:

• mild tremor
• clumsiness
• lack of concentration
• difficulty remembering
  things
• mood changes, including
  depression
• sometimes,
  aggressive antisocial behaviour

As the disease continues, the symptoms
become progressively worse, and lead to incapacitation.

Symptoms fall into three categories:

Physical symptom

Physical
symptoms
include chorea (involuntary movements of the
limbs, face and body). Chorea may lead to difficulty walking, speaking and
swallowing. Choking is a particular hazard, due to reduced ability to control
the muscles of the tongue, neck and diaphragm. People often lose weight because
they have difficulty eating and burn more calories due to the continuous
movement.

Emotional
symptoms

Emotional symptoms include depression, not only because of the
burden of having a progressive disorder, but also as a direct result of the
damage to certain brain cells. People often become frustrated at being unable
to work or carry out previously simple tasks. They also seem to behave
stubbornly, probably due to a reduced ability to react flexibly and to
understand the needs and emotions of others. People with

Huntington

's may also become more irritable
and antisocial than usual, or make inappropriate sexual advances.

Cognitive symptoms

Cognitive
symptoms
include a loss of drive and initiative. People
with

Huntington

's
may appear to be lazy or uninterested in life, spending days doing little or
neglecting personal hygiene. They may also lose the ability to organise
themselves, as planning skills and ability to carry out more than one task at
once deteriorate. In later stages, people may get memory loss and be less able
to understand speech.

The behavioural changes that occur in
people with Huntington's disease are often the most distressing for them, their
family and their carers. People with previously full and active lives gradually
lose their independence and mobility. At the same time, their personality may
become gradually more self-centred and apathetic, straining personal
relationships.

Juvenile
Huntington's disease

A
juvenile form of Huntington's disease also exists. Symptoms start before the
age of 21 and the condition is usually inherited from the father. Symptoms are
similar to those of adult

Huntington

's,
but develop more rapidly and include muscular rigidity and fits.

Treatment

Most people who have Huntington's disease
eventually become physically and mentally disabled. As the disease progresses,
long-term nursing home care may be necessary.

No satisfactory treatment is available to
stop or reverse Huntington's disease, but some approaches can control signs and
symptoms.

Medications

Tranquilizers such as clonazepam and antipsychotic drugs such as haloperidol
and clozapine can help control movements, violent outbursts and hallucinations.

Various medications, including fluoxetine ,
sertraline and nortriptyline , can help control depression and the
obsessive-compulsive rituals that some people with Huntington's disease
develop. Medications such as lithium can help control extreme emotions and mood
swings.

Side effects from many of the drugs used to
treat the symptoms of Huntington's disease may include hyperexcitability,
fatigue and restlessness. In some instances, antipsychotic drugs may cause side
effects that mimic the signs of Parkinson's disease, including involuntary
twitching in your face and body (tardive dyskinesia).

Speech therapy

Huntington's disease can impair your speech, affecting your ability to express
complex thoughts. You may find that speech therapy helps. Remind friends,
family members and caregivers that if you don't speak, it doesn't necessarily
mean that you don't understand what's going on. Ask people to continue talking
to you and keep your environment as normal as possible.

Diagnosis

Tests for Huntington's
disease are offered to individuals with a history of the disease in the family,
although this must be accompanied by counselling to help such individuals come
to terms with the future. A great deal of anxiety can be caused when those
living in the shadow of Huntington's disease spend time looking for the symptoms
and anticipating their onset. Prenatal tests for Huntington's disease are also
available, although the prospect of terminating a pregnancy because the child
may develop a disease in middle age raises considerable ethical concerns.

Genetic tests

Tests are available to identify whether
someone has the faulty gene. These fall into three categories: diagnostic,
pre-symptomatic and antenatal.

Diagnostic tests

These are carried out in people who have
symptoms of Huntington's disease who come from families with members who have
the condition. The aim is to confirm a diagnosis.

Pre-symptomatic tests

These tests are carried out in people who
are not showing symptoms of Huntington's disease, but have a family history of
it. Taking such a test tells the individual if they will develop the disease,
but not when this might happen.

The decision to take a test is a serious
one: a positive result can be devastating since it tells the individual that
they will one day become severely mentally ill.

There are also issues surrounding testing
when the individual's parents have themselves not been tested, since a positive
result indicates that one parent also has the faulty gene.

Advice from a genetic counsellor about the
implications of taking the test is needed before going ahead. They are not
available in the UK for people under 18 years old.

Antenatal tests

These are carried out early in pregnancy on
the unborn children of couples from families affected by Huntington's disease.
They can be used to calculate the risk of that child going on to develop the
disease in their adult life. Again, the implications of a positive result are
serious, and couples need advice and support from a specialist doctor or
counsellor to help them in their decisions.

Prevention:

If you have a family history of
Huntington's disease, you may want to consider genetic counseling before
starting a family. A blood test can determine the presence of the faulty gene,
even before you show signs or symptoms. If one parent carries the defective
gene, his or her child has a 50 percent chance of developing Huntington's
disease.

If you're at risk of passing the genetic
defect that causes Huntington's disease to your children, you may wish to
consider adoption or certain forms of assisted reproduction. One possibility is
in vitro fertilization with pre-implantation screening. In this procedure,
embryos are screened for the Huntington's disease gene mutation, and those that
don't have the mutation are then implanted in the woman's uterus.

Self-Care:

Having Huntington's disease presents a
number of challenges that require daily or regular attention. The following
steps may improve how you feel:

• 
  Exercise regularly.
  
  People with
  Huntington's disease who exercise regularly tend to fare better than those
  who don't exercise, and physical activity can help you feel better
  mentally and physically. Keep your home free of sharp, hard objects in
  case you fall while moving around. Consider wearing special padding to
  protect yourself from falls that may happen while you're on walks. Wearing
  sturdy, properly fitting shoes may help with stability.
• 
  Maintain proper
  nutrition.
  
  People with Huntington's disease may burn as many as
  5,000 calories a day, so be sure to get adequate nutrition to maintain
  your body weight, and consider extra vitamins and supplements. Because
  Huntington's disease can impair coordination, you may need assistance when
  eating. Allow plenty of time for meals. Cutting food into small pieces or
  eating pureed food may make swallowing easier and prevent choking. Dairy
  products may make you secrete excess mucus, which may increase your risk
  of choking. Occupational therapists may make other suggestions on how to
  improve your swallowing. Using cups with lids and suction cups and
  tableware designed for people with disabilities may prevent spills.
• 
  Drink plenty of fluids.
  
  Huntington's disease
  can make you vulnerable to dehydration. Drink large amounts of liquids,
  especially during hot weather. Some people find that bendable straws make
  drinking easier.

References:

1.
Stephen
B. Dunnett and Anne E. Rosser, Cell Therapy in
Huntington's Disease,


NeuroRx. 2004 October; 1(4):
394–405.

2.
Richard
Twyman, Huntington's disease,

A
progressive neurodegenerative disorder that usually strikes in middle to late
adult life.

7/1/04.

3.

Songming
Chen, Frank A. Ferrone and Ronald Wetzel, Huntington

's

disease

age-of-onset linked to
polyglutamine aggregation nucleation, PNAS, September 3, 2002
, Vol. 99, no. 18 ,11884-11889.

4.
Huntington's disease From MayoClinic.com Special to CNN.com.

5.
Huntington's
disease Published by BUPA's Health Information Team
February 2004.

6.
Bezprozvanny, I.,
Hayden, M.R. (2004, August). Deranged neuronal calcium signaling and
Huntington's disease.

Biochemical and Biophysical Research Communications
322

(2004), 1310-1317.

7.
Bossy-Wetzel, E.,
Schwarzenbacher, R., Lipton, S.A. (2004, July). Molecular pathways to
neurodegeneration.

Nature Medicine 10

(Supplement), S2-9.

8.
Gardian,
G., Vecsei, L. (2004, July). Huntington's disease: Pathomechanism and
therapeutic perspectives.

Journal of Neural Transmission 111

(2004), 1485-1494.

9.
Cattaneo E,
Rigamonti D,
Goffredo D,
Zuccato C,
Squitieri F,
Sipione S., Loss
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Trends Neurosci.2001 Mar; 24(3): 182-8.

About Authors:

Jai Kumar Tripathi

For Correspondence:

Jai Kumar Tripathi, D.J.College of Pharmacy, Niwari Road , Modinagar (U.P.)-201204.

Kamal Dua

V.K.Sharma

Dr.U.V.Singh Sara