Pre pared by :

Prof Dr. MOHD AFIQ HANNAN (Dr. Hannan)

Forensic Pathologist-to be
p/s:pray for me, insya-allah, amin!

http://hdroster.iu.edu/AboutHD/Images/piH
DvC.jpg

“Approximately 30,000 people in the United States have

Huntington's Disease, which affects men and women equally across
all ethnic and racial lines.” http://www.helpguide.org/elder/huntingtons_disease.htm#treatments
Progressive neurodegenerative
disorder

Inherited brain disorder – progressive

deterioration physical, cognitive and
emotional self

CONFIRM!! ENDED WITH DEATH IN

10-40 YEARS AFTER ONSET
Mood Swings, hormonal imbalance

Impaired Cognitive Functions

Chorea
 Huntington’s Disease is caused by a gene mutation that
creates excess copies of the CAG codon which genetically
program the degeneration of the neurons of the brain.

 The cells of the basal ganglia, caudate nucleus, cortex,

globus pallidus nuclei of the brain are specifically targeted in
HD.

 The number of CAG codons varies and so does the severity

of the disease
 Age of onset varies
based on the number of
repeats.

The earliest onset of

Huntington’s ever
documented was a two
year old boy who was
found to have nearly
100 CAG repeats.

The symptoms of HD
can also develop at 55
or later, in which case
it is harder to
http://www.scielo.br/img/fbpe/anp/v58n1/1 recognize.
251f3.gif
 10% of Huntington’s
cases.
 Usually 80-100 CAG
repeats
 stiffness or rigidity in
joints as opposed to chorea
for adult-onset HD
 1/3 of Juvenile HD
patients have recurring
seizures.
 Believed to inherit large
numbers of repeats from
father.
 HD occurs in about 1 out of every 10,000 Caucasian individuals
 Approximately 2.5 times more individuals are at risk for the disorder because of the midlife
peak in age at onset
 About 40% of those at risk actually have the gene and are too young to exhibit symptoms
 HD affects males and females equally
However the juvenile form of the disease tends to be inherited from fathers
 Symptoms are frequently recognized by people who
have history with the disease, but for others
there is testing.
 Huntington’s can be diagnosed by a simple blood
test at any age.
 There are three types of tests that can be taken
to determine an HD diagnosis:
Prenatal testing
Pre-symptomatic testing
Confirmatory testing
Presymptomatic Testing: Testing for people
who are genetically at risk for getting HD.
Confirmatory Testing: Testing that
determines whether people who are showing
symptoms actually have HD.
Prenatal Testing: Testing used to
determine whether a fetus is at risk for
HD.
http://video.on.nytimes.com/?fr_story=d962010d883be3d1278974769d12
 Amniocentesis involves testing a
sample of amniotic fluid from the
womb. Usually done when woman is
between 16 and 20 weeks.

 Chronic Villi Sampling: performed

earlier than amniocentesis - between
the 10th and 12th weeks of pregnancy.
In CVS, a catheter or thin needle is
inserted into the womb to extract
some of the chorionic villi - cells from
the tissue that will become the
placenta. The chorionic villi contain the
same chromosomes as the fetus.
Usually includes sessions devoted to:
genetic counseling, a neurological exam, a
psychological interview, discussion of the
results, and follow-up.

Neurological exam is meant to determine

whether the patient has any symptoms, in
which case they may choose to
discontinue testing procedure.

Sessions are meant to ensure that the

person about to undergo testing
understands the implications of the
knowledge of the results
It is usually strongly advised to bring a
supportive friend to all testing sessions.
It is not recommended to bring a
sibling of someone else who is at risk
for HD.
The testing process is a fairly simple
blood test. The blood the presence or
absence of the HD mutation.
It is encouraged that patients have
either a blood sample from a family
member who has HD or the results of
his/her genetic test for the purpose of
confirming the diagnosis.
Accuracy of a positive or negative test result
is almost 100% provided that another family
member is known to have the gene for HD.

Positive test results cannot predict when the

symptoms will begin.

Test results should always be confidential.

 HD generally runs its full
terminal course in 10-30
years but it has been
discovered that the earlier the
onset of HD
symptoms, the faster the
progression of the disease

 Juvenile HD usually runs its

course much faster and death
generally occurs about 10 years
after symptoms first appear.
 There is no cure for Huntington’s Disease and no treatment
to stop or reverse the course of the disease; however
there are ways to treat the symptoms that can even delay
the onset of the disease.
Medications
Proper Diet and Nutrition
Exercise
 CoQ10
 BDNF and REST
 Glutamic acid (Glutamate)
 Huntington’s Disease is a “Tri-nucleotide Repeat” Disorder
 CAG Repeats on specific gene
 It is an Autosomal Dominant disease
 Not sex-linked
 HD onset is found generally in adults around the
age of 40
 HD is caused by a faulty gene on the 4th chromosome which
is responsible for producing the protein Huntingtin
 CAG Repeats are found on the HD gene on Chromosome
 >40 repeats you develop HD, children 50% chance of developing disease
 36-39 repeats “Grey Zone” May develop HD, children may or may not
develop HD
 26-35 repeats the individual will not develop HD, children may
 <26 repeats, the individual will not develop HD, children will not develop
HD

*A very small percentage of people will develop HD with no family history of

the disease
 The HD Gene was specifically located in 1993 by
researchers at MIT, on the 4th Chromosome
 It is responsible for producing the protein
Huntingtin
 Researchers are not completely sure what
Huntingtin does, however they do know that it is
somehow very important for the normal functioning
of Brain Cells
 The symptoms are caused by a loss of neurons in the brain that occurs
about the time that disease becomes first manifest
 The basal ganglia and cortex are ravaged, which can be followed up with
a MRI
 In the caudate nucleus, populations of enkephalin and substance P
containing medium-sized spiny GABAergic projection neurons are the first
to be affected
 The exhibit wilted and recurved dendritic endings and changes in the density, shape and size of the
spines.
 The large acetylcholine rich or smaller somatostatin and neuropeptide Y
containing a spiny interneurons are spared by the disease process
 It is this characteristic pattern of neuronal cell loss in the basal ganglia
that forms the basis for the neurophathological grading of HD
 The repeating CAG codons work to encode 8 to 36 glutamine
residues

 A broken array of around 40 glutamine residues are produced

by an adjacent stretch of CAG and CCG codons

 Further 3’ in Exon 58, the “∆2642 polymorphism” is responsible

for producing part of the major haplotype (closely related link
of inherited alleles).
 1 kD = 1,000 Daltons 350 kD = 350,000 Daltons
1 Dalton = 1 amu = 350,000 amu
1 amu = 1.67 ×10 −24 grams
 Huntingtin’s exact function is not known but it is known that:
 It serves a vital in cellular function, acting as a “housekeeper”
 Not required for immediate survival and function of the cell
 Is required for the survival and function of the organism as a whole

 The transcripts from normal and the disease allele are both
expressed in the cells and tissues of Heterozygous HD
patients.
 This suggests that the pattern of neuronal cell death in the
striatum is due to the relatively high levels of Huntingtin
expression found in medium sized neurons
 But this doesn’t explain why neuronal cell types in other regions of the
brain that also express high levels of huntingtin are not affected by the
disease

 In neurons, huntingtin immunoreactivity is found in cytoplasm

throughout the body, axons, dentrites, and perikarya.
 Suggesting a role in trafficking or neurotransmission from Huntingtin
 Jeopardy!
Genetics Testing Basic Facts

100 100 100

200 200 200

300 300 300

400 400 400

What chromosome Chromosome 4.
is the HD gene
located on?
What protein does Huntingtin.
the functional HD
gene produce?
How many CAG 40 repeats.
repeats guarantee
HD symptoms?
What is the 4p16.3
specific location of
the HD gene?
True or False: False; patients are
patients advised to bring a
undergoing friend or family
presymptomatic member to all
testing are not sessions unless
advised to bring a that person is also
close friend or at risk for HD.
family member to
sessions.
Provided that a Almost 100%
patient has a accurate.
family member
know to have HD,
how accurate is
the test for that
patient?
What are the three Presymptomatic,
types of testing for Confirmatory, and
HD? Prenatal
Give three reasons Discrimination in
a person at risk for the workplace,
HD may choose personal
not to undergo relationships may
presymptomatic change, emotional
testing. trauma, expenses,
health insurance,
etc.
What is Chorea? Uncontrollable,
dance-like
movements of the
hands and feet.
When do the It depends greatly
symptoms of HD on the number of
appear? repeats occurring
in the patients
genes.
What percentage About 10%.
of HD cases are
juvenile HD?
What are the three Proper diet and
main elements of nutrition, exercise,
treatment for and medication.
Huntington’s?