Huntingtons Chorea

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Huntingtons Chorea
http//hdroster.iu.edu/AboutHD/Images/piHDvC.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/hunti
  ngtons_disease.htmtreatments
• Cable/DSL (3.38MB)

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What Are The Major Effects of HD?

• Mood Swings
• Impaired Cognitive Functions
• Chorea

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What Causes HD?

• Huntingtons 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
  and cortex of the brain are specifically targeted
  in HD.
• The number of CAG codons varies and so does the
  severity of the disease

4
When Do Symptoms Appear?

• Age of onset varies based on the number of
  repeats.
• The earliest onset of Huntingtons 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 recognize.

http//www.scielo.br/img/fbpe/anp/v58n1/1251f3.gif
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What is Juvenile HD?

• 10 of Huntingtons
• 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.

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How is HD Diagnosed?

• Symptoms are frequently recognized by people who
  have history with the disease, but for others
  there is testing.
• Huntingtons 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

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What Is The Prognosis for People with HD?

• 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.

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What Are The Treatment Options?

• There is no cure for Huntingtons 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

9
What Research Is Being Done?

• CoQ10
• BDNF and REST

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Living with Huntingtons

• My husband knew he had a 50 chance of
  inheriting the disease from the age of seven. We
  married at age 35 and he kept the ravages of the
  disease to himself. I noticed then, 21 years ago
  that his foot moved most of the time. I also
  noticed he did not swing his arms when walking,
  hiking, ect. While working on my Masters Degree
  in Counseling, my research led me to information
  on neurological disease and a chill went up my
  spine when I read of tics and inability to move
  arms when walking. I tried to talk to him about
  it, but he turned his back to me and didnt talk.
  Finally, from a niece who developed HD young and
  rapid progression, I was able to learn from a
  previously estranged sister in law the whole
  family history. I knew in my mind and heart my
  husband had inherited the disease. He was
  becoming depressed and lost three jobs in
  succession. Now, it is 21 years later since I
  noticed his foot moving. He is bedridden,
  incontinent, has pureed food, etc. He cannot walk
  and his speech is slurred past recognition.
  The saddest part is that he stays angry and will
  lash out with no warning. I have been hit many,
  many times just trying to help him eat or change
  his depends. I have an aide in the morning hours.
  He gets along with her. However, this service
  is expensive and deleting our savings. I have had
  back surgery from lifting him and now I need a
  total knee replacement but cant leave him with
  anyone for three days hospitalization. This
  disease affects the family and the caregiver,
  which is myself. I know it is a horrible life my
  husband is living and I do not complain. I
  have tried four different nursing homes but his
  violent behavior has caused him dismissal. I love
  him dearly and really do not want him placed in a
  State Hospital where he will not have all the
  attention, good food, careful inspection for
  bedsores and medicine pulverized in his favorite
  puddings. At this point, I am at my wits end. I
  am bi-polar and fight depression and mania
  myself. I have laid down my life for a friend
  but when will it ever end.
• http//livingwith.neurologychannel.com/huntingtons
  -disease/20070919_2571

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The Genetics of Huntingtons

• Huntingtons 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

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Tri-nucleotide Repeat

• CAG Repeats are found on the HD gene on
  Chromosome
• gt40 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
• 29-35 repeats the individual will not develop HD,
  children may
• lt29 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

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The Gene and its Normal Function

• 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

14
Statistics

• 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

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Neuropathology

• 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 or PET
• 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 aspiny
  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

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What About the Gene?

• Unique in its Genome
• Spans approximately 185 kb (kilobases) in 4p16.3
• Comprised of 67 Exons
• Directs the Synthesis of two major RNA
  transcripts
• The HD CAG repeat is located in Exon
• Only 17 codons from the ATG start of translation

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Gene Transcription

• 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).

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Huntingtin

• HD mRNA encodes a protein that is 350 kD
  (KiloDaltons) in mass, called Huntingtin.
• The CAG repeat is translated into glutamine
  residues
• Found in the cytoplasm of neuronal and
  non-neuronal cells in humans
• Scientists know that
• In the basal ganglia, the huntingtin distrubition
  of immunoreactivity is homogeneous, with targets
  of the mutation, medium sized neurons exhibit
  variable levels of the protein
• However large neurons not affected by the
  disease display low or undetectable signs of
  protein
• The levels of Huntingtin required for an organism
  to function is fairly modest.
• Part of reason why symptoms are not shown until
  around 40 years of age

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Huntingtin Again

• Huntingtins 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.

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Even More Huntingtin

• The mutated Huntingtin in cells follows same
  pattern as normal protein
• The CAG repeats in the lengthened gene exhibit
  enhanced reactivity to monoclonal reagents
• Produces embryos that fail during gastrulation
  7.5 days before they form a nervous system

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What does all this mean?

• 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 doesnt 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

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Other CAG Repeat Disorders

• Spinal and Bulbar Muscular Atrophy- Causes the
  progressive loss of anterior horn cells in the
  spinal cord as well as consequent muscle
  weakness.
• Dentatorubral-Pallidoluysian Atrophy- Results in
  neuronal cell loss in both the Dentatofugal and
  Pallidogfugal systems
• Spinocerebellar Ataxia- Creates progressive
  cerebellar ataxia(loss of muscle coordination),
  muscular atrophy, and a loss of proprioception
  and vibration sense.

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Impact

• The discovery of the HD Gene along with the
  understanding of the CAG repeat mutation lead to
  the understanding and accurate diagnosis of
  Huntingtons Disease.
• This improved the clinical management of the
  disease
• As scientists discover more information about
  Huntingtons and the HD mutation, they also grow
  closer to helping individuals suffering from
  similar pathogenic processes
• The disease process involves pathways common to
  many cells as well as pathways unique to neuronal
  cells.
• The ability to compare numerous disorders caused
  by the unstable repeat of CAG nucleotides affords
  promising routes that accelerate the task of
  overcoming the problems caused by HD (ex neural
  cell death)

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Types of 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_storyd962010d883b
e3d1278974769d1226cf0ed34933
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Prenatal Testing

• 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.

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Presymptomatic Testing

• 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

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Support

• 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.

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Testing Process

• 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.

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Testing Costs

• Costs vary from center to center.
• Some centers provide the test for free for
  patients involved in their studies.
• Most centers range in price from 600 to 1,500.

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Health Insurance and Testing

• Some insurance providers cover presymptomatic
  testing.
• Making a claim could lead to genetic
  discrimination.
• Although unusual, it is possible that an
  insurance company could deny health coverage or
  cancel an existing policy because of a positive
  HD test.
• A positive test result could also be considered a
  pre-existing condition making it difficult to
  obtain future health coverage.
• Most people choose to wait until they get their
  results, and only seek reimbursement if they
  dont carry the gene

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Results of the Test

• 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.

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Testing Ethics

• Personal relationships may change
• Reduction of uncertainty
• Preparation for the future
• Expenses
• Emotional trauma
• Discrimination

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Jeopardy!!
Jeopardy!
35
Genetics 100Questions

• What chromosome is the HD gene located on?

• Chromosome 4.

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Genetics 200Questions

• What protein does the functional HD gene produce?

• Huntingtin.

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Genetics 300Questions

• How many CAG repeats guarantee HD symptoms?

• 40 repeats.

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Genetics 400Questions

• What is the specific location of the HD gene?

• 4p16.3

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Testing 100 Questions

• True or False patients undergoing presymptomatic
  testing are not advised to bring a close friend
  or family member to sessions.

• False patients are advised to bring a friend or
  family member to all sessions unless that person
  is also at risk for HD.

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Testing 200Questions

• Provided that a patient has a family member know
  to have HD, how accurate is the test for that
  patient?

• Almost 100 accurate.

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Testing 300 Questions

• What are the three types of testing for HD?

• Presymptomatic, Confirmatory, and Prenatal

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Testing 400 Questions

• Give three reasons a person at risk for HD may
  choose not to undergo presymptomatic testing.

• Discrimination in the workplace, personal
  relationships may change, emotional trauma,
  expenses, health insurance, etc.

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Basic Facts 100 Questions

• What is Chorea?

• Uncontrollable, dance-like movements of the hands
  and feet.

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Basic Facts 200 Questions

• When do the symptoms of HD appear?

• It depends greatly on the number of repeats
  occurring in the patients genes.

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Basic Facts 300 Questions

• What percentage of HD cases are juvenile HD?

• About 10.

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Basic Facts 400 Questions

• What are the three main elements of treatment for
  Huntingtons?

• Proper diet and nutrition, exercise, and
  medication.