Huntington's Disease


Student 3 and Student 4


Background Information of Huntington's Disease

George Huntington's was the first to acknowledge the condition. Huntington's disease bears his name because he described the condition 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. See wikisource for the text of this paper.

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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Huntington’s chorea is a neurodegenerative disease characterized by motor, cognitive, and emotional symptoms. The age of onset for symptoms is generally 30-50 years. The genetic basis of the disease is an amplification in a gene with an (as yet) unknown function. A triplet (CAG) is repeated 20-50 times in asymptomatic individuals; having more than 50 repeats is associated with disease symptoms. This amplification can be detected by restriction enzyme digestion and Southern blot analysis, since the size of the fragment bound by the probe is increased as a result of the amplification of the triplet repeat. Huntington’s disease is considered a dominant disorder, since one copy of the amplified gene appears to be sufficient to cause disease symptoms.

Biology of Huntington's Disease

Unlike many diseases, Huntington's Disease is caused by the mutation of one single gene. In February of 1993, after an intensive and wide ranging international search effort, the Huntington's gene was found onthe short arm of chromosome 4. The gene is also called IT15 (interesting transcription 15). Chromosome 4 is one not the "sex specific" chromosome pair, so both males and females can get Huntington's Disease and pass it on to their children of either sex. The Huntington's Disease gene is dominant. If an individual has the defective Huntington's gene (greater than 40 repeats), then he or she will eventually develop the disease. Huntington's Disease affects men and women equally and in couples where one parent has the disease there is a 50 percent chance of the disease gene being passed on to their children.

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The Huntington's gene is a long one by gene standards, with over three hundred thousand base pairs. These three hundred thousand base pairs work together to produce a protein that no other gene makes. This protein is called "huntingtin." Huntington's, with an "on" at the end is the name of the disease, the gene, and by genetic convention is capitalized. The protein is called "huntingtin" with an "in." By convention, "huntingtin", the protein, is not capitalized.
Despite extensive research, the function of the Huntington's gene has not been fully determined. It is believed that the huntingtin protein produced by the normal Huntington's gene has a protective effect on the neurons in the brain.

It is also known that neurons in individuals who have the defective Huntington's gene contain clumps of material that is believed to be caused by the extra glutamines in the defective huntingtin protein. It has not been resolved whether the observed clumps are the cause of the neuron death that occurs in Huntington's Disease or are simply an innocent byproduct of the disease process. However, recent research results support the idea that the clumps cause at least part of the disease. In any event, the defective huntingtin protein seems to react with many more compounds in the brain than the normal protein does and this reaction is contributing to neuron death.



Symptoms and Treatment of Huntington's Disease

PHYSICAL SYMPTOMS:
-Development of tics (involuntary movement) in the fingers, feet, face, or trunk.
-Increased clumsiness
-Loss of coordination and balance
-Slurred speech
-Jaw clenching or teeth grinding
-Difficulty swallowing or eating
-Continual muscular contractions
-Stumbling or falling

MENTAL SYMPTOMS:
-Decreased concentration
-Forgetfulness and memory decline
-Poor judgment
-Difficulty making decisions or answering questions
-Difficulty driving

EMOTIONAL SYMPTOMS:
-Hostility/irritability
-Lack of energy
-Ongoing disinterest in life (lack of pleasure or joy)
-Bipolar disorder (manic-depression) in some Huntington's patients
-A person with Huntington's Disease may eventually begin to exhibit psychotic behavior, such as:
-Delusions
-Hallucinations
-Inappropriate behavior (e.g., unprovoked aggression)
-Paranoia

The symptoms of Huntington's Disease are often subtle in the beginning and the disease frequently is misdiagnosed. Part of the reason for this is that many families do not know that they have a genetic legacy of Huntington's. Earlier generations may have died from other causes before the disease progressed.
In other families, the disease may have been misdiagnosed as alcoholism, drug addiction, menopause, trauma, or another condition. Adopted children often don't know their genetic heritage. Until recently, medical textbooks did not allow for the possibility that genetic mutations could cause Huntington's Disease to appear in a family that never had experienced it before, something that today we know can occur.

As Huntington's Disease progresses, concentration and short-term memory become worse. The involuntary movements of the head, trunk, and limbs increase. The individual affected may make uncontrolled facial grimaces. Walking, talking, and swallowing abilities decline. Eventually the affected individual becomes unable to care for him or herself. Death generally occurs about 10 to 30 years after the signs and symptoms first appear, but misdiagnosis can shorten the apparent timetable. Death often results from complications such as choking, lung infection, or heart failure.

There is no cure for Huntington's Disease. Treatment such as diet and supplements, exercise, and spirtiual and psychosocial support are used to help control symptoms. Research for a cure to Huntington's Disease is ongoing and led by a dedicated group of scientists. A number of these highly motivated researchers have the disease in their own families. Progress is being made towards a cure, but not always in a straight line. There are approximately 30,000 people in the United States with Huntington's Disease. Since there are so few individuals in the U.S. that have the disease, pharmaceutical companies do not have programs to develop drugs specifically to treat Huntington's Disease.

Diagnostic Testing of Huntington's Disease

Diagnostic genetic testing refers to the use of a gene test in a patient who has symptoms suggestive of Huntington's Disease, with or without a family history. If the clinical suspicion is strong, this may be the only diagnostic test needed. It is important to remember that the presence of the huntingtin gene with an increased repeat number does not mean that a patient's current symptoms are caused by Huntington's Disease because the gene is present throughout life. Particularly in children, who have the most to lose by premature genetic diagnosis, the gene test should be used sparingly and only when the neurologic symptoms strongly suggest the onset and progression of Huntington's Disease.

Confirmatory testing should be performed in a patient who appears to have Huntington's Disease even if no other affected family members have previously had a gene test. This is done to be sure that the "family disease" is really Huntington's Disease and not some other condition. Diagnostic genetic testing is also very useful in the evaluation of an individual who appears to have Huntington's Disease, but who has a negative or absent family history.
Polymerase Chain Reaction (PCR) Assay and Southern Blot are the two tests used to detect the Huntington's Disease gene and determine if it contains the repeat sequences associated with the disease.

The presence of an expanded Huntington's Disease gene in one individual has direct implications for that person's children, siblings, and perhaps his parents and collateral relatives. Any physician who diagnoses Huntington's Disease in a patient must be prepared to face questions from and about these additional family members. Consultation with a genetic counselor may help to make this difficult situation easier.

Case A Description

Susan is a 23-year-old whose father, age 55, and paternal aunt, age 61, have been diagnosed with Huntington’s chorea. A paternal uncle, age 66, appears to be unaffected by the disease. Susan wants to know if she inherited the mutated gene from her father so that she can prepare for that future if necessary. She arranges to undergo DNA testing for Huntington’s disease. Her 17-year old brother, John, also decides to be tested after talking with Susan.

Case A Testing Results

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Case A Statement to Family

The results indicate that Susan and her uncle do not have Huntington's Disease. However, Susan's aunt, father, and younger brother John have inherited Huntington's Disease.
First, we will bring Susan and her uncle in and explain to them their situation. Then, we will bring the rest of the family in and explain the situation to them. If any of the family members want to re-test or have questions about the results we will be more than happy to help them in any way that we can.

Case B Description

Josiah and Eldrea were worried about their 52-year old father. He was starting to act sometimes like his older brother, their uncle Theo. Theo was 15 years older than their father and he had been recently diagnosed with Huntington disease. After speaking with the family physician they learned a diagnostic DNA test was available. They wanted their father to have the test, and they decided they should take it themselves so that they can better prepare for their future.

Case B Testing Results

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Case B Statement to Family

First, we would bring Eldrea into the office and tell her her results and that she does not have Huntington's Disease. Then, we would bring in Josiah, Uncle Theo, and Josiah and Eldrea's father to tell them their symptoms and that they have tested positive for Huntington's Disease. We would make them aware that if they have any further questions or need help finding couseling, more tests, etc. we would be more than happy to help them in any way that we can.

Case C Description

Forty-four year old Jerry is haunted by the specter of Huntington disease. It took his grandmother, a favorite uncle, and now he sees signs of motor impairment in his 67-year old mother, Sophie. He worries that he mights have inherited the disease and wonders, too, if he may have passed it to any of his children. After several late night family discussions, a date is set for them to provide samples for DNA testing. While he is certain he and his mother should be tested, he wonders if his children are making the right choice.

Case C Testing Results

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Case C Statement to Family

First, we would bring Sophie (Jerry's mother) and Jerry (father) in and discuss the situation with them. We would inform them that they are infected with Huntington's Disease and inform Jerry that he has passed it on to two of his children, the 19-year-old daughter and 18-year-old son. Jerry's 22-year-old son does not have Huntington's Disease. After informing Sophie (Jerry's mother) and Jerry, we would then bring Jerry's children in and explain the situation to them. If they have any questions about the test results or want to re-test we would be more than happy to help. If they need a family counselor, we can help arrange one for them.

Additional Information

This link is to an article that talks about a mother who is in the final stages of Huntington's Disease and her daughter who has a 50/50 chance of inheriting the disease, but hasn't been tested yet. Picture above is Shana Martin and her mother, Deborah.
http://www.jsonline.com/story/index.aspx?id=41400

References

The University of Utah, Genetic Science Learning Centerhttp://images.google.com/imgres?imgurl=http://learn.genetics.utah.edu
http://www.helpguide.org/elder/huntingtons_disease.htm
http://www.hdsa-wi.org/facts.htm
http://student.bmj.com/issues/03/10/education/images/view_8.jpg
http://biobasics.gc.ca/english/View.asp?x=765
http://www.jsonline.com/story/index.aspx?id=41400