Huntington’s Disease All the characteristics of Huntington disease (HD) – from the involuntary dancing movements, to the irritability, to the memory loss – can ultimately be traced back to a small change in the huntingtin gene on chromosome 4.  People who have Huntington disease have a huntingtin gene that is slightly larger than usual.  The gene is bigger in a region where three letters of code ­ C-A-G ­ are repeated many times. The number of CAG repeats varies from person to person.  People without Huntington have between 9 and 35 repeats. People with Huntington have between 36 and 121. The number of repeats in the gene is directly related to the age when symptoms appear.  People with 36 to 41 repeats may not ever show signs of the disease, while a person with 50 or more repeats usually shows signs before age 20.  The mean age of onset is between 35 and 44. An excess of CAG repeats in the gene changes the shape of the protein, called huntingtin, produced from the gene.  Each CAG repeat in the gene tells the body's protein factory to put a particular amino acid – glutamine  – into the protein.  If there are 41 CAG repeats in a row inside the gene, there will be 41 glutamines attached to each other in a row inside the huntingtin protein. With so many glutamines, mutant huntingtin folds into a different shape than normal. Mutant huntingtin interacts with all sorts of other proteins that might normally be ignored, particularly in the spiny neurons deep inside the brain. Here inside the neuron, researchers believe one of these other proteins cuts mutant huntingtin into two.  One of the pieces finds its way into the neuron's nucleus where the cell's DNA resides. As more and more mutant huntingtin proteins are cleaved, the pieces accumulate in the nucleus and start to clump together.  

However, the role of the clumps in Huntington disease is unclear.  Some researchers believe the clumps directly kill the cell, but most believe the clumps are harmless byproducts of the mutated huntingtin. What mutant huntingtin is doing is still a mystery.  Recent research has even questioned the presumed role of the cleaved huntingtin fragment in the disease, instead pointing a finger at the full-sized mutant protein.  ARROWS POINT TO CLUMPS OF HUNTINGTIN INSIDE NEURONS Whatever this protein is doing to the brain cells, it starts before much cell death has occurred.  Not until the later stages of HD, when the patient becomes more rigid and unable to communicate, do MRIs and other imaging tools reveal the shrinking brain. When a physician suspects Huntington disease (HD) based on family history, patterns of movement, personality changes, and a decline in rational thinking, a genetic test can easily confirm the diagnosis.  The test detects 99% of people with HD by counting the number of CAG repeats inside the huntingtin gene. In a nutshell, the huntingtin genes (in which the HD-causing mutation lies) are isolated from a patient's DNA sample, and a geneticist makes a DNA "fingerprint" of the genes.  The vertical position of the genes in the fingerprint reveals the number of repeats in the genes.  The fingerprint below shows one gene (the band on top) is larger than the other. The geneticist uses a “genetic ruler” next to the DNA fingerprint to more precisely measure the number of repeats.  The big gene in this snapshot has 42 repeats, over the threshold for HD, so this person has Huntington disease. To get this fingerprint of the genes, a geneticist isolates the patient’s DNA from the blood sample and adds two small DNA “primers” to it. Primer A attaches to the DNA just to the left of the string of CAG repeats in the huntingtin gene, while primer B attaches just to the right of the repeats. After the primers attach, a chemical reaction called PCR (polymerase chain reaction) essentially makes a million identical copies of the DNA that lies between the two primers.  Each copy contains all of the CAG repeats inside the person’s huntingtin gene. If a person has more CAG repeats, his copies will be larger. The size of the copies is proportional to the number of repeats inside the gene. The geneticist can thus measure the size of the copies to determine the number of repeats. Armed with a slab of gelatin and an electric current, she loads the DNA copies into a groove at the top of the gel. When she sends an electric current through the gel, the current pushes the DNA pieces straight down toward the bottom of the gel. As the pieces move down the gel, they wind their way through the tangled molecules that make up the gel.  Small pieces do this easily so they zip through the gel quickly.  Big pieces have a harder time so they move more slowly. After a set period of time, the electric current is turned off, and the DNA pieces stop moving.  Small pieces have migrated to the bottom, while large pieces remain near the top.  Pieces of the same size congregate in one spot and form a dark band. The geneticist simply looks in each person's column for a gene greater than 35 repeats.  Each person has two bands representing his or her two huntingtin genes (one from each chromosome).  Only one large gene is needed to cause HD, so the presence of a gene high in the gel indicates the person has HD.  In this gel, person 2 has HD, but person 1 does not. The same DNA test used in diagnosis can also predict if someone without symptoms will develop HD in the future.  

Many people at risk for HD wish to know their future, others don’t.  The Huntington Disease Society of America (HDSA) recommends every person considering the test to consult with a psychologist or social worker at an HDSA testing center before making a decision. The same test used for diagnostic and predictive testing can also determine, either prenatally or before implantation of an in vitro embryo, if an unborn child will develop HD. However, if the test reveals the fetus carries the HD gene, it also reveals that the at-risk parent carries the gene.  A different genetic test – called linkage analysis – can be performed instead when the parent does not want to know if he or she carries the HD gene. A person inherits Huntington disease (HD) when he or she inherits an expanded huntingtin gene from one parent.  In this example, the mother has the expanded gene in one of her two chromosome 4's (the one in red).  The father has two normal-sized genes, one on each chromosome. When a female produces eggs, only one of her chromosome 4's enters each egg.  (One member of each of the other 22 pairs of chromosomes also enters, but this is not shown).  About half of her eggs will contain the chromosome with the expanded huntingtin gene.  Similarly, when a male produces sperm, only one chromosome 4 enters each sperm cell. When an egg containing the chromosome with the expanded huntingtin gene is fertilized, the resulting child will inherit the gene and the disease. Though we have shown a child inheriting HD from his mother, the gene can also be passed down from the father. When a sperm carrying the expanded gene fertilizes an egg, the resulting child will inherit the gene and disease. Because everybody who carries the expanded gene develops Huntington disease, nearly all people with HD have a parent with HD.  In some cases, though, neither biological parent has the disease.  This happens sometimes when the father has a huntingtin gene with an intermediate number of CAG repeats (between 27 and 35). This number of repeats does not cause HD, so the father does not have the disease.  But his gene can gain more repeats in the sperm he produces, or in the early embryo after fertilization. When this sperm fertilizes an egg, the resulting child will develop HD if the sperm’s huntingtin gene contains 40 or more repeats.  The child may develop HD if the gene has a smaller number between 36 and 39. 

Additionally, a few people develop HD in the absence of an affected parent when they inherit a gene (from the father or mother) with 36 to 41 repeats.  Genes of this size, represented by the orange chromosome, cause HD in some people, but not in others. The risk of having a child that will develop HD later in life depends on the size of the parent’s huntingtin gene.  If one parent (in this example, the father) carries a gene with 40 or more repeats, each of his/her children has a 50% chance of inheriting the gene and developing the disease. To see why this is, we’ll construct a Punnett square.  First, we arrange the parents’ huntingtin genes on the outer edges of the square.  Each parent has two huntingtin genes, one on each chromosome 4.  A big H represents the mutated gene, and the little h represents the normal-sized gene. Each parent donates only one of their huntingtin genes to the child, so we place one of the father’s genes and one of the mother’s genes into each box.  Each completed box contains a potential combination (a.k.a. genotype) in the child, and the entire square contains all possible combinations. Next we count the boxes that contain a HD-causing genotype (the Hh combo).  Two out of four boxes contain this genotype, so the chance of this couple’s child receiving the Hh genotype and developing HD later in life is also two out of four, or 50%.Though we have shown an example with the father as the partner carrying the mutated gene, the results are exactly the same if the mother carries the gene instead. Two out of four boxes contain the HD-causing combo (Hh or hH), so the chance of this couple's child inheriting Huntington disease is also 2 out of 4, or 50%.The most important thing to remember about these odds is that they apply to every child this couple has.  It may be useful to think of the Punnett square as a roulette wheel.  Each child is a separate "spin of the wheel," so each child has a 50% chance of receiving the mutation. In this family, one in four children has an HD-causing gene.  Other couples with the mutation may have two, three, four, or even no children with the gene. Huntington disease (HD) is an inherited disorder and is not contagious.  HD is a dominant disease; a person only needs to inherit one copy of the mutated huntingtIn gene to develop HD.  Consequently, every child of a person with HD has a 50% chance of inheriting the gene and developing the disease. Early signs of Huntington disease include mood swings and irritability, depression, loss of memory, and uncontrolled movements.  As the disease progresses, walking and speech become more difficult, and memory and intellectual functions continue to decline. In people of western European descent, about 1 in 20,000 are born with a gene that causes Huntington disease.  It is less common in Asia and Africa, where about 1 in a million are born with the gene. The diagnosis of Huntington disease depends on characteristic physical and mental changes, a positive family history, and a DNA test.  The DNA test can also determine if an asymptomatic person will later develop the disease. Huntington disease is a genetic disorder that develops in people who have inherited a larger than normal huntingtin gene.  The larger gene produces an abnormal protein that begins to kill brain cells in middle age. Loss of these cells causes the characteristic symptoms and eventually, death. There is no cure for Huntington disease, though there are drugs that can help control movement problems and treat depression and other emotional/mental problems. 

Treatment Dr. Chris Ross talks about treatments for some of the symptoms of Huntington disease. Cell death Dr. Chris Ross talks about the cell deaths involved in Huntington disease. Protein Toxicity Dr. Chris Ross talks about how the huntingtin protein may cause cell death and how this may lead to new treatments. HD Mice Dr. Chris Ross talks about using mouse models to study Huntington disease. Resources Dr. Chris Ross talks about available resources for people with Huntington disease and their families. Finding a Neurologist Nancy and Barry Goldring talk about the need to find a specialist who has experience in dealing with Huntington, and who knows about the newest treatment options and studies. What is it? What causes it? How is it inherited? How is it diagnosed? How is it treated? What is it like to have it? For more information… Acknowledgments Initial Signs Suzanne Doggett and Nancy Goldring talk about the early signs of Huntington that they noticed. Dr. Chris Ross talks about the classic clinical signs of Huntington. First Reactions Nancy Goldring talks about how her husband Barry reacted to the news of his Huntington diagnosis. Life After Diagnosis Nancy Goldring talks about how Barry’s Huntington has changed her family’s view on life. Living with HD Nancy Goldring talks about her husband Barry and the progression of his Huntington. Keeping Up With Research Nany Goldring talks about how Barry works to keep himself informed about Huntington. Suzanne Doggett talksabout the types of facilities and health care available to her mother who had Huntington. Long-term Care Nancy Goldring discusses the need for investigating long-term care choices. Children at Risk Nancy Goldring answers the question: Is it better to know if your child inherited Huntington? HD Testing Suzanne Doggett talks about how she made the decision to get tested for Huntington. Getting Tested Suzanne Doggett talks about issues that need to be considered in getting tested for Huntington.