Huntington's disease (HD) is an inherited disease that causes certain nerve cells in the brain to waste away. People are born with the defective gene, but symptoms usually don't appear until middle age. Early symptoms of HD may include uncontrolled movements, clumsiness, and balance problems. Later, HD can take away the ability to walk, talk, and swallow. Some people stop recognizing family members. Others are aware of their environment and are able to express emotions.

If one of your parents has Huntington's disease, you have a 50 percent chance of getting it. A blood test can tell you if have the HD gene and will develop the disease. Genetic counseling can help you weigh the risks and benefits of taking the test.

There is no cure. Medicines can help manage some of the symptoms, but cannot slow down or stop the disease.

Huntington's disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition).

Adult-onset Huntington's disease, the most common form of this disorder, usually appears in a person's thirties or forties. Early signs and symptoms can include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. Many people with Huntington's disease develop involuntary jerking or twitching movements known as chorea. As the disease progresses, these movements become more pronounced. Affected individuals may have trouble walking, speaking, and swallowing. People with this disorder also experience changes in personality and a decline in thinking and reasoning abilities. Individuals with the adult-onset form of Huntington's disease usually live about 15 to 20 years after signs and symptoms begin.

A less common form of Huntington's disease known as the juvenile form begins in childhood or adolescence. It also involves movement problems and mental and emotional changes. Additional signs of the juvenile form include slow movements, clumsiness, frequent falling, rigidity, slurred speech, and drooling. School performance declines as thinking and reasoning abilities become impaired. Seizures occur in 30 percent to 50 percent of children with this condition. Juvenile Huntington's disease tends to progress more quickly than the adult-onset form; affected individuals usually live 10 to 15 years after signs and symptoms appear.

Variants (also called mutations) in the HTT gene cause Huntington's disease. The HTT gene provides instructions for making a protein called huntingtin. Although the function of this protein is unclear, it appears to play an important role in nerve cells (neurons) in the brain.

The HTT variant that causes Huntington's disease involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington's disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington's disease, while people with 40 or more repeats almost always develop the disorder.

An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington's disease.

Normal Function

The HTT gene provides instructions for making a protein called huntingtin. Although the exact function of this protein is unknown, it appears to play an important role in nerve cells (neurons) in the brain and is essential for normal development before birth. Huntingtin is found in many of the body's tissues, with the highest levels of activity in the brain. Within cells, this protein may be involved in chemical signaling, transporting materials, attaching (binding) to proteins and other structures, and protecting the cell from self-destruction (apoptosis). Some studies suggest it plays a role in repairing damaged DNA.

One region of the HTT gene contains a particular DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene.

Health Conditions Related to Genetic Changes

Huntington's disease

The inherited variant (also called mutation) that causes Huntington's disease is known as a CAG trinucleotide repeat expansion. This variant increases the size of the CAG segment in the HTT gene. People with Huntington's disease have 36 to more than 120 CAG repeats. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington's disease, while people with 40 or more repeats almost always develop the disorder.

The expanded CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. It has also been suggested that loss of the huntingtin protein's DNA repair function may result in the accumulation of DNA damage in neurons, particularly as damaging molecules increase during aging. Regions of the brain that help coordinate movement and control thinking and emotions (the striatum and cerebral cortex) are particularly affected. The dysfunction and eventual death of neurons in these areas of the brain underlie the signs and symptoms of Huntington's disease.

As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington's disease (which appears in mid-adulthood) typically have 40 to 50 CAG repeats in the HTT gene, while people with the less common, juvenile form of the disorder (which appears in childhood or adolescence) tend to have more than 60 CAG repeats.

Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington's disease, but they are at risk of having children who will develop the disorder. As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with Huntington's disease (36 repeats or more).

Other Names for This Gene

• HD
• HD_HUMAN
• huntingtin (Huntington disease)
• Huntington's disease protein
• IT15

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. An affected person usually inherits the altered gene from one affected parent. In rare cases, an individual with Huntington's disease does not have a parent with the disorder.

As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington's disease typically have 40 to 50 CAG repeats in the HTT gene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats.

Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington's disease, but they are at risk of having children who will develop the disorder. As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with Huntington's disease (36 repeats or more).

• Failure to recognize the disease in family members
• Early death of a parent before the onset of symptoms
• The presence of an intermediate allele (an allele with 27-35 CAG repeats) or an HTT allele with reduced penetrance (with 36-39 CAG repeats), which may or may not result in HD in an asymptomatic parent
• Late onset of the disease in an affected parent

Symptoms of HD typically appear in middle-aged people (adult HD). They can also appear in children (juvenile HD), but this is rare. The disease gets worse over time.

Early signs of HD can vary, but often include mild clumsiness or problems with balance or movement, cognitive or psychiatric symptoms (problems with thinking or emotion), and changes in behavior.

For some people, chorea can make it harder to walk, which increases the chances of falling. Some people with HD do not develop chorea; instead, they may become rigid (stiff) and move very little or not at all. This condition is called akinesia. Other people may start out with chorea but become rigid as the disease progresses.

In addition to chorea, some individuals have unusual fixed (unchanging) postures, which is known as dystonia. The two movement disorders (akinesia and dystonia) can blend or alternate.

Other symptoms may include tremor (unintentional back-and-forth movement in the person's muscles) and unusual eye movements. The eye movements can happen early in the disease.

Physical changes may include slurred speech and problems with swallowing, eating, speaking, and especially walking. People with HD may lose weight because of problems with feeding, swallowing, choking, and chest infections. Other symptoms may include insomnia (having trouble sleeping), loss of energy, fatigue, and seizures. Eventually the person will need to stay in bed or in a wheelchair.

Changes in thinking (cognitive changes)may include problems with attention or judgment and having difficulty solving problems or making decisions.

Other changes may include trouble with driving, prioritizing (deciding which things are more important to do and which are less important), and organizing, learning new things, remembering a fact, putting thoughts into words, or answering a question.

These cognitive changes get worse as the disease progresses, until people with HD are not able to work, drive, or care for themselves.

When the cognitive problems are severe enough that the person cannot function in daily life, the condition is described as dementia. But many people with HD stay aware of their environment and can express their emotions.

Changes in behavior may include mood swings; feeling irritable (cranky); not being active; or feeling apathetic (uninterested), depressed, or angry. These symptoms may decrease as the disease progresses. But in some people, the symptoms can continue and may include angry outbursts, thoughts of suicide, deep depression, and psychosis (losing touch with reality). People with HD may withdrawal from social activities.

In general, doctors use a combination of tests and other information to see if a person has HD. These include medical history, neurological and lab tests, brain imaging, and genetic testing.

• Neurological exam and medical history—A neurologist will conduct an in-depth interview to obtain a medical and family history for the individual and to rule out other conditions. Neurological and physical exams may review reflexes, balance, movement, muscle tone, hearing, walking, and mental status. Laboratory tests may also be ordered, and individuals with HD may be referred to specialists such as psychiatrists, genetic counselors, clinical neuropsychologists, or speech pathologists for specialized management and/or to support diagnosis.
• Diagnostic imaging—In some cases, especially if a person's family history and genetic testing are inconclusive, the physician may recommend brain imaging, such as computed tomography (CT) or, more likely, magnetic resonance imaging (MRI). As the disease progresses, these scans typically reveal shrinkage in parts of the brain and enlargement of fluid-filled cavities within the brain called ventricles. These changes do not necessarily indicate HD, because they can occur in other disorders. A person can have early symptoms of HD and still have normal findings on a CT or MRI scan.
• Genetic tests—Genetic testing can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. Genetic testing makes it possible to predict with a higher degree of certainty if someone will develop HD. The most effective and accurate method of testing for HD—called the direct genetic test—counts the number of CAG repeats in the HD gene, using DNA taken from a blood sample. The presence of 36 or more repeats supports a diagnosis of HD. A test result of 26 or fewer repeats rules out HD. Prenatal testing is an option for people who have a family history of HD and are concerned about passing the disease to a child.

There is no treatment that can stop or reverse HD, but some of the symptoms can be treated:

• The drugs tetrabenazine and deuterabenazine can treat chorea associated with HD
• Antipsychotic drugs may ease chorea and help to control hallucinations, delusions, and violent outbursts. Some antipsychotic medications can have side effects that make muscle contraction symptoms of HD worse. Individuals using antipsychotic drugs for Huntington's disease symptoms should be closely monitored for side effects.
• Drugs may be prescribed to treat depression and anxiety

Side effects of drugs used to treat the symptoms of HD may include fatigue, sedation, decreased concentration, restlessness, or hyperexcitability. These drugs should be only used when HD symptoms create problems for the person living with HD.

Huntington disease (HD) is progressive, eventually leading to disability and death (usually from a coexisting illness or infection). However, the disease affects everyone differently; the age of onset, specific symptoms, and rate of progression varies for each person with HD.

While the symptoms of HD are well-characterized, their progression (especially in the early and middle stages) remains unpredictable. With the approach of late-stage HD, affected people have speech difficulty and weight loss. In the late stage, affected people lose bowel and bladder control.

The duration of the disease (from onset until death) varies considerably, with an average of approximately 19 years. Most people with HD survive for 10-25 years after the onset of symptoms. The average age at death ranges from 51-57 years, but the range may be broader. In a large study, pneumonia and cardiovascular (heart) disease were the most common primary causes of death.

The length of the CAG repeat (the type of mutation in the HTT gene responsible for HD) is the most important factor that determines age of onset of HD. However, there is still a lot of variability. Both genetic and environmental factors are thought to play a role on the age of onset in people with a mutation. Inheritance through the father can lead to more repeat expansion and earlier onset through succeeding generations, a phenomenon called anticipation.

People with HD, family members, and/or caregivers with specific questions about prognosis should speak with their health care provider.

Researchers are learning more about Huntington's disease over time. Below are some important updates that may improve how doctors care for this disorder in the future.

Understanding Huntington's disease mechanisms

NINDS-funded researchers are trying to better understand the cellular and molecular mechanisms involved in HD by investigating, for instance, how the huntintin protein affects cell signaling and how its altered structure can contribute to disease. The following provides an overview of this research:

• A new avenue of NINDS-supported research is asking whether additional changes to the Huntington gene during development and in adulthood impact disease onset and severity, and whether the Huntington gene affects the brain's overall ability to maintain healthy, undamaged DNA. This work is a promising area for identifying new modifiers of HD onset and progression that may be attractive drug targets.
• Excessive chemical signaling between cells in the brain may lead to chronic overexcitation (overactivation of neurons to turn on), which is toxic to neurons. Several labs are investigating whether drugs that counteract excitotoxicity might help against HD.
• Cutting-edge methods such as optogenetics (where neurons are activated or silenced in the brains of living animals using light beams) are being used to probe the cause and progression of cell circuit defects in HD.

Biomarkers

The NINDS-funded PREDICT-HD study and several international studies are working to identify and validate biomarkers for HD. Biomarkers are biological indicators that can be used to predict, diagnose, or monitor a disease. One goal of PREDICT-HD is to determine if the progression of the disease correlates with changes in brain scan images, or with chemical changes in blood, urine, or cerebrospinal fluid. Another goal is to find measurable changes in personality, mood, and cognition that typically precede the appearance of motor symptoms of HD. A third phase of PredictHD is ongoing.

A related NINDS-supported study aims to identify additional human genetic factors that influence the course of the disease. Finding genetic variants that slow or accelerate the pace of disease progression promises to provide important new targets for disease intervention and therapy.

Stem cells

Through a NINDS-funded consortium, researchers are using cultures of cell lines (created from people with HD who have donated skin and blood samples for research) to understand why neurons malfunction and die in HD, and to rapidly test potential new drugs. Another approach may be to mobilize stem cells that are already there and can move into damaged tissue.

Turning research into treatment

Testing investigational drugs may lead to new treatments and at the same time improve our understanding of the disease process in HD. Classes of drugs being tested include those designed to control symptoms, slow the rate of progression of HD, block the effects of excitotoxins, provide support factors that improve neuronal health, or suppress metabolic defects that contribute to the development and progression of HD.

Several groups of scientists are using gene-editing or specific molecules that can interfere with the production of the Huntingtin protein in cells or animals to stop production of Htt in inappropriate locations or amounts.

Imaging

Scientists are using imaging technology to learn how HD affects the chemical systems of the brain, characterize neurons that have died, view changes in the volume and structures of the brain in people with HD, and to understand how HD affects the functioning of different brain regions.

Brain development

Altered brain development may play an important role in HD. Huntingtin is expressed during embryonic development and throughout life. Studies in animals have shown that the normal HD gene is vital for brain development. Adults who carry the mutant HD gene but have not yet displayed symptoms show measurable changes in the structure of their brain, even up to 20 years before clinical diagnosis.

A NINDS-funded study is evaluating brain structure and function in children, adolescents, and young adults up to age 30 who are at risk for developing the disease because they have a parent or grandparent with HD. This study is trying to capture potential HD effects during the late stages of brain development. Participants who carry the expanded gene will be compared to individuals who carry the gene but have fewer than 9 CAG repeats, as well as to individuals who do not have a history of HD in their family. Changes in brain structure and/or function in the gene-expanded group may point to a developmental component in HD.