What is Huntington's disease?

Huntington's disease (HD) is an inherited disorder that causes nerve cells (neurons) in parts of the brain to gradually break down and die. The disease attacks areas of the brain that help to control voluntary (intentional) movement, as well as other areas. People living with HD develop uncontrollable dance-like movements (chorea) and abnormal body postures, as well as problems with behavior, emotion, thinking, and personality.

For example, uncontrolled movements in the person's fingers, feet, face, or torso. These movements are signs of chorea. They can get more intense when the person is nervous or distracted; as HD progresses, the person's movements can become more extreme and obvious.

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 difficulty 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.

Who is more likely to get Huntington's disease?

HD is an inherited disorder. It is passed from parent to child through a mutation (a change) in a particular gene. When a parent has HD, each child has a 50 percent chance of inheriting the copy of chromosome 4 that carries the HD mutation. If a child does not inherit the HD mutation, he or she will not develop the disease and cannot pass it on to future generations. When HD occurs without a family history, it is called sporadic HD.

HD is caused by a mutation in the gene for a protein called huntingtin. The defect causes the building blocks of DNA called cytosine, adenine, and guanine (CAG) to repeat many more times than they normally do.

Most people have fewer than 27 CAG repeats in their HD gene, so they are not at risk for the disease. People who have CAG repeats in the middle range (27 to 35) are not likely to develop the disease, but they could still pass it on to future generations. People with HD may have 36 or more CAG repeats.

Each child of a parent with HD has a 50 percent chance of inheriting the HD gene. A child who does not inherit the HD gene will not develop the disease, and generally, they cannot pass it on to their children or other future generations.

How is Huntington's disease diagnosed and treated?

Diagnosing HD

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 the medical history (including any family history, called a pedigree or genealogy) 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 diagnostic clarification.

• 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 structural 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.

  • An older genetic test, called linkage testing (also called prenatal exclusion testing) requires a sample of DNA from a closely related affected relative, preferably a parent, to identify markers close to the HD gene and to determine if a fetus has inherited a chromosome 4 mutation from an affected grandparent. A version of the linkage method is sometimes used for prenatal testing.

  • Prenatal testing is an option for people who have a family history of HD and are concerned about passing the disease to a child. Prenatal testing can be done using either the direct method or the linkage method. As with adult testing, the direct method provides higher certainty.

Treating HD

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

• 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.

What are the latest updates on Huntington's disease?

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 changes 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 promise 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 that 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 HTT in cells or animals to reduce or eliminate the production of HTT.

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 CAG repeats of 39 or less, 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.