Huntington's Disease

What Causes Huntington’s Disease?

Huntington’s disease is caused by an abnormal variation (a mutation) in a specific gene that controls the production of a protein called huntingtin. Scientists don’t know precisely what huntingtin does, but it appears to play an essential role in the function of the brain’s nerve cells.

The huntingtin gene contains a linked string of the compounds cytosine, adenine, and guanine. The three compounds are chained together in a pattern referred to as a CAG trinucleotide repeat. In a normal huntingtin gene, the CAG sequence repeats 10-35 times. In a Huntington’s disease patient, the gene contains 36-120 or more CAG repeats.

The abnormal CAG chain results in the production of an abnormal form of the huntingtin protein. The body’s cells then process the abnormal protein into toxic compounds that bind to the brain’s nerve cells and impair their function. As the toxic compounds build up in the brain, the impairment grows worse, and the nerve cells eventually die. The loss of functional nerve cells produces the symptoms of the disease.

Is Huntington’s Disease Hereditary?

Huntington’s disease is almost always inherited when a parent with the mutated huntingtin gene passes the gene on to their child. The condition is passed on in an autosomal dominant pattern, meaning that the child needs only to inherit the gene from one parent to develop the disease. This is in contrast to an autosomal recessive pattern, in which the disease won’t develop unless the child inherits the gene from both parents.

Huntington’s disease usually develops when the huntingtin gene carries 40 or more CAG repeats. When the gene has 36-39 repetitions, the disease might not develop. However, the length of the CAG chain increases as the gene is passed from parent to child. That means that a parent with 36-39 CAG repeats might not have the disease, but their child’s gene might have enough CAG repeats to trigger the disease. Even parents with 27-35 CAG repeats pass on the risk of developing the disease to their children.

The length of the CAG repeat chain also influences the timing of the onset of the disease. People with 40-50 repeats typically have the adult-onset form, while those with 60 or more repetitions are more likely to develop the juvenile form.

How Is Huntington’s Disease Detected?

Huntington’s disease can be challenging to detect in its early stages because symptoms may be subtle or look like some other disorder symptoms. However, early detection is essential because some of the disease’s complications can be serious, even early on. For example, patients are at higher risk of suicide, most likely because of disease-associated depression, in the early stages, often before diagnosis.

Early signs of Huntington’s disease include:

• Depression
• Irritability
• Problems with balance or coordination
• Small involuntary muscle movements
• Mental fogginess

How Is Huntington’s Disease Diagnosed?

Suppose your doctor suspects Huntington’s disease may be the cause of your symptoms. In that case, the diagnostic process will typically move through a series of steps designed to rule out other possible causes. A physical exam and a medical history will be the first step, followed by expanded testing, often with the involvement of a neurologist, that includes:

• Neurological exam. This exam tests neurological functions such as balance, coordination, reflexes, muscle strength, muscle tone, and sensory perception. Other exams may test areas such as memory, reasoning, and cognitive function.
• Psychological testing. These tests will look for symptoms in the areas of mood and behavior. A psychiatrist will often administer these tests.
• Imaging. Magnetic resonance imaging (MRI) or computerized tomography (CT) may examine brain structure and function. These tests may be able to spot brain activity characteristics particular to Huntington’s disease, or they may be used to rule out other potential disorders.
• Genetic testing. This test looks for the presence of the mutated huntingtin gene. The test may be utilized to confirm the diagnosis of Huntington’s disease, but because it has no bearing on treatment, it is not always performed.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Huntington’s Disease Treated?

There is no cure for Huntington’s disease, and no treatment will reverse its symptoms. Medications are commonly used to control symptoms; however, various non-drug therapies can help the sufferer maintain daily functioning as long as possible.

Medications

Drugs used to treat Huntington’s disease symptoms include:

• Treatments for movement problems. Tetrabenazine can be used to control involuntary movements, but it may worsen symptoms such as depression. Amantadine, levetiracetam, and clonazepam are effective for movement symptoms, but they may worsen cognitive symptoms or have other side effects. Antipsychotics such as haloperidol and chlorpromazine are sometimes used, but they, too, can have significant side effects.
• Antidepressants. Citalopram, escitalopram, fluoxetine, and sertraline are often used to treat depression, OCD, and other psychological disorders.
• Antipsychotics. Quetiapine, risperidone, and olanzapine may be used to treat agitation and other more severe behavioral disorders.
• Mood stabilizers. Valproate, carbamazepine, and lamotrigine may be used to treat the symptoms of bipolar disorder.

Other Therapies

Non-drug therapies used to treat the symptoms and complications of Huntington’s disease include:

• Speech therapy
• Physical therapy
• Occupational Therapy
• Psychotherapy

How Does Huntington’s Disease Progress?

Huntington’s disease symptoms get worse over time, and treatment will not stop the progression of the disease. Eventually, the sufferer will be unable to walk or speak and will require constant care.

Death usually comes as a result of complications or circumstances arising as a result of the symptoms. Common causes of death include:

• Pneumonia
• Heart failure
• Infections
• Injuries from falls
• Choking or complications from being unable to swallow

How Is Huntington’s Disease Prevented?

There is no way to prevent Huntington’s disease in someone who has the genetic predisposition to develop the disease. Genetic testing can detect the mutated huntingtin gene’s presence, but identifying the gene will not affect whether or not the disease develops. If you think that you may be at risk, a genetic counselor can help you assess whether testing is right for you.

People with a family history of Huntington’s disease may be at risk of passing the condition on to their children, even if they are not showing symptoms of the disease. Again, a genetic counselor can help potential parents assess the risk and evaluate their options.

Huntington’s Disease Caregiver Tips

Caring for someone with Huntington’s disease takes a toll on the caregiver. As the disease progresses, caregiving responsibilities become greater and greater, and caregivers must be sure to take care of themselves, too. If you’re caring for a loved one with the disease, remember these tips:

• Avoid isolation. The symptoms of Huntington’s disease often encourage sufferers to withdraw from family and social interactions. Isolation, however, can make psychological symptoms even worse. Help your loved one stay engaged with the broader world as much as possible.
• Know when to get help. The caregiving demands of Huntington’s disease are immense, and they grow more significant as the disease progresses. Ask your medical providers for recommendations for support groups or agencies that can help you find assistance when you need it.
• Don’t hide from the disease. Huntington’s disease has ramifications for the sufferer and family members who must come to terms with the risk to themselves and their children. Coping with questions about the disease can be easier with the support of professionals and peers in your situation. Ask your medical provider for a list of resources in your area, or find help online.

Many people with Huntington’s disease (HD) also suffer from other brain and mental health-related issues, a situation called co-morbidity. Here are a few of the disorders commonly associated with HD:

• About a third of people with HD also suffer from depression or an anxiety disorder.
• People with HD are at increased risk of suicidal behavior.
• HD has been associated with obsessive-compulsive behaviors.
• Alcohol abuse is sometimes associated with HD.

Huntington’s Disease Brain Science

Although scientists at least partially understand how genetic mutations trigger the development of Huntington’s disease, a thorough understanding of how the huntingtin protein affects the brain remains elusive. Research projects aim to figure out the biochemical and neurological mechanisms at play in both normal brains and the brains of Huntington’s disease patients.

Active areas of research include:

• Optogenetics. In this field of study, scientists genetically engineer brain cells to be sensitive to light. The researchers can then use light to activate and deactivate the brain cells, allowing them to study neurological circuitry activity more effectively. This approach could help scientists better understand how huntingtin proteins make cells behave differently in healthy and unhealthy brains.
• Biomarker identification. Earlier detection of Huntington’s disease could help scientists understand how the disease progresses, leading to better treatments. For that reason, some research is looking at the disease’s biomarkers, measurable indicators that indicate the condition in its early stages (or even before it develops). For example, one recent project developed a test designed to detect mutant huntingtin protein in patients’ blood.

Huntington’s Disease Research

Title: Preparing for Prevention of Huntington’s Disease (PREVENT-HD) (PREVENT-HD)

Stage: Not Yet Recruiting

Contact: Jane S. Paulsen, PhD

University of Wisconsin, Madison

Madison, WI 

This is a prospective investigation that aims to address critical challenges to the design of clinical trials to prevent the onset of Huntington’s disease (HD). The project will provide necessary psychometric data for clinical outcome assessments (COAs) and biomarkers (BMs) in the cerebral spinal fluid (CSF) to address questions of central importance to the success of these measures for premanifest clinical trials. Of the 258 participants: 52 will be low risk of motor diagnosis, 102 high risk of motor diagnosis, 52 with diagnosed HD (stages I or II), and 52 healthy controls. Participants can expect to be on study for up to 2 years.

Title: Neurobiological Predictors of Huntington’s Disease (PREDICT-HD) (PREDICT-HD)

Stage: Recruiting

Principal investigator: Jane S Paulsen, PhD

University of Iowa

Iowa City, IA 

Huntington’s Disease (HD) is an inherited disease that causes changes in a person’s ability to control movements, thinking, and feelings. This study intends to learn more about the beginning changes in thinking skills, emotional regulation, and brain structure and function as a person begins the transition from health to HD.

Preliminary studies indicate that people with HD may have marked decline before an actual diagnosis. This study will reveal the earliest indicators of the disease and what factors influence the age at which a person carrying the gene develops the condition. It is necessary to get information on HD’s early stages to develop drugs that can slow or postpone HD’s onset. The investigators hope this study will provide essential information for future trials of experimental drugs for HD.

During this study, participants will undergo several detailed tests, including MRI scans of the brain, cognitive assessments, physical exams, biospecimen (blood, urine, cerebral spinal fluid) collection, and neurological and psychiatric testing.

Title: Child to Adult Neurodevelopment in Gene Expanded Huntington’s Disease (ChANGE HD)

Stage: Recruiting

Principal investigator:  Peggy C Nopoulos, MD

University of Iowa

Iowa City, IA

Huntington’s Disease (HD) is an autosomal dominant disease manifested in a triad of cognitive, psychiatric, and motor signs and symptoms. HD is caused by a triplet repeat (CAG)expansion in the gene Huntingtin (HTT). This disease has classically been conceptualized as a neurodegenerative disease. However, recent evidence suggests that abnormal brain development may play an important role in HD’s etiology. Huntingtin (HTT) is expressed during development and through life. In animal studies, the HTT gene is vital for brain development. This suggests that a mutant form of HTT (gene-expanded or CAG repeats of 40 and above) would affect normal brain development. In addition, studies in adults who are gene-expanded for HD but have not yet manifested the illness (pre-HD subjects) have significant changes in the structure of their brain, even up to 20 years before the onset of clinical diagnosis. How far back these changes are evident is unknown. One possibility is that these brain changes are present throughout life due to changes in brain development, though initially associated with only subtle functional abnormalities.

To better understand the developmental aspects of this brain disease, the current study proposes to evaluate brain structure and function in children, adolescents, and young adults (ages 6-30) who are at risk for developing HD – those who have a parent or grandparent with HD. Brain structure will be evaluated using Magnetic Resonance Imaging (MRI) with quantitative measures of the entire brain, cerebral cortex, as well as white matter integrity via Diffusion Tensor Imaging. Brain function will be assessed by cognitive tests, behavioral assessment, and physical and neurologic evaluation. Subjects that are gene-expanded (GE) will be compared to subjects who are gene non-expanded (GNE). Changes in brain structure and/or function in the GE group compared to the GNE group would support the notion that this disease has a significant developmental component.