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What is Huntington’s disease?

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormality in a gene located on the 4th of our 23 chromosomes that codes for an essential protein called “huntingtin.”  This protein is present in almost all cells in the body but abnormalities in this gene and its protein cause the greatest damage in cells in the brain. 

Though HD is considered a relatively rare disorder, more than 40,000 people in North America have HD, and another 200,000 or more are considered “at risk” for inheriting the illness because they have (or had) a parent or sibling with HD. Not everyone has a clear family history of HD. Some individuals also have spontaneous mutations. Most of those impacted by the illness will develop symptoms in middle adult life, but about 10% will have onset prior to age 20 (juvenile HD) and another 20% after age 60. Men and women are equally likely to inherit the gene and develop the illness. HD can occur in people of all ethnic groups, but is more common among those of European descent.

What Are the Characteristics of HD?

Onset is usually in mid-life, but symptoms can occur any time from childhood to old age. The initial signs of this disorder may be subtle. HD is characterized by slowly progressive changes in the control of movements and is often associated with excessive involuntary movements referred to as chorea.  In addition to movement issues, there are often behavioral changes and cognitive disturbances which can occur before, at the same time or after the onset of outward signs of HD. Signs and symptoms vary from person to person. For instance, one person with HD may have a very obvious movement disorder, but only mild psychiatric symptoms and intellectual deterioration, while another individual might suffer with depression, anxiety, or progressive cognitive symptoms for years before showing any abnormal movements.

The Genetics of HD

HD is an autosomal dominant disorder.  This means that if one parent has or had HD then each of their children independently have a 50% chance of inheriting the disorder.  Though it was known even in the late 1800’s that HD was an autosomal disorder, it was not until 1993 that the gene causing HD was identified.  This delay in identifying the cause was in part due to HD being caused by a different type of genetic defect than most previously described genetic disorders.  HD is caused by a phenomenon called a trinucleotide repeat expansion. Nucleotides are molecules that are the building blocks of DNA.  Each series of three nucleotides codes for a different amino acid.  Chains of amino acids make the proteins that our bodies are made of and that control the function of our cells. In the case of HD, the three nucleotides that are repeated are cytosine (C), adenine (A), and guanine (G), referred to as CAG repeats. HD is referred to as a “CAG trinucleotide repeat disorder.” CAG sequences in the DNA code for the amino acid glutamine.  Because of the gene’s CAG duplications, also called repeats or expansions, there are an excessive number of glutamines in the proteins produced by the expanded huntingtin gene. 

Since 1993, it has become possible to test whether an individual has the genetic expansion that causes HD by doing a blood test, a test of saliva, or swab of the inner cheek. Those with CAG repeat sizes below 26 are not at risk for getting HD. Those who have a repeat size between 27-35 are considered to have an intermediate range expansion. They are unlikely to develop HD themselves. However, the number of CAG repeats may increase in subsequent generations, especially when it is inherited from the father. If the number of repeats increase, the children of an individual within the intermediate range may inherit a higher number of repeats and develop HD. People with repeats greater than 36 are considered gene positive and at risk for developing HD symptoms. There is a general correlation of CAG repeat size and the age of symptom onset. The higher the repeat size, the younger the age of symptom onset. However, there is much variability in age of onset even between individuals with the exact same repeat size. We do not know for certain why this variability happens, but recent results of studies looking at all genes (genome wide gene sequencing) have identified some differences in genes that may influence the disease process and contribute to this variability. These findings have the potential to provide us with further insight into developing future treatments to delay or prevent HD onset.  The Huntington Study Group is currently collaborating on investigating these and other issues that may affect age of symptom onset in clinical trials involving at-risk individuals. If you would like to learn more about some of the clinical trials and observational studies we have in progress, click here.

More About the Movement Disorder in HD

A person with HD typically develops involuntary movements, that initially may just seem like fidgetiness or a nervous restlessness, but that usually evolve into movements that can be difficult to control. These movements are often flowing, dance-like movements referred to as chorea. The individual may not be aware that they are moving. Sometimes the movements are more rapid and appear to be tic-like or sudden jerks. Children and teenagers with HD, as well as those in the later stages of the illness, may have slow, stiff movements with abnormal or fixed postures.

More About the Cognitive Disorder in HD

HD causes difficulties in mental flexibility, so it may become hard for the person with HD to switch quickly from one mental task to another. It may become difficult to learn new information or to remember things. However, a person with HD can usually recognize previously-learned information when it is presented to them. Cognitive changes can cause difficulties in the workplace and home before other symptoms of HD become evident. Though problems with memory occur in HD, these usually occur later in the disease course. The pattern of memory decline in HD is different than in dementias such as Alzheimer’s disease and current medications used to treat Alzheimer’s disease are not beneficial for those with HD.

More About the Psychiatric Disorder in HD

Many of the psychiatric aspects of HD can be improved using currently available medications used to treat mood and behavioral disorders. Depression and anxiety are common in HD and may precede the onset of other signs and symptoms of the illness. Severe depression may even lead to suicidal thoughts and attempts. Since depression and anxiety are also common in the general population, it can be difficult to tell whether these symptoms really represent the onset of HD in a person who is at-risk. Other psychiatric difficulties seen in some people with HD include obsessiveness, irritability, impulsiveness, social withdrawal, apathy, and trouble initiating activity. A few individuals with HD may have aggressive outbursts or even psychosis (hallucinations or delusions).

A Brief History of Huntington’s Disease

Wexler, Alice & Wild, Edward & Tabrizi, Sarah. (2016). George Huntington: A legacy of inquiry, empathy and hope. Brain. 139. aww165. 10.1093/brain/aww165.

Though the disease has long been present in humans throughout the world and had been described briefly in several medical scientific reports over the years, the clearest and most detailed description in English was reported by George Huntington from Pomeroy, Ohio in 1872 and published in in the Medical and Surgical Reporter based on his observations of generations of residents observed while he was living on Long Island, NY.  

At the 1972 Centennial Symposium on Huntington’s Disease held in Columbus, Ohio, a description of cases in a remote area in Venezuela with a high incidence of HD was presented.  Out of this meeting a collaborative research effort to study this population was developed, the Huntington’s Disease Collaborative Research Group that included founding investigators Alice Wexler, David Houseman and James Gusella. However, it was not until 1983 that the HD genetic defect was localized to chromosome 4 through the efforts of this consortium of clinicians and scientists. Finally, in 1993, a collaborative group of investigators were able to identify the exact gene where a CAG trinucleotide expansion leads to HD and now referred to as the “huntingtin gene.” As a result of this discovery, it is now possible to perform predictive testing or confirm HD in individuals with blood or tissue samples. However, despite much effort we still do not have a complete understanding of all the functions of the normal HD gene nor all the ways the expanded gene disrupts cell function. We do not yet have a proven treatment to cure or slow disease progression. However, our HSG teams have been instrumental in getting the first three FDA medications approved for the treatment of chorea in HD. There is an immense ongoing international effort including members of the HSG, foundations, pharmaceutical industries, and academic centers around the world to better understand the nature of this disorder and to identify treatments for symptoms, to slow the progression of the disorder and hopefully to prevent the disease from even starting. 

Important Information About HD Genetic Testing

It is important to understand that while people are born with the mutated gene for HD, in most cases they will not develop the symptoms until later in life. In other words, someone can be without symptoms for years or decades. Genetic tests for HD can be used to confirm the presence of the huntingtin gene expansion in individuals suspected of showing symptoms of HD, to confirm the diagnosis. Testing can be used in individuals who are at risk for HD to predict whether they have the gene expansion and will develop symptoms of HD in the future. In specialized labs, we can even test embryos for the gene prior to use in invitro fertilization to guarantee that their child will not carry the HD gene expansion. People who are at risk may want to undergo predictive testing to put their minds at ease, to plan for their medical needs, or prior to having children. The decision to have such a test is a serious one and should not be taken lightly. Most experienced clinics that do predictive testing require genetic counseling before and after the test.

The Course of HD

Although HD is a progressive illness, the rate of progression varies from person to person even among members of the same family. Many people with HD are able to live independently or with only minor assistance for many years. However, HD eventually causes physical and mental disability requiring significant assistance at home or in a care facility. Once an individual develops signs of HD, the course of the disease can last anywhere from ten to thirty years. Observational studies following large numbers of individuals over time are critical to help us understand the different manifestations and time courses of disease progression. Some of these studies include PHAROS, Cohort-HD, Predict-HD, TRACK-HD, REGISTRY, and the 10+ (and growing) years of the ENROLL-HD study. Traditionally the course of HD has been roughly divided into three clinical stages:

Early Stage

In this stage individuals can still perform most of their usual daily activities. They may still be working and may still be able to drive. Involuntary movements are mild and infrequent, speech is still clear, and cognitive difficulties, if noticeable at all, are mild.

Middle Stage

At this stage, individuals are more disabled and may need assistance with some of their activities of daily living. It is at this stage that modifications and accommodations may be needed at places of employment. An individual will eventually no longer be able to work or drive. Falls, weight loss, and swallowing difficulties may become a problem. Thinking and memory difficulties are more obvious to the casual observer. Involuntary movements usually become more pronounced.

Late Stage

Individuals entering this stage of the disease require increasing supervision and assistance and eventually almost total care. They may no longer be able to walk or speak full sentences. They may become more stiff and rigid or show fewer involuntary movements. Individuals in late stage may not be able to swallow food. Some people and their families choose to have feeding tubes placed. When the individual passes away, the cause of death is usually related to malnutrition, pneumonia, or heart failure.

More recently, a new staging system, referred to as the HD Integrated Staging System (HD-ISS), has been developed for research purposes to better help in the development of new and earlier diagnostic and treatment interventions.

Stage 0

Individuals with positive genetic test results for HD but with no clinical symptoms of the disease and before any changes can be seen in research biomarkers.

Stage 1

Individuals with no clinically obvious symptoms of the disease but in whom markers such as subtle changes on brain morphometrics imaging measures using carefully controlled and validated research assessments are identified.

Stage 2

Individuals who have begun to show clinical signs of the HD phenotype using validated clinical/research tools for the assessment of specific aspects of neuropsychiatric cognitive tests and/or clinically documented abnormalities on specific measures of motor function.

Stage 3

Individuals who have begun to show decline on specific research tools used to measure overall function and independence.

What Treatments Are Available?

Treatments for HD can be divided into two categories: those that are aimed at treating the symptoms of the illness (such as depression or chorea) and those that slow down the underlying progression of the illness or preventing the disorder from causing disease symptoms. Effective medications are currently available to improve the mood and behavioral symptoms of HD. There are currently three medications that are FDA approved to help treat the chorea associated with HD (tetrabenazine, deutetrabenazine, valbenazine).  The HSG team was instrumental in helping to get all three of these medications approved.  Although there are currently no treatments proven to slow down disease progression or to delay its onset, there are clinical trials and observational studies in progress which aim to identify such treatments.

 

Medications currently indicated for other conditions may be prescribed by a physician to treat symptoms of HD. These medications should be used with caution in a person with HD. Although the medication was tested and FDA-approved for a specific condition, it is unlikely the effect and possible side effects were systematically studied in HD.

 

A person with HD may respond differently to medications in different stages of the illness, so medication lists should be periodically reviewed. In general, an approach which starts medications at a low dose and increases slowly as needed works best. Ideally, medications should be given under the supervision of a physician experienced in the care of patients with HD. A person with HD may have difficulty taking medications on a schedule, so it is a good idea to keep the schedule as simple as possible and to use pill boxes or direct supervision by a care provider as necessary. As the disease progresses, the need for each medication should be reevaluated.