Genetics provide path to strategies for managing Huntington’s disease
Huntington’s disease is a fatal genetic disorder that results in the deterioration a person’s physical and mental abilities. It is known as the “quintessential family disease” because every child of a parent with Huntington’s disease has a 50-50 chance of inheriting the HD gene, according to the Huntington’s Disease Society of America (HDSA). There are approximately 41,000 Americans with Huntington’s disease (HD) and more than 200,000 at risk for inheriting the disease.
Patients with HD progress through early, middle and late stages of disease that are characterized by declines in the ability to perform activities of daily living and motor, cognitive, and emotional functioning. Motor symptoms, which are often the first observable sign of the disease, tend to develop between the ages of 30 to 50, but subtle changes may begin much earlier. The disease results in mortality approximately 15-20 years after visible symptoms begin.
Genetic testing can now identify whether someone will develop HD even if they are presymptomatic. In addition, gene-based therapies for the disease are in clinical trials, but current treatments primarily focus on alleviating symptoms, according to Jee Bang, MD, MPH, clinical director of the Johns Hopkins Huntington Disease Center of Excellence and assistant professor of neurology at Johns Hopkins University School of Medicine. Bang spoke with Healio Neurology about how practitioners help patients navigate the social and clinical challenges of HD, as well as the hope that a treatment could eventually modify the progression of the disease.
Question: Is a general neurologist likely to see Huntington’s Disease during their career?
Answer: A general neurologist is not likely to see a patient with HD in their career. It is not an exceedingly rare disease, though; the estimated prevalence is between 5 to 7 patients per 100,000 people. Many HD patients are referred to HD specialty centers, such as the HDSA Centers of Excellence, of which there are 50 throughout the country. They are usually referred by their general practitioners, neurologists or are self-referred.
HD is an autosomal dominant disease, so for each person who has HD, each of their children has a 50% chance of having received the mutant HD gene from that person. Therefore, it has a potentially significant impact on the entire family of the individual being referred. At HD specialty centers, people can receive multidisciplinary care, which often includes genetic counseling, genetic testing, neurological and psychiatric evaluation, and physical, occupational and speech therapies as needed.
Question: What are some of the biggest challenges that patients with this disease face?
Answer: There are three broad categories of symptoms. One category of symptoms affects your movements, such as balance or coordination; it can also cause involuntary movements known as chorea, that make someone appear fidgety, twitchy, or restless. Another category of symptoms in HD includes emotional or behavioral changes. People with HD can also commonly have depression, irritability, anxiety or apathy. The third category of symptoms is cognitive symptoms. It is not like Alzheimer’s disease, where you are forgetful per se; HD mainly affects executive functions, so it affects people’s ability to concentrate, multitask or problem solve.
One person with HD can be very different from the next in regard to their predominant symptom. Even within the same family, it can be very different. A parent’s disease course, for example, does necessarily predict the course for their child. Genetic modifiers and environmental factors can influence and affect how the disease course is going to play out. There is active research exploring what those factors are.
Chorea is common in HD. The disease used to be called Huntington’s chorea, but we do not use that term anymore because we recognize it is not just the movements that are affected. There are often subtle cognitive or emotional changes preceding the motor symptoms by several years. People may also experience changes in their personality, or they might start to have some difficulties at work, especially if the nature of their work changes because they may be not as good at learning new information. Sometimes that can start to unmask the non-motor symptoms that are already brewing before anything visible, like the motor symptoms, becomes more apparent. The cognitive and emotional symptoms can be very impairing; they often cause greater disability than the motor symptoms. People may lose their jobs or have to make significant changes to their usual jobs.
There are a lot of social problems associated with HD as well. Some people become alienated from family or friends because of personality changes, especially if the HD history is not known to either the patient or those around the patient. Even if they are aware of their family history, they might not recognize that those changes may be the start of their HD symptoms. Alienation or estrangement from families and friends may lead to loss of their social support system.
Question: What strategies are available to help patients as they cope with various symptoms?
Answer: There are two common types of motor symptoms: chorea and motor incoordination. Chorea can sometimes be disabling or socially embarrassing for some patients. There are several medications available for chorea treatment. Two of them are specifically FDA-approved for chorea associated with HD. Motor incoordination, including imbalance and bradykinesia, are often more disabling than chorea. Physical therapy is most helpful in treating those symptoms.
For the emotional symptoms, we have a lot of medication options that are used much like we would treat anyone else with depression, irritability or anxiety. Like with anybody else with those symptoms, sometimes it takes several trials or more than one medication until we find the right one. In addition, we have patients work with psychologists or therapists in counseling to help them cope with those symptoms. Social work is a critical part of care for HD; a lot of patients may need help with disability paperwork or getting resources like transportation arranged for them. Family dynamics are also sometimes negatively impacted, so patients may get individual, couples and family counseling.
For cognitive symptoms, there is currently no effective medication. Patients undergo cognitive rehabilitation, which can help them compensate for the cognitive impairment. A more effective therapy is an unmet need.
Question: How has the understanding of the genetics of the disease changed over time?
Answer: The disease was described in 1872 by Dr. George Huntington, but the gene itself was identified in 1993. The disease is caused by the mutant form of the huntingtin protein, formed by the abnormally expanded polyglutamine tract consisting of CAG repeats. If the CAG repeat expansion length is 40 or above, the person with this expansion will develop HD. There are also genetic modifiers that can either hasten or delay the onset of the disease. Increasing huntingtin expression levels have been associated with disease severity and toxicity. In terms of therapeutics, HD is a great model for neurodegenerative diseases and gene-based therapies because it is a single-gene disease.
Based on the recent technology developments, experimental drugs that are targeting the huntingtin mRNA, and therefore decreasing the amount of huntingtin protein production, are in human clinical trials.
Question: How do practitioners use this genetic information?
Answer: People can choose to be tested to see if they have the mutant HD gene. The testing can be done in an adult with no apparent symptoms of HD (presymptomatic testing) or in someone with suspected symptoms of HD for genetic confirmation.
Our role is to provide the person and their family members with genetic counseling before they undergo the genetic testing, because the result can impact the whole family and not just the individual at risk for HD. We discuss the basic genetic background of the disease and its autosomal dominant inheritance pattern. Social and family issues are discussed in line with the individual’s motivation for testing, as well as their goals and priorities.
We are at a major turning point in HD research, which is the development of gene-based therapy. Anti-sense oligonucleotides, or ASOs, are one type of huntingtin-lowering drugs in clinical trials now. These synthetically made molecules can be specifically designed to target the huntingtin mRNA and take advantage of the natural cellular degradation mechanism, leading to decreased production of the huntingtin protein. ASOs are delivered intrathecally. RNA interference, or RNAi, is another type of huntingtin-lowering drug. It is also designed to target the mRNA and lead to decreased production of the huntingtin protein. In contrast to ASOs, it is delivered directly into the brain tissue via a minimally invasive neurosurgical procedure. This drug is also in a clinical trial right now. These drugs have the potential to be disease-modifying, which is why the HD community is excited; we are working diligently with cautious optimism. There are many other drug targets in preclinical development as well, some of which are close to beginning human trials.
Question: What are the greatest unmet needs in the treatment of HD?
Answer: Treatment of cognitive symptoms is one. To date, no medications or strategies are clearly effective. Another area of unmet need is managing some of the emotional symptoms like apathy. While we have relatively effective treatments for depression, anxiety and irritability, apathy is tougher to treat. The impact of apathy on social dynamics and quality of life is significant, especially if the person does not recognize that they are apathetic. It can be really hard on the family as well.
When it comes to unmet needs regarding therapeutics, it is important to remember later-stage patients. A lot of the excitement surrounding the newer therapies is focused on patients with early symptoms, and it is important that we follow that population so we can look for noticeable changes. It becomes harder to tease out what the drug is doing in patients who are pre-symptomatic or, conversely, experiencing advanced symptoms. Continued comprehensive attention and multidisciplinary care for later-stage patients is not really an unmet need, necessarily, but we need to make sure we do not neglect them. I do not think this is happening, but we need to always keep them in mind and strive to help them as much as other patients.
While the HD community has always been hopeful, the potential disease-modifying therapies give more legitimacy to that hope. Our colleagues working with spinal muscular atrophy recently had successful ASO trials that led to the FDA approval of the drug. But we recognize that HD and SMA are two different diseases; we need to remain cautious and vigilant as we continue to search for HD treatments that will hopefully lead to significant benefits for patients with HD.
Huntington’s Disease Society of America. Overview of Huntington’s disease. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/. Accessed Nov. 2, 2020.
Huntington’s Disease Society of America. Huntington’s disease stages. https://hdsa.org/what-is-hd/huntingtons-disease-stages/. Accessed Nov. 2, 2020.
Huntington’s Disease Society of America. Age of onset. https://hdsa.org/what-is-hd/age-of-onset/. Accessed Nov. 2, 2020.
Huntington’s Disease Society of America. Juvenile onset HD. https://hdsa.org/what-is-hd/history-and-genetics-of-huntingtons-disease/juvenile-onset-hd/. Accessed Nov. 2, 2020.
NIH Genetics Home Reference. Huntington disease. https://ghr.nlm.nih.gov/condition/huntington-disease. Accessed Nov. 2, 2020.