Huntington Disease: 5 Things to Know

Huntington disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. It is caused by a genetic mutation affecting the HTT gene, leading to production of a toxic form of the huntingtin protein. Symptoms typically manifest between 30 and 50 years, although onset can occur at any age. Motor symptoms include involuntary movements, rigidity, and impaired coordination. Cognitive impairments often involve difficulties with planning, organizing, and decision-making; psychiatric symptoms can include depression, anxiety, and irritability.

Currently, there is no cure for HD, and treatment focuses on managing symptoms and providing supportive care. Healthcare providers play a crucial role in diagnosing HD through genetic testing, monitoring disease progression, and offering multidisciplinary care to improve quality of life for patients and their families. Genetic counseling is also essential for at-risk individuals and family members to understand inheritance patterns and make informed decisions about testing and family planning.

Here are five things to know about HD.

1. Diagnosing HD involves a combination of clinical assessment and genetic testing.

HD is caused by a mutation in the HTT gene. This mutation follows an autosomal dominant inheritance pattern, meaning that a child of an affected parent has a 50% chance of inheriting the mutated gene and developing the disease. Clinical evaluation focuses on identifying motor symptoms, such as involuntary movements, rigidity, and impaired coordination, as well as cognitive impairment and psychiatric symptoms that include depression, anxiety, and irritability. Neurologic, neuropsychological, and psychiatric assessments are often used to evaluate these symptoms.

Genetic testing for HD can be performed using blood samples or saliva samples to identify the presence of the mutated HTT gene. Presymptomatic individuals who seek predictive testing for HD on the basis of known family history should undergo counseling before genetic testing. Individuals who are symptomatic for HD and thus seek confirmatory genetic testing also may benefit from genetic counseling. Testing is not recommended for people younger than 18 years unless symptoms consistent with HD are present. A positive genetic test confirms the diagnosis of HD; a negative test indicates that an individual has not inherited the mutated gene and will not develop the disease. Early diagnosis through genetic testing allows for better management of symptoms and planning of care.

2. HD is a progressive neurodegenerative disorder that evolves through distinct stages, each marked by specific symptoms and signs.

In the initial stages of HD, individuals may experience deficits in short-term memory, followed by motor dysfunction such as involuntary movements known as chorea. Cognitive changes also are prominent, with diminished verbal fluency, problems with attention and executive dysfunction, and challenges in visuospatial processing and abstract reasoning. Early behavioral changes may include irritability, untidiness, and loss of interest in previously enjoyed activities.

As the disease advances, cognitive slowing and intellectual impairment become more pronounced, accompanied by progressive memory disturbances. The chorea that is characteristic of early HD may coexist with, and eventually be replaced by, dystonia and parkinsonian features such as bradykinesia (slowness of movement), rigidity, and postural instability. This transition is crucial for nonspecialists to recognize, especially those who may encounter HD patients with advanced disease nearing the end of life. In the most advanced stages of HD, individuals may develop akinetic rigid syndrome, characterized by minimal or no chorea, severe rigidity, and bradykinesia. This syndrome can also manifest in juvenile-onset HD, indicating the severity and variability of the disease across different age groups.

3. HD presents unique challenges and considerations for individuals who are pregnant or planning to conceive.

Given the autosomal dominant inheritance pattern of HD, there is a 50% chance that an affected parent will pass the mutated gene on to their child. As a result, many individuals at risk for HD may consider prenatal testing or preimplantation genetic testing to assess the genetic status of the fetus or embryo. Prenatal testing involves procedures such as chorionic villus sampling or amniocentesis to obtain fetal cells for genetic analysis. These tests can provide information about whether the fetus has inherited the mutated HTT gene associated with HD. Preimplantation genetic testing, on the other hand, allows for the screening of embryos created through in vitro fertilization to select those without the HD mutation before implantation. For individuals with HD who are using donated eggs, sperm, or embryos, it is essential to ensure that the donor does not carry the mutated gene to prevent transmission of HD to the child.

Balance issues and chorea associated with HD can pose risks during pregnancy, potentially leading to falls or injuries that could harm both the mother and the fetus. Judgment issues and cognitive impairments may also result in behaviors that are dangerous to the fetus, such as alcohol or substance use during pregnancy.

The progressive nature of HD raises concerns about the individual's ability to participate in pregnancy and parenting as the disease advances. As symptoms worsen over time, individuals may experience increasing difficulties with motor function, cognition, and emotional regulation, possibly affecting their capacity to care for a child effectively. Therefore, comprehensive preconception counseling and multidisciplinary care are crucial for individuals with HD to make informed decisions about family planning and to support them throughout pregnancy and parenting.

4. In people with HD, quality of life is significantly affected by a range of motor, cognitive, and psychiatric symptoms.

Chorea, the hallmark motor symptom of HD, is characterized by involuntary movements. Chorea can be not only physically debilitating but also socially stigmatizing and emotionally distressing. It can interfere with daily activities, communication, and independence, thereby affecting overall well-being and quality of life.

Psychiatric symptoms are also prevalent in HD and can have a profound impact on quality of life. Depression is a common psychiatric complication, and selective serotonin reuptake inhibitors are often considered first-line treatment. Other antidepressants such as bupropion, venlafaxine, mirtazapine, and tricyclic antidepressants also may be used. In severe cases, electroconvulsive therapy can be considered. Anxiety and impulsivity are other psychiatric symptoms that can contribute to decreased quality of life and may require pharmacological and behavioral interventions. Individuals with HD have a suicide risk that is several times higher than that of the general population; therefore, it is crucial to monitor for symptoms of depression or suicidal ideation and to treat them aggressively if they develop.

Hallucinations, delusions, and schizophrenia-like syndromes can occur in HD, necessitating the use of antipsychotic medications. Newer antipsychotic agents are preferred because they are associated with a lower incidence of extrapyramidal adverse effects and a decreased risk for tardive syndromes.

Maintaining daily functioning and independence is essential for preserving quality of life in HD. Home-based exercise programs, physical therapy, and occupational therapy can help manage motor symptoms, improve mobility, and enhance overall well-being. Individuals with HD often experience speech and swallowing difficulties, and both speech therapy and diet modifications can be beneficial in addressing these symptoms and improving overall quality of life. These interventions not only address physical limitations but also promote self-esteem, social engagement, and a sense of purpose, thereby contributing to a better quality of life for individuals with HD.

5. Treatment and management of HD aims to manage symptoms, improve quality of life, and support caregivers.

A multidisciplinary approach involving neurology, psychiatry, social work, physical therapy, neuropsychology, and supportive care is often necessary to address the complex and varied manifestations of HD. For agitation and behavioral disturbances in HD, pharmacologic interventions such as benzodiazepines, antipsychotics, and antiepileptics may be prescribed. These medications can help control irritability, aggression, and impulsivity, which are common psychiatric symptoms in HD. However, careful monitoring is required owing to the risk for adverse effects, including sedation, cognitive impairment, and extrapyramidal symptoms.

Chorea can be managed with several medications. Tetrabenazine works by inhibiting vesicular monoamine transporter 2 (VMAT2), reducing dopamine release and thereby mitigating chorea. It has demonstrated efficacy in reducing chorea and has been used for many years in the treatment of HD. Deutetrabenazine was approved in 2017 and offers a longer duration of action and potentially fewer adverse effects compared with tetrabenazine. Valbenazine, another VMAT2 inhibitor, gained approval for the treatment of chorea associated with HD in August 2023, following positive results from the KINECT-HD trial.

Bradykinesia, or slowness of movement, can be managed with levodopa or dopamine agonists, commonly used treatments for Parkinson disease. These medications aim to enhance dopamine function in the brain, improving motor symptoms such as rigidity, bradykinesia, and postural instability.

The cognitive symptoms of HD can be effectively managed through a multifaceted approach. It is essential to reduce sedating medications that may exacerbate cognitive impairment and to structure the environment to support the patient's cognitive function. Neuropsychological testing can help assess deficits and suggest tailored strategies to counteract them, optimizing cognitive abilities.

Social work support is crucial for assisting with disability applications, securing long-term placement options, and providing ongoing family support. Counseling services are invaluable for both the patient and their family to cope with role changes and the progressive nature of the disease. Additionally, psychiatric support plays a vital role in addressing any associated mental health challenges.

Emerging therapies for HD offer promising avenues for more targeted and potentially disease-modifying treatments. Gene silencing aims to reduce the production of the mutant huntingtin protein responsible for HD through RNA interference or antisense oligonucleotide technology. This approach has shown promise in preclinical and early-phase clinical trials, raising hopes for slowing or halting disease progression.

Gene editing technologies such as CRISPR/Cas9 offer the possibility of correcting the genetic mutation responsible for HD, although these approaches are still in the experimental stages and face significant challenges related to specificity, delivery, and safety.

Stem cell therapy holds potential for replacing damaged neurons and restoring normal brain function in HD. These studies are in the early stages of development.

Neuroprotective therapies aim to preserve neuronal function and prevent further neurodegeneration in HD. These therapies target various cellular pathways involved in disease progression, including oxidative stress, mitochondrial dysfunction, and inflammation. Although neuroprotective strategies have yet to demonstrate definitive efficacy in clinical trials, ongoing research continues to explore promising agents and approaches.

The management of HD requires a comprehensive and individualized approach, tailored to the specific needs and symptoms of each patient. Current treatments focus on symptom relief and supportive care, with emerging therapies offering hope for more targeted and disease-modifying interventions in the future. Collaboration between healthcare providers, researchers, and patients and their families is essential to optimize care, enhance quality of life, and advance understanding and treatment of this devastating neurodegenerative disorder.