Huntington’s Disease (HD)

Written By Isabel M Antony

Disease Overview

Huntington’s Disease (HD) is a rare autosomal dominant progressive degenerative disorder named after George Huntington, an American physician. In other words, this disease is inherited and targets nerve cells or neurons in different parts of the brain which control voluntary movement like the basal ganglia. According to the National Institute of Neurological Disorders and Stroke, people suffering from this disease display uncontrolled movement like chorea, abnormal and fixed body posture, as well as cognitive problems. The symptoms of the disease usually appear in middle aged people and rarely in children.

Epidemiology

HD is a rare disease that is prevalent in around 2-10 people in a group of 100,000 people. The main symptoms of the disease appear at around the age of 30-50. Additionally, HD can be found equally in both genders. However there appears to be an effect depending on which gender of parent the mutation was inherited from. If the gene is inherited by the paternal line, then the disease appears earlier in the child as to the maternal line. (Sharma, 2023)

Penetration of Autosomal Dominant Gene

Huntington’s disease is caused by the elongation of CAG repeats on chromosome 4 in the HTT gene. This discovery was found by Dr. Wexler who is a professor of neuropsychology at the College of Physicians in Columbia University. The particular gene that is penetrated by HD, codes for the HTT protein, which plays a role in synaptic function and post embryonic period. WHile is is typical for a person to have CAG repeats, having 40 or more repeats indicates the presence of HD. The CAG length is an important factor for the progression of the disease especially when considering cognitive, motor, and neurological disturbances.As the gene is passed down the mutation manifests the disease with greater severity at an earlier age. This common phenomenon in HD is known as Genetic Anticipation. This phenomenon appears in the paternal line of inheritance, which is caused by the instability of CAG repeats in spermatogenesis. Spermatogenesis is a process in which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. Furthermore, it is important to visualize HD as being an expansion rather than a mutation.

Clinical Presentation of HD

As mentioned in the overview, HD’s symptoms encompass both motor and non motor manifestations. The main motor manifestations include:

Chorea:

Chorea is a movement disorder resulting from problems in the basal Ganglia nerve structure which in effect causes involuntary movement of hands, feet, and face (WebMD Editorial Contributors, Medically reviewed by Christopher Melinosky). It is believed that Chorea is caused when the Basal Ganglia receives too much dopamine, a chemical which plays an important role in nerve function. While most cases in Chorea are curable, in Huntington’s it is incurable and leads to death.

Parkinsonism:

Parkinsonism in HD can manifest as bradykinesia, rigidity, tremors, and postural instability. Bradykinesia refers to the slowness of movement and can make simple tasks much more time consuming and strenuous. Rigidity leads to the stiffness in muscle movement, making smooth muscle movement for those affected difficult. Tremors involve involuntary skating and trembling in certain body parts like the fingers.Lastly postural instability leads to a decrease in coordination causing many falls.

Imbalances:

As mentioned in the other two symptoms above, imbalances are caused by gradual degeneration of neurons in the Basal Ganglia, particularly the striatum. The striatum plays a crucial role in coordinating movements by receiving and processing signals from other parts of the brain. As the neurons degenerate, the communication within the basal ganglia circuitry is disrupted. In Huntington's disease, there is an imbalance of dopamine, with an initial increase followed by a decline as the disease progresses. This imbalance contributes to the motor symptoms seen in HD, including instability and imbalance.The basal ganglia receives input from various parts of the brain, including the cortex. In Huntington's disease, there is a breakdown in the cortico-striatal pathways, which are essential for coordinating voluntary movements.

Dysphagia:

Dysphagia is difficulty and or discomfort in swallowing. The automatic coordination of bringing food to the mouth, chewing, forming a bolus and swallowing, while simultaneously inhibiting breathing, breaks down. Food may spill from the mouth. People with HD may inadequately chew foods, and commonly add more mouthfuls of food before swallowing. Poor coordination may lead to frequent choking on liquids and on solid food. Aspiration of liquids or food may lead to pneumonia or even to death by choking (Huntington’s Disease Society of America).

Other:

Other symptoms which revolve round motor controlled functions include but are not limited to dystonia, myoclus, and tics. All of these symptoms result in uncontrolled movement and imbalances which are caused by high levels of dopamine in the Basal Ganglia.

The non motor manifestations include:

Cognitive Impairment:

The cognitive impairments which come with Huntington’s disease include Executive Dysfunction, memory impairment, difficulty in attention and concentration, struggle to shift between cognitive tasks, and difficulties in language and communication. Executive dysfunction is when Individuals with HD experience difficulties with executive functions, which include planning, organizing, initiating, and monitoring goal-directed behaviors. Memory deficits can occur, especially affecting working memory and short-term memory.

Psychiatric Manifestations:

One of the main manifestations in HD is depression. This causes individuals to experience persistent sadness, loss of interest, and lack of appetite. Individuals may also experience high levels of anxiety causing excessive worry, restlessness, and irritability.

Agitation:

Agitation is mainly caused by other symptoms in HD which include disruption of neural circuits in the Basal Ganglia, anxiety, cognitive decline, chorea, and pain. Agitation refers to a state of restlessness, nervousness, or heightened activity that can be disruptive and challenging for both the affected individual and their caregivers. Individuals may experience heightened emotional responses to stimuli, leading to restlessness. As HD progresses, cognitive functions decline, and individuals may have difficulty understanding their surroundings or communicating their needs. Frustration arising from these challenges can manifest as agitation. Furthermore, these symptoms have caused high rates of suicide in individuals affected by HD.

Psychosis:

Psychosis refers to a state in which an individual experiences a loss of contact with reality, leading to distortions in thoughts, perceptions, and behaviors. Psychotic symptoms can occur in individuals with Huntington's disease (HD), adding to the complexity of the clinical presentation. It's important to note that not all individuals with HD will experience psychosis, and when it does occur, it often manifests in the later stages of the disease.

Apathy:

Apathy is a common behavioral symptom in Huntington's disease (HD). Apathy refers to a lack of motivation, interest, or initiative in activities that were previously enjoyable or necessary. It can significantly impact the quality of life for individuals with HD and add to the burden of the disease. Living with a progressive and debilitating disease can be emotionally challenging. Apathy may be influenced by feelings of helplessness, hopelessness, or frustration related to the impact of HD on one's life.

Weight Loss:

Weight loss is a common symptom in Huntington's disease (HD), a genetic neurodegenerative disorder. The progressive nature of HD, along with various factors associated with the disease, can contribute to changes in weight. The neurobiological changes in HD affect various aspects of metabolism. There may be disruptions in energy balance and metabolic processes, contributing to weight loss. The hypermetabolic state associated with HD, along with increased movement and restlessness, can result in an elevated energy expenditure. This can contribute to weight loss if the individual is not able to compensate by consuming enough calories.

Treatment for HD

As per the National Institute of Neurological Disorders and Stroke, while there's no cure for Huntington's disease (HD), certain symptoms can be managed. Tetrabenazine and deutetrabenazine are medications effective in treating HD-associated chorea. Antipsychotic drugs can also help alleviate chorea and manage hallucinations, delusions, and aggressive episodes. However, some antipsychotics may worsen muscle contraction symptoms. Individuals using these drugs for HD symptoms need careful monitoring due to potential side effects. Additionally, medications may be prescribed for addressing depression and anxiety. It's important to note that these drugs may cause side effects such as fatigue, sedation, decreased concentration, restlessness, or hyperexcitability. They should only be utilized when HD symptoms significantly impact the individual's well-being.

HD Imaging

While all methods capable of structural brain imaging reveal morphological changes in Huntington's disease, MRI is the preferred choice due to its superior spatial and contrast resolution. Regarding MRI findings, the most notable feature is caudate head atrophy, and there is also significant putaminal volume loss, especially in younger patients, which may not be easily discernible through visual inspection but is well observed through morphometry. This combination results in the enlargement of frontal horns, often giving them a distinctive "box-like" configuration.

As for PET imaging, it showcases hypometabolism evidenced by decreased FDG uptake in the basal ganglia and frontal cortex, even before noticeable caudate nucleus volume loss becomes apparent.

Bibliography

“Huntington’s Disease.” Alzheimer’s Disease and Dementia, www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/huntington-s-disease. Accessed 25 Dec. 2023.

“Huntington’s Disease.” National Institute of Neurological Disorders and Stroke, U.S. Department of Health and Human Services, www.ninds.nih.gov/health-information/disorders/huntingtons-disease#:~:text=What%20is%20Huntington’s%20disease%3F,as%20well%20as%20other%20areas. Accessed 25 Dec. 2023.

Pringsheim T;Wiltshire K;Day L;Dykeman J;Steeves T;Jette N; “The Incidence and Prevalence of Huntington’s Disease: A Systematic Review and Meta-Analysis.” Movement Disorders : Official Journal of the Movement Disorder Society, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/22692795/#:~:text=The%20worldwide%20service%2Dbased%20prevalence,CI%3A%204.42%2D7.35. Accessed 25 Dec. 2023.

Sharma, Rohit. “Huntington Disease: Radiology Reference Article.” Radiopaedia, Radiopaedia.org, 10 Dec. 2023, radiopaedia.org/articles/huntington-disease#:~:text=Huntington%20disease%20(HD)%2C%20also,and%20putamen%20(dorsal%20striatum).

“Chorea: The Causes, Symptoms, and Treatments.” WebMD, WebMD, www.webmd.com/brain/what-to-know-chorea. Accessed 25 Dec. 2023.