Huntington’s Disease: An Overview
Huntington’s Disease (HD), sometimes referred to as Huntington’s chorea, is a largely hereditary neurological disorder. The primary symptom is “chorea,” a hyperkinetic movement disorder presenting as excessive, uncoordinated, and involuntary movement of the body.
The “chorea” is similar to, and therefore often mistaken as, Amyotrophic Lateral Sclerosis (ALS), Parkinson’s Disease (PD), or spinocerebellar ataxia (SCA).
Onset age varies -- on average, symptoms become evident between 30 and 50 years of age, with the exception of its juvenile form, “juvenile HD,” which begins around before 20 years of age.
Sadly, there is still no cure, though treatments exist to help manage symptoms and improve quality of life. Life expectancy following diagnosis is between 15 and 20 years.
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What Are The Symptoms Of Huntington’s Disease?
HD symptoms present as motor (most noticeable), cognitive, and psychiatric symptoms [1, 2, 3]. Mild cognitive and psychiatric symptoms tend to develop in distinct early and middle stages of HD, making an early diagnosis difficult. The canonical motor symptoms generally appear in the later stages of HD.
Motor Symptoms
In Early Stage HD:
- Impaired motor skills -- slight difficulties with fine motor skills, often attributed to other causes.
In Middle and Late Stage HD:
- Dystonia -- involuntary contractions of muscles that often result in repetitive involuntary movements or twisting of limbs or body. In Late Stages, dystonia develops into difficulty speaking, swallowing, and speaking, and results in sleeping disturbances and weight loss.
- Chorea -- the hallmark symptom of HD: slowed eye movements, jerkiness and incoordination of movement, and involuntary or uncontrolled movements. These become more obvious within three years and develop into constant writhing or complete rigidity in Late Stages.
Cognitive Symptoms
In Early Stage HD:
- Impaired judgment and cognitive “rigidity” -- Difficulty focusing on tasks, delayed decision-making, impaired learning or processing new tasks, poor impulse control (action inhibition), and difficulty with planning and abstract thinking.
In Middle and Late Stage HD:
- Full cognitive decline -- Severe memory deficits, which begin with short-term memory, such as where one has left their coffee. Complications with memory eventually evolve into symptoms similar to Alzheimer’s Disease, including faulty procedural memory, such as forgetting how to tie one’s shoelaces, and faulty episodic memory, meaning forgetting memories about life experiences like one’s own wedding.
Psychiatric symptoms:
In Middle and Late Stage HD:
- Anxiety and depression will begin to emerge in Middle Stages, often followed in Late Stages by reduced expression of emotions, aggression, hallucinations, mania, delusion, and obsessive-compulsive disorder. It remains unclear, however, whether the development of these symptoms is caused by the genetic mutation causing HD, or is a byproduct of worsening cognitive and motor symptoms.
- Increased risk of suicide or suicidal behavior (9% of HD fatalities are a result of suicide.)
Other associated symptoms or comorbidities:
- Pneumonia, resulting from difficulties synchronizing movement related to drinking and eating, as well as clearing the lungs, causing a third of all HD fatalities.
- Cardiovascular issues, causing almost a quarter of all HD fatalities.
- Malnutrition, extreme weight-loss and metabolic changes.
- Physical injuries, most commonly from falls.
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What Causes Huntington’s Disease? The Genetics Behind Developing Huntington's.
HD is a genetic disorder, and is mostly hereditary: most cases are inherited from one’s parents genes.
HD is caused by a mutation in the huntingtin gene (HTT), which produces the huntingtin protein (Htt). The HTT gene features a short repeat in nucleotides, which can vary between generations, but once a critical number of repetitions is reached, the htt protein becomes mutated, now called mHtt.
This faulty gene eventually causes symptoms of HD in adulthood and poses risk of inheritance to offspring. HD is an autosomal dominant disease, meaning that offspring with one copy of the mutated HTT gene will develop HD. The inheritance is sex-independent, meaning that the HTT gene does not reside on either X or Y chromosome, and that offspring of an affected parent and a non-affected parent have a 50% chance of developing HD.
Importantly, severity of the disease and risk to offspring varies in a dose-dependent manner: 36 to 39 repetitions of the genetic sequence will result in later onset and slower progression of the disease such that it may not even be detected during life, but still poses a 50% inheritance risk. Forty to 60 repetitions guarantee development of HD, with a 50% inheritance risk, and greater than 60 repetitions can result in “juvenile HD” [3].
Additionally, around 10% of HD cases are caused by spontaneous mutations: random increases in repetitions of the genetic sequence in the HTT gene that have not been inherited from the parents.
What Are The Mechanisms of Huntington’s Disease? The Neuroscience and Biology Behind Worsening HD Symptoms.
On a larger scale, HD first, and most severely, damages neurons, or brain cells, in the basal ganglia, a network of nuclei found within the brain and primarily regulating movement, habit formation, task-learning, emotion, and cognition [3, 4]. The basal ganglia mainly execute their normal brain function via the neurotransmitter dopamine.
Development of HD eventually affects the hippocampus (required in memory), the thalamus (involved in inter-brain region communication), and the cerebellum (controlling instinctive and learned movements). In HD patients, these brain areas all contain the mutant huntingtin protein, mHtt, and are all sites of severe inflammation, cellular dysfunction, and cell death [3].
On a molecular level, the huntingtin (Htt) protein interacts with at least 150 other proteins, which likely contributes to the variety of symptoms and their severity [8, 9]. Some of these interactions include:
- GIT1 - a cell-membrane receptor which localizes to neurons and enhances the synthesis and aggregation of mutant HTT (mHtt) in the brain.
- Caspase - an enzyme crucial for programmed cell death which, when interrupted, can lead cellular toxicity and to eventual cognitive decline.
- Brain-derived neurotrophic factor - a protein that protects neurons and allows the growth and rehabilitation of new neurons in certain tissues.
- Synapsin-1 - a neuronal protein critical for neuronal release of glutamate, which is important for precise motor control and muscle function.
- Reactive oxygen species - Htt indirectly mediates mitochondrial function, which also controls metabolism and delivery of energy to muscular and neural tissue.
What Is The Prevalence Of Huntington’s Disease?
HD is far more prevalent in those with European Ancestry. In Europe and North America, HD prevalence is roughly 7.62 per 100,000 people. However, in Africa and East Asia, prevalence is much lower: 0.25 and 0.41 per 100,000, respectively [10].
While there has been an increase in HD prevalence in the last decade, this is largely attributed to improved genetic testing (read below), longer life-expectancies due to recent medical advances, and possible de novo, or newly arising, spontaneous genetic mutations.
How Is Huntington’s Disease Diagnosed?
HD is a relatively rare disorder, but genetic tests for HD, more-specifically for the mutation of the HTT gene, are quite developed: it is possible to test an embryo between 6 and 18 weeks of the pregnancy. [11]
Diagnostic genetic tests, via blood draw, are also available for those who are at risk for inheritance (whose parents are carriers or are affected by HD). Genetic tests can detect an abnormal number of genetic repetitions with 100% accuracy. [12]
However, since the number of repetitions defines the severity of symptoms in some cases (see above), genetic tests cannot always predict the symptoms with great accuracy.
A “positive” genetic test does not qualify as a diagnosis until symptoms develop, but it does allow for the patient to access genetic counseling and help with decision-making regarding healthcare and life-style choices until symptoms do appear.
How Is Huntington’s Disease Treated?
There is unfortunately no known cure for HD, though patients are often referred to physiotherapy and occupational therapy, to help adapt to changes in daily activities and maintain mobility.
HD patients also often seek psychotherapy to help manage movement and psychiatric symptoms as they develop. Psychiatric symptoms are treated with medications typical for depression, anxiety, etc, as well as antipsychotics for mania and delusions in advanced stages of HD.
Treatment tends to focus on symptom management, and often will transition to palliative hospice care in the final years.
There have only been two major drugs approved from clinical trials for the treatment of chorea in HD so far: tetrabenazine, [13] and its derivative, deutetrabenazine [14]. Both are generally prescribed for hyperkinesia as well.
While some other treatments have made it to Phase II clinical trial, it has so far proven extremely challenging: only one clinical trial, experimenting with surgical delivery of a drug to the basal ganglia in the brain, remains active today [15].
Further, pre-clinical and clinical research studies are currently underway to investigate genetic therapies, specifically targeting the mutated HTT gene and trying to uncover other possible therapeutic strategies.