Written in the Code: Exploring Huntingtons Disease
This image was generated using Google Gemini [2]
Learning Outcomes:
By the end of this module students should be able to:
- Identify the type of disease Huntington's is and what the affected cell type is.
- Identify the 3 major categories of Huntington’s symptoms. Name examples for each category.
- Identify what the mutated gene in Huntington’s disease is.
- Identify what the likelihood is that a parent will pass on the disease to a child, if only one or both parents are affected.
- Describe symptom management strategies for Huntington’s disease.
- Summarize current and emerging experimental therapies for HD.
- Explain the neuronal pathways affected in HD and their link to motor symptoms.
- Describe the etiology, pathogenesis, complications/sequelae, prognosis and epidemiology of Huntington’s disease.
- Outline the stages of Huntington's disease.
What is Huntington's Disease and its Genetic Basis
Part 1
What is Huntington's Disease?
Huntington’s disease is a genetic condition caused by a mutation in a single gene. This mutation causes the build-up of an abnormal protein in brain cells. Over time this build up causes the neurons of the central nervous system to degenerate leading to a variety of symptoms that affect movement, cognition and overall mental health [1]. Click on the buttons to the left to dive deeper into Huntington’s disease.
Types of Huntington's Disease
Physical Symptoms of Huntington's Disease
Cognitive and Mental Symptoms of Huntington's Disease
Symptoms in Adult vs Juvenile Huntington's
This image was generated using Google Gemini [2]
Genetic Basis of Huntington's Disease
What is the Affected Gene?
What is the Type of Genetic Disorder?
How does the Mutation Expand?
How is it Diagnosed?
This image was generated using Google Gemini [2]
What is the Gene Affected in Huntington's Disease?
The gene that is affected in Huntington’s disease is the HTT gene on chromosome 4 which provides the genetic instructions for the protein huntingtin[5]. Each person has two copies of this gene, one of which comes from each of your parents. This is an autosomal dominant disorder which means that if you have one affected HTT gene you will develop Huntington’s disease. Let’s take a look at an example of the inheritance pattern. If one of your parents have the affected gene lets call that xHTT and the other has the unaffected gene you would have a 50% chance of getting the disease. See the punnet square to the left where I have highlighted the two affected genotypes in red.
What Type of Genetic Disorder is Huntington's Disease?
- Huntington's is a type of genetic condition that is referred to as a trinucleotide expansion disorder[5].
- A trinucleotide expansion is when a 3 nucleotide block is unstable in the DNA and expands in tandem[6].
- In tandem means that the expanded nucleotide block is directly beside the original block, for example CAGCAG
- In a normal HTT gene there is a CAG segment that is typically between 10-35 repeats long[5].
- The issue of expansion often occurs when DNA replication is occurring, the DNA polymerase slips backwards causing additional repeats to be created[6].
- The extra CAG units are what makes the protein irregular and build up in the neurons[5].
Imagine you are filling up your shopping basket with 30 chocolate bars, as you count and put them in the basket it would be very easy to miscount and add an additional one or two. We see that when in life things are repetitive sometimes it’s difficult to keep track of everything and people and our DNA machinery can makes mistakes.
Check out this diagram for further understanding!
This image was generated using Google Gemini [2]
How Does the Mutation Expand in Huntington's Disease?
- The expansion for Huntington’s disease takes place during spermatogenesis[6].
- This means that a man may be in the anticipatory range which is 27-35 repeats. The men in this range do not have the disorder but are at risk of expanding to 40 which is when the disease occurs[5].
- If a man in the anticipatory range has children there is a high risk of the children getting the disease.
- It is possible for the expansion to occur in oogenesis as well, but this is much less common because the allele is more unstable in spermatogenesis[7].
- The number of repeats an individual has can indicate what type of Huntington’s they will get. Adult-onset is associated with 40-50 repeats and juvenile Huntington’s is associated with more than 60 repeats[5].
Click me to test your knowledge!
Click here for an explanation of the answer
How is Huntington's Disease Diagnosed?
- Huntington’s can be diagnosed by physical, neurological and psychological exams if the person is presenting with Huntington’s like symptoms[3].
- The diagnosis can then be confirmed by a blood test where the length of the CAG repeat is examined in both the maternal and paternal copy of the gene.
- The DNA test may also be used to see if a child has inherited the disease from an affected parent.
- PCR or polymerase chain reaction is a technique used to amplify the section of DNA of interest, in this case the HTT gene[8].
- Once the gene is amplified a gel electrophoresis is ran to determine the length of the gene[8].
This image was generated using Google Gemini [2]
This image was generated using Google Gemini [2]
Click here to understand the test results
How can Huntington's Disease be Managed and Treated?
Part 2
Is there a cure for Huntington's?
Currently, there are no treatments available that can slow down the progression of Huntingtons disease. However, some treatments can help in managaing symptoms [3]. Click through the picture carousel to explore some treatment options, then click the next button to learn more!
These images were generated using Google Gemini [2]
Treating Movement Disorders
Chorea (involuntary jerky movments) can occur as a result of HD [3]. Medications are available to help deal with the symptoms, but these medications cannot change the course of the disease [3]. Click on the medications in the image to the right to learn about different medications to help with movement disorders related to HD and their mechanisms! Click next when you're ready to move on.
This image was generated using Google Gemini [2]
Treating Mental Health Conditions
Mental health conditions like depression and bipolar disorder (BPD) can result from dealing with HD [3]. Medications are available to help deal with the symptoms, but like medications for movement disorders, these cannot change the course of the disease [3]. Click on the treatment options in the image to learn about different medications availabale to help with mental health disorders related to HD and their mechanisms!
This image was generated using Google Gemini [2]
Lifestyle Adaptation Therapies
Click the images to learn more!
This image was generated using Google Gemini [2]
Current Experimental Approaches to Huntington's Disease
Part 3
Current Experimental Approaches
Click on the arrows beside each experimental therapy to learn more!
Stem cell therapies
RNAi therapies
Antisense oligonucleotides (AGOs)
Antibody therapies
Oral splicing modifiers
Future Research Directions
Current directions for ASOs are focused on improving gene splicing methods [13]. Scientists are focused on developing ASOs that are more precise and have less off target effects [13]. For RNAis, the focus is to improve duration of therapy while for small molecules, the aim is to investigate if zinc-finger proteins, or CRISPR can be used to attempt to block or modify the HTT gene [13]. Overall, the future for experimental therpies are highly motivated to develop safer, and more effective treatments to treat HD [13]!
This image was generated using Google Gemini [2]
Neural Pathways Affected by HD
Click on the text below the numbers that highlight the pathways to learn more!
Corticostriatal → Basal Ganglia → Thalamocortical Loop
Cortical Projection Neuron Pathways
Striatal Output Pathways: Indirect First, Then Direct
How can Huntington's Disease be described?
Part 4
Click on the arrows for an indepth exploration of how Huntington's Disease can be described!
Prognosis
Pathogenesis
Epidemiology
Complications/Sequelae
Etiology
Etiology
CAG Trinucleotide Repeat Tract Healthy vs Disease State [19]
Genetic Insults
Click here to compare healthy vs disease state!
The defective htt gene[16] on chromosome 4 codes for the protein Huntington [17, 18]
- The defect causes the building blocks of DNA called cytosine, adenine, and guanine (CAG) to repeat many more times than they normally do [18]
- The gene follows autosomal dominant inheritance with 50% chance of transmission to offspring [3, 19]
- When a parent has HD, each child has a 50% chance of inheriting the copy of chromosome 4 that carries the HD mutation[3, 19].
- If a child does not inherit the HD mutation, he or she will not develop the disease and cannot pass it on to future generations [18]
- When HD occurs without a family history, it is called sporadic HD, this would be considered an acquired form of HD[18].
[6] Created in https://BioRender.com
Etiology
Environmental Insults
Stress was seen to accelerate memory and olfactory deficits and worsen cellular dysfunctions in HD mice [19]
- Experiment:
- Impacts of stress in a mouse model for Huntington's Disease (HD) compared to wildtype (WT) controls [19]
- HD mouse models showed greater sensitivity to stress than WT control mice [19]
- Reasoning:
- Stress increases cortisol (stress hormone) via the HPA axis, which is abnormally elevated in HD[19].
- This can worsen symptoms such as memory deficits, depressive-like behaviour, and olfactory impairment[19].
- HD patients also show abnormal cortisol rhythms, suggesting dysregulated stress responses[19].
- Managing stress (e.g., cognitive therapy or coping strategies) may help slow symptom progression and improve quality of life[19].
Pathogenesis
Sequence of Events in Huntington's Disease Development[16]
Stage One
Stage Two
Stage Five
Stage Three
Stage Four
Click on the arrows beside each stage to learn more!
Pathogenesis
Click on each mechanism to understand how they impact HD!
Contributors to the pathogenic process
This image was generated using Google Gemini [2]
Click on this diagram for further understanding!
Complications/Sequelae
This image was generated using ChatGPT [22]
Prognosis
Anticipated course of disease
- Huntington disease has no cure[21].
- The course of the disease commonly lasts 15 to 20 years[21].
- The CAG repeats provide information on the age of clinical onset and predict the age of death[21].
- The larger the CAG repeat sizes, the greater the rate of deterioration of motor, cognitive, and functional measures[21].
- The progression of behavioral symptoms is unrelated to the size of CAG repeats[21].
Morbidity and Mortality
- The progression of the disease leads to patients who are completely dependent on everyday life, ultimately resulting in full-time care and, finally, death[21].
- Aspiration pneumonia is the most frequent cause of death, which is followed by suicide [21].
Click here to learn more about prevalence!
Epidemiology
Incidence vs Prevalence
- Incidence (# of NEW cases in the population)
- Worldwide incidence of 0.48 cases per 100,000 person-years [23]
- Prevalence (# of TOTAL cases in the population)
- Worldwide prevalence of 2.7 per 100,000 person-years [21]
This image was generated using ChatGPT [22]
Quiz
Part 5
Q1:
[19]
Q2:
[16]
Q3:
[7]
Q4:
[1]
Q5:
[18]
Q6:
[3]
Q7:
[7]
Q8:
[11]
Q9:
[13]
Q10:
[14]
Scan the QR code above to access the references used throughout this learning module.
Thanks For Learning!
We hope this module has been an informative, fun, and interactive experience in learning more about Huntington's Disease!
This image was generated using Google Gemini [2]
As stated in the content it is much more common for the expansion to occur during spermatogenesis. Spermatogenesis is a process that occurs in biological males. There was only one option choice with a male, hence that is the correct answer. Great work!
This image was generated using Google Gemini [2]
Psycotherapy in collaboration with psychiatrists and professional therapists can help people with HD in planning coping statagies to deal with the progressive nature of the disease. These strategies can also be beneficial in family counselling to support HD patients and prepare families in caring for patients with HD [3].
Psychotherapy
This image was generated using Google Gemini [2]
2. Deutetrabenazine (Austedo)
Like Tetrabenazine, Deutetrabenazine is also a VMAT2 inhibitor and mechanistically works in the same way [11]. It largely helps patients with HD manage symptoms associated with chorea and dyskinesia [11]. Deutetrabenazine uses molecules of deuterium instead of the hydrogen used in tetrabenazine, resulting in improved pharmacologicl properties. It is typically initally prescribed in 6mg pills to be taken once a day under the brand name Austedo.
This image was generated using Google Gemini [2]
Axonal Transport Defect
- Mutant huntingtin protein disrupts the system that moves materials along axons in neurons[16].
- Important molecules like BDNF are transported less efficiently between brain regions[16].
- This leads to poor communication between neurons and contributes to neuron death[16].
Neuroglia Dysfunction
- Support cells in the brain, such as astrocytes and microglia, do not function normally in Huntington’s disease[16].
- Astrocytes remove less glutamate, which can overstimulate and damage neurons[16].
- Activated microglia release inflammatory molecules that contribute to neuron damage[16].
- Overall, leading to neuroinflammation[16].
Antibody therapies
Antibody therapies use specifically designed proteins to target the processes involved in HD [13]. For example, instead of lowering HTT directly, they instead aim to reduce inflammation in the brain and protect neurons [13]. Typically these therapies are administered through intravenous infusion and target pathways involved in initiating inflammation [13]. Click the image on the left to learn about ANX005, a type of antibody therapy currently in clinical trials.
This image was generated using Google Gemini [2]
This image was generated using Google Gemini [2]
Stage Three
Late Intermediate Phase [16]
Duration - Continues from 5 to 16 years of disease onset. Functions - Loss of workability, drive, mismanagement of finances, and household chores except eat, dress, and personal hygiene. Symptoms - Worsen of cognitive, psychiatric, and motor features.
Complications of Huntington's Disease
- Prior dystonia and swallowing difficulties can accelerate complications[21].
- Chorea can lead to injury and poor positioning. It can also lead to fractures and head trauma[21].
- Behavioural issues can be severely disabling, causing distress for patient, the family and caregivers[21].
- Cause of death is usually related to complications arising from immobility (eg, pneumonia, cardiac disease, or infection)[21].
- Approximately 25% of the patients attempt suicide[21].
Common antidepressants used to help manage HD symptoms include citalopram, escitalopram, fluoxetine, and sertraline [3]. All of these are SSRIs and work through similar mechanisms [11]. They inhibit the reuptake of seratonin, allowing it to remain in the neural cleft for longer and retain activity without effecting other neurotransmitters [11]. SSRIs can come in many forms (tablets, capsules, liquids) and are typically prescribed to be taken once daily [11]. Common side effects include weight changes, sexual dysfunction or gastrointestinal distress [11].
Antidepressants
This image was generated using Google Gemini [2]
Striatal Output Pathway: Indirect First, Then Direct
The main cells affected in the striatum are spiny neurons which regulate movement through the direct and indirect pathway [14]. The indirect pathway is like a brake to supress unwanted movements. This pathway is typically damaged first resulting in chorea [14]. As HD progresses, the direct pathway, which helps inititate movement also becomes affected [14]. As a result, movement becomes slower and harder to initiate [14]. This leads to characteristic symptoms like ridgidity, bradykinesia, and difficulty with speech [14].
This image was generated using Google Gemini [2]
Stem Cell Therapies (SCTs)
SCTs aim to replace damaged brain cells or support existing neurons in people with HD [13]. Unlike the other approaches, this method works towards protecting existing brain tissue instead of lowering HTT levels. This is typically done through replacing lost neurons and releasing factors to reduce inflamation and help existing cells survive [13]. Some challenges associated with SCTs are the possibility of immune rejections, the uncertainty for long term durability and ethical considerations particulrly with fetal tissue sources [13]. Click the image to learn about one approach of SCT.
This image was generated using Google Gemini [2]
Oral splicing modifiers
These therapies are taken orally which is a big advantage for dosage and controlability [13]. They work by changing how the HTT gene is processed (splicing) [13]. By altering the HTT gene they induce an early stop signal which causes the RNA to be broken down before the HTT protein is made [13]. One limitation of this is that because the drug circulates throughout the body, there are increased systemic effects which can increase the risk for off target side effects [13]. This makes this style of therpy less specifc locationally compared to those injected directly into the brain [13]. Click the image to learn about PTC518.
This image was generated using Google Gemini [2]
[9]
1. Tetrabenazine (Xenazine)
Tetrabenazine is a synaptic vesicular monoamine transporter 2 (VMAT2) inhibitor [11]. It results in reduced amounts of monoamines like seratonin and dopamine in nerve terminals which effectively reduces jerky movemnts in areas like the extremities and face [11]. It is typically perscribed as 12.5 mg under the brand Xenazine [11]. Side effects can include drowsiness, depressions and nausea [11].
This image was generated using Google Gemini [2]
Ubiquitin-Protease System Impairment
- Mutant huntingtin proteins fold incorrectly and accumulate in the cell[21].
- Accumulation of these mutant protein aggregates could lead to an impairment of the ubiquitin-proteosome pathway[21].
- The system that normally removes damaged proteins cannot keep up with the buildup[16].
- These toxic protein clumps disrupt normal cell function[18].
Stage Four
Early Advanced Stage [16]
Duration - Continues from 9 to 21 years of disease onset Functions - Dependent on extended care facility provided by the family. Symptoms - Requires major assistance with basic functions (financial management, domestic responsibilities and living activities).
Physical Symptoms
You may have heard of Huntington’s also referred to as Huntington’s chorea. Chorea refers to the involuntary movements of the body that the disease causes. These involuntary movements are most often seen in the extremities as well as the face and tongue[3]. As you can imagine involuntary movement will impact your regular voluntary movements such as walking. Other physical symptoms include difficulty with speech and swallowing as well as lack of coordination[1].
This image was generated using Google Gemini [2]
Check out a patient with chorea [4]
Cognitive and Mental Symptoms
Huntington’s disease can cause cognitive symptoms. These include lack of impulse control, difficulty processing and focusing on tasks, lack of self-awareness in terms of behaviour and getting hyper focused or stuck on a specific topic or action[3]. Lastly there are also mental health conditions that can accompany Huntington’s disease. The most common one is depression with symptoms including sadness, being withdrawn from social situations, suicidal thoughts, lack of energy and irritability[3]. Other mental health conditions that may arise though less common than depression are OCD, mania and bipolar disorder[3].
Geographical Importance
A higher prevalence of 10.6 to 13.7 per 100,000 is observed among populations of Caucasian descent, whereas it's much lower for Asian and African nations [21]. The prevalence varies among geographical locations by more than 10-fold, with differences largely attributed to ethnic variation in the CAG repeat length [21]. An average CAG repeat length of 18.4 to 18.7 in people of Caucasian descent versus 17.5 to 17.7 in people of East Asian descent [21].
Mood Stabilizers
Common mood stabilizers and anticonvulsants used to help people with HD manage BPD include carbamazepine, and lamotrigine. These drugs work through similar mechanisms. They both supress rapid firing of neurons by prolonging the incactivation of Na+ channels [12]. Carbamazepine is typically prescribed for focal seizures whereas lamotrigine is prescribed for generalized seizures and mood stabalization [12].
This image was generated using Google Gemini [2]
Cortical Projection Neuron Pathways
HD has been shown to affect large pyramidal projection neurons in the deep cortex [14]. These neurons are crucial in sending signals to the striatum [14]. The loss of these neurons results in communication disruptions between the cortex and other pathways [14].
This image was generated using Google Gemini [2]
Stage One
Early Stage [16]
Duration - Continues from 0 to 8 years of disease onset. Functions - Work, drive, handle money, and live independently Symptoms - Mild cognitive symptoms and psychiatric changes.
A mutation of <39 CAG repeats or longer guarantees disease manifestation given a normal lifespan[19].
Huntington's Disease
Lengths below 35 repeats are generally considered non-pathological[19]. Mutations of 36–39 repeats show incomplete penetrance, meaning the patient may or may not develop the disease[19].
Healthy State
VS
This image was generated using Google Gemini [2]
Stage Two
Early Intermediate Phase [16]
Duration - Continues from 3 to 13 years of disease onset.Functions - Functional but lower work capacity. Symptoms - Chorea
Transcriptional Dysregulation
- Mutant huntingtin interferes with proteins that control gene expression in neurons[16].
- This causes important brain genes, such as those that produce BDNF (brain derived neurotrophic factors) that act to promote growth, survival and maintenance of the neurons in the brain, to be turned off[16].
- As a result, neurons lose important survival signals and become more vulnerable to damage[16].
RNA Interference (RNAi) Therapy
This approach uses small RNA molecules called microRNA (miRNA), shorthair RNA (shRNA) and short interference RNA (siRNA) to reduce the amount of harmful HTT protein [13]. These molecues work by guiding the RISC complex within the cell to breakdown specific messenger RNA responsible for coding mutant HTT protein [13]. Typically, RNAi therapies are delivered via viral vectors or injected into the brain for longer lasting effects [13]. The limitation is lack of control, because the induced genetic material can continue to produce RNA molecules over time. There is also concerns over off target effects where the induced RNA may affect unintended genes [13]. Click the image to learn about AMT-130, a type of RNAi in clinical trials.
This image was generated using Google Gemini [2]
Corticostriatal → Basal Ganglia → Thalamocortical Loop
This pathway connects the cortex, striatum, basal ganglia, thalamus, and back to the cortex in a functional loop that controls how movements are initiated and timed [14]. In HD, the damage begins in the striatum which is acts as a filter for the loop [14]. Disruption to this part of the pathway results in trouble starting and stopping movements [14]. Because of this, people with HD might exhibit excessive, reduced, jerky, or poorly timed movements [14].
This image was generated using Google Gemini [2]
Stage Five
Advanced Stage [16]
Duration - Continues between 11 and 26 years from disease onset. Functions - Require support in all events of daily living. Symptoms - Difficulties with swallowing, communication, and weight loss.
Antisense oligonucleotides (ASOs)
ASOs are small single standed RNA molecules that are designed to attach to RNA that codes for the Huntingtin protein (HTT) [13]. This way, they can help trigger the breakdown of the RNA, block the cell from using the RNA to make the protein, or change how the RNA is processed (splicing)[13]. This aims to reduce the amount of harmful HTT responsible for symptoms of HD [13]. In order to reach the brain cells where HTT is made, ASO therapy is delivered into the cerebrospinal fluid using a lumbar puncture [13]. Click the image to learn about the main approaches of ASOs!
This image was generated using Google Gemini [2]
Types of Huntington's
Huntington’s disease is split up into two different categories based on the age when symptoms arise.
There is adult-onset Huntington’s which is when the symptoms start when you are between 30-40. There is also juvenile Huntington’s disease which is when symptoms start to present before 20 years old. Adult-onset Huntington’s is much more common[1].
This image was generated using Google Gemini [2]
Adult vs Juvenile Symptoms
In adults the symptoms described in the previous tabs increase in severity over time. The disease differs in juveniles with their symptoms progressing much quicker and presenting slightly different than adult on-set[3]. Signs in youth would be sudden issues in school, decreased attention span, behavioural changes, tremors, clumsiness and rigid muscles[3].
3. Valbenazine (Ingrezza)
Mechanistically, Valbenazine works through VMAT2 inhibition, the same way Tetrabenazine and Deutetrabenazine do [10]. It helps reduce chorea and tardive dyskinesia which characteristically involves facial tics and uncontrolled tongue rolling movements. This helps patients manage facial movements, and can make speaking and eating easier. Initially, it is prescribed as 40 mg tablets under the brand Ingrezza. Side effects are similar to those of Tetrabenazine.
This image was generated using Google Gemini [2]
PULSE Team #36 - Written in the Code: Exploring Huntingtons Disease
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Transcript
Written in the Code: Exploring Huntingtons Disease
This image was generated using Google Gemini [2]
Learning Outcomes:
By the end of this module students should be able to:
What is Huntington's Disease and its Genetic Basis
Part 1
What is Huntington's Disease?
Huntington’s disease is a genetic condition caused by a mutation in a single gene. This mutation causes the build-up of an abnormal protein in brain cells. Over time this build up causes the neurons of the central nervous system to degenerate leading to a variety of symptoms that affect movement, cognition and overall mental health [1]. Click on the buttons to the left to dive deeper into Huntington’s disease.
Types of Huntington's Disease
Physical Symptoms of Huntington's Disease
Cognitive and Mental Symptoms of Huntington's Disease
Symptoms in Adult vs Juvenile Huntington's
This image was generated using Google Gemini [2]
Genetic Basis of Huntington's Disease
What is the Affected Gene?
What is the Type of Genetic Disorder?
How does the Mutation Expand?
How is it Diagnosed?
This image was generated using Google Gemini [2]
What is the Gene Affected in Huntington's Disease?
The gene that is affected in Huntington’s disease is the HTT gene on chromosome 4 which provides the genetic instructions for the protein huntingtin[5]. Each person has two copies of this gene, one of which comes from each of your parents. This is an autosomal dominant disorder which means that if you have one affected HTT gene you will develop Huntington’s disease. Let’s take a look at an example of the inheritance pattern. If one of your parents have the affected gene lets call that xHTT and the other has the unaffected gene you would have a 50% chance of getting the disease. See the punnet square to the left where I have highlighted the two affected genotypes in red.
What Type of Genetic Disorder is Huntington's Disease?
Imagine you are filling up your shopping basket with 30 chocolate bars, as you count and put them in the basket it would be very easy to miscount and add an additional one or two. We see that when in life things are repetitive sometimes it’s difficult to keep track of everything and people and our DNA machinery can makes mistakes.
Check out this diagram for further understanding!
This image was generated using Google Gemini [2]
How Does the Mutation Expand in Huntington's Disease?
Click me to test your knowledge!
Click here for an explanation of the answer
How is Huntington's Disease Diagnosed?
This image was generated using Google Gemini [2]
This image was generated using Google Gemini [2]
Click here to understand the test results
How can Huntington's Disease be Managed and Treated?
Part 2
Is there a cure for Huntington's?
Currently, there are no treatments available that can slow down the progression of Huntingtons disease. However, some treatments can help in managaing symptoms [3]. Click through the picture carousel to explore some treatment options, then click the next button to learn more!
These images were generated using Google Gemini [2]
Treating Movement Disorders
Chorea (involuntary jerky movments) can occur as a result of HD [3]. Medications are available to help deal with the symptoms, but these medications cannot change the course of the disease [3]. Click on the medications in the image to the right to learn about different medications to help with movement disorders related to HD and their mechanisms! Click next when you're ready to move on.
This image was generated using Google Gemini [2]
Treating Mental Health Conditions
Mental health conditions like depression and bipolar disorder (BPD) can result from dealing with HD [3]. Medications are available to help deal with the symptoms, but like medications for movement disorders, these cannot change the course of the disease [3]. Click on the treatment options in the image to learn about different medications availabale to help with mental health disorders related to HD and their mechanisms!
This image was generated using Google Gemini [2]
Lifestyle Adaptation Therapies
Click the images to learn more!
This image was generated using Google Gemini [2]
Current Experimental Approaches to Huntington's Disease
Part 3
Current Experimental Approaches
Click on the arrows beside each experimental therapy to learn more!
Stem cell therapies
RNAi therapies
Antisense oligonucleotides (AGOs)
Antibody therapies
Oral splicing modifiers
Future Research Directions
Current directions for ASOs are focused on improving gene splicing methods [13]. Scientists are focused on developing ASOs that are more precise and have less off target effects [13]. For RNAis, the focus is to improve duration of therapy while for small molecules, the aim is to investigate if zinc-finger proteins, or CRISPR can be used to attempt to block or modify the HTT gene [13]. Overall, the future for experimental therpies are highly motivated to develop safer, and more effective treatments to treat HD [13]!
This image was generated using Google Gemini [2]
Neural Pathways Affected by HD
Click on the text below the numbers that highlight the pathways to learn more!
Corticostriatal → Basal Ganglia → Thalamocortical Loop
Cortical Projection Neuron Pathways
Striatal Output Pathways: Indirect First, Then Direct
How can Huntington's Disease be described?
Part 4
Click on the arrows for an indepth exploration of how Huntington's Disease can be described!
Prognosis
Pathogenesis
Epidemiology
Complications/Sequelae
Etiology
Etiology
CAG Trinucleotide Repeat Tract Healthy vs Disease State [19]
Genetic Insults
Click here to compare healthy vs disease state!
The defective htt gene[16] on chromosome 4 codes for the protein Huntington [17, 18]
[6] Created in https://BioRender.com
Etiology
Environmental Insults
Stress was seen to accelerate memory and olfactory deficits and worsen cellular dysfunctions in HD mice [19]
Pathogenesis
Sequence of Events in Huntington's Disease Development[16]
Stage One
Stage Two
Stage Five
Stage Three
Stage Four
Click on the arrows beside each stage to learn more!
Pathogenesis
Click on each mechanism to understand how they impact HD!
Contributors to the pathogenic process
This image was generated using Google Gemini [2]
Click on this diagram for further understanding!
Complications/Sequelae
This image was generated using ChatGPT [22]
Prognosis
Anticipated course of disease
Morbidity and Mortality
Click here to learn more about prevalence!
Epidemiology
Incidence vs Prevalence
This image was generated using ChatGPT [22]
Quiz
Part 5
Q1:
[19]
Q2:
[16]
Q3:
[7]
Q4:
[1]
Q5:
[18]
Q6:
[3]
Q7:
[7]
Q8:
[11]
Q9:
[13]
Q10:
[14]
Scan the QR code above to access the references used throughout this learning module.
Thanks For Learning!
We hope this module has been an informative, fun, and interactive experience in learning more about Huntington's Disease!
This image was generated using Google Gemini [2]
As stated in the content it is much more common for the expansion to occur during spermatogenesis. Spermatogenesis is a process that occurs in biological males. There was only one option choice with a male, hence that is the correct answer. Great work!
This image was generated using Google Gemini [2]
Psycotherapy in collaboration with psychiatrists and professional therapists can help people with HD in planning coping statagies to deal with the progressive nature of the disease. These strategies can also be beneficial in family counselling to support HD patients and prepare families in caring for patients with HD [3].
Psychotherapy
This image was generated using Google Gemini [2]
2. Deutetrabenazine (Austedo)
Like Tetrabenazine, Deutetrabenazine is also a VMAT2 inhibitor and mechanistically works in the same way [11]. It largely helps patients with HD manage symptoms associated with chorea and dyskinesia [11]. Deutetrabenazine uses molecules of deuterium instead of the hydrogen used in tetrabenazine, resulting in improved pharmacologicl properties. It is typically initally prescribed in 6mg pills to be taken once a day under the brand name Austedo.
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Axonal Transport Defect
Neuroglia Dysfunction
Antibody therapies
Antibody therapies use specifically designed proteins to target the processes involved in HD [13]. For example, instead of lowering HTT directly, they instead aim to reduce inflammation in the brain and protect neurons [13]. Typically these therapies are administered through intravenous infusion and target pathways involved in initiating inflammation [13]. Click the image on the left to learn about ANX005, a type of antibody therapy currently in clinical trials.
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Stage Three
Late Intermediate Phase [16]
Duration - Continues from 5 to 16 years of disease onset. Functions - Loss of workability, drive, mismanagement of finances, and household chores except eat, dress, and personal hygiene. Symptoms - Worsen of cognitive, psychiatric, and motor features.
Complications of Huntington's Disease
Common antidepressants used to help manage HD symptoms include citalopram, escitalopram, fluoxetine, and sertraline [3]. All of these are SSRIs and work through similar mechanisms [11]. They inhibit the reuptake of seratonin, allowing it to remain in the neural cleft for longer and retain activity without effecting other neurotransmitters [11]. SSRIs can come in many forms (tablets, capsules, liquids) and are typically prescribed to be taken once daily [11]. Common side effects include weight changes, sexual dysfunction or gastrointestinal distress [11].
Antidepressants
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Striatal Output Pathway: Indirect First, Then Direct
The main cells affected in the striatum are spiny neurons which regulate movement through the direct and indirect pathway [14]. The indirect pathway is like a brake to supress unwanted movements. This pathway is typically damaged first resulting in chorea [14]. As HD progresses, the direct pathway, which helps inititate movement also becomes affected [14]. As a result, movement becomes slower and harder to initiate [14]. This leads to characteristic symptoms like ridgidity, bradykinesia, and difficulty with speech [14].
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Stem Cell Therapies (SCTs)
SCTs aim to replace damaged brain cells or support existing neurons in people with HD [13]. Unlike the other approaches, this method works towards protecting existing brain tissue instead of lowering HTT levels. This is typically done through replacing lost neurons and releasing factors to reduce inflamation and help existing cells survive [13]. Some challenges associated with SCTs are the possibility of immune rejections, the uncertainty for long term durability and ethical considerations particulrly with fetal tissue sources [13]. Click the image to learn about one approach of SCT.
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Oral splicing modifiers
These therapies are taken orally which is a big advantage for dosage and controlability [13]. They work by changing how the HTT gene is processed (splicing) [13]. By altering the HTT gene they induce an early stop signal which causes the RNA to be broken down before the HTT protein is made [13]. One limitation of this is that because the drug circulates throughout the body, there are increased systemic effects which can increase the risk for off target side effects [13]. This makes this style of therpy less specifc locationally compared to those injected directly into the brain [13]. Click the image to learn about PTC518.
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[9]
1. Tetrabenazine (Xenazine)
Tetrabenazine is a synaptic vesicular monoamine transporter 2 (VMAT2) inhibitor [11]. It results in reduced amounts of monoamines like seratonin and dopamine in nerve terminals which effectively reduces jerky movemnts in areas like the extremities and face [11]. It is typically perscribed as 12.5 mg under the brand Xenazine [11]. Side effects can include drowsiness, depressions and nausea [11].
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Ubiquitin-Protease System Impairment
Stage Four
Early Advanced Stage [16]
Duration - Continues from 9 to 21 years of disease onset Functions - Dependent on extended care facility provided by the family. Symptoms - Requires major assistance with basic functions (financial management, domestic responsibilities and living activities).
Physical Symptoms
You may have heard of Huntington’s also referred to as Huntington’s chorea. Chorea refers to the involuntary movements of the body that the disease causes. These involuntary movements are most often seen in the extremities as well as the face and tongue[3]. As you can imagine involuntary movement will impact your regular voluntary movements such as walking. Other physical symptoms include difficulty with speech and swallowing as well as lack of coordination[1].
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Check out a patient with chorea [4]
Cognitive and Mental Symptoms
Huntington’s disease can cause cognitive symptoms. These include lack of impulse control, difficulty processing and focusing on tasks, lack of self-awareness in terms of behaviour and getting hyper focused or stuck on a specific topic or action[3]. Lastly there are also mental health conditions that can accompany Huntington’s disease. The most common one is depression with symptoms including sadness, being withdrawn from social situations, suicidal thoughts, lack of energy and irritability[3]. Other mental health conditions that may arise though less common than depression are OCD, mania and bipolar disorder[3].
Geographical Importance
A higher prevalence of 10.6 to 13.7 per 100,000 is observed among populations of Caucasian descent, whereas it's much lower for Asian and African nations [21]. The prevalence varies among geographical locations by more than 10-fold, with differences largely attributed to ethnic variation in the CAG repeat length [21]. An average CAG repeat length of 18.4 to 18.7 in people of Caucasian descent versus 17.5 to 17.7 in people of East Asian descent [21].
Mood Stabilizers
Common mood stabilizers and anticonvulsants used to help people with HD manage BPD include carbamazepine, and lamotrigine. These drugs work through similar mechanisms. They both supress rapid firing of neurons by prolonging the incactivation of Na+ channels [12]. Carbamazepine is typically prescribed for focal seizures whereas lamotrigine is prescribed for generalized seizures and mood stabalization [12].
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Cortical Projection Neuron Pathways
HD has been shown to affect large pyramidal projection neurons in the deep cortex [14]. These neurons are crucial in sending signals to the striatum [14]. The loss of these neurons results in communication disruptions between the cortex and other pathways [14].
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Stage One
Early Stage [16]
Duration - Continues from 0 to 8 years of disease onset. Functions - Work, drive, handle money, and live independently Symptoms - Mild cognitive symptoms and psychiatric changes.
A mutation of <39 CAG repeats or longer guarantees disease manifestation given a normal lifespan[19].
Huntington's Disease
Lengths below 35 repeats are generally considered non-pathological[19]. Mutations of 36–39 repeats show incomplete penetrance, meaning the patient may or may not develop the disease[19].
Healthy State
VS
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Stage Two
Early Intermediate Phase [16]
Duration - Continues from 3 to 13 years of disease onset.Functions - Functional but lower work capacity. Symptoms - Chorea
Transcriptional Dysregulation
RNA Interference (RNAi) Therapy
This approach uses small RNA molecules called microRNA (miRNA), shorthair RNA (shRNA) and short interference RNA (siRNA) to reduce the amount of harmful HTT protein [13]. These molecues work by guiding the RISC complex within the cell to breakdown specific messenger RNA responsible for coding mutant HTT protein [13]. Typically, RNAi therapies are delivered via viral vectors or injected into the brain for longer lasting effects [13]. The limitation is lack of control, because the induced genetic material can continue to produce RNA molecules over time. There is also concerns over off target effects where the induced RNA may affect unintended genes [13]. Click the image to learn about AMT-130, a type of RNAi in clinical trials.
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Corticostriatal → Basal Ganglia → Thalamocortical Loop
This pathway connects the cortex, striatum, basal ganglia, thalamus, and back to the cortex in a functional loop that controls how movements are initiated and timed [14]. In HD, the damage begins in the striatum which is acts as a filter for the loop [14]. Disruption to this part of the pathway results in trouble starting and stopping movements [14]. Because of this, people with HD might exhibit excessive, reduced, jerky, or poorly timed movements [14].
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Stage Five
Advanced Stage [16]
Duration - Continues between 11 and 26 years from disease onset. Functions - Require support in all events of daily living. Symptoms - Difficulties with swallowing, communication, and weight loss.
Antisense oligonucleotides (ASOs)
ASOs are small single standed RNA molecules that are designed to attach to RNA that codes for the Huntingtin protein (HTT) [13]. This way, they can help trigger the breakdown of the RNA, block the cell from using the RNA to make the protein, or change how the RNA is processed (splicing)[13]. This aims to reduce the amount of harmful HTT responsible for symptoms of HD [13]. In order to reach the brain cells where HTT is made, ASO therapy is delivered into the cerebrospinal fluid using a lumbar puncture [13]. Click the image to learn about the main approaches of ASOs!
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Types of Huntington's
Huntington’s disease is split up into two different categories based on the age when symptoms arise.
There is adult-onset Huntington’s which is when the symptoms start when you are between 30-40. There is also juvenile Huntington’s disease which is when symptoms start to present before 20 years old. Adult-onset Huntington’s is much more common[1].
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Adult vs Juvenile Symptoms
In adults the symptoms described in the previous tabs increase in severity over time. The disease differs in juveniles with their symptoms progressing much quicker and presenting slightly different than adult on-set[3]. Signs in youth would be sudden issues in school, decreased attention span, behavioural changes, tremors, clumsiness and rigid muscles[3].
3. Valbenazine (Ingrezza)
Mechanistically, Valbenazine works through VMAT2 inhibition, the same way Tetrabenazine and Deutetrabenazine do [10]. It helps reduce chorea and tardive dyskinesia which characteristically involves facial tics and uncontrolled tongue rolling movements. This helps patients manage facial movements, and can make speaking and eating easier. Initially, it is prescribed as 40 mg tablets under the brand Ingrezza. Side effects are similar to those of Tetrabenazine.
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