Category: Huntington’s Disease

Introduction

Three of the world’s most concerning psychological disorders are Huntington’s disease, schizophrenia, and dissociative identity disorder (DID). Over ten million adults in the United States are affected by a severe mental illness. The difficulty people must face to cope with the effects along with the recovery of one of these diseases is a constant battle. Today, the concept of recovery for these patients is a determined mindset with international concord. The notion of recovery is “a commitment to the principle that people should be helped to live their lives to the fullest extent possible within the limitations of their illness” (Kirby). The people that are affected by a mental illness go against their own mind invariably. The character Bertha Mason in Jane Eyre is a perfect exemplar of someone who is dealing with a mental illness. She displays similar side effects and emotions to a more severe disease. Jane Eyre by Charlotte Bronte was first published in 1847 and is about an orphan named Jane Eyre, who grows up longing for love, independence, and has a passion for life. She lives with her aunt and cousins at Gateshead Hall. After years of being awfully mistreated, she is sent to Lowood Institution. After spending six years at Lowood, Jane finds a job as a governess at Thornfield Hall, where she meets her employer: Edward Rochester. Jane gradually falls in love with Rochester, but he is put to the standard of marrying the socially eminent Blanche Ingram. Eventually, Rochester declares his love for Jane. He proposes to get married. On the wedding day, Jane finds out they cannot be legally married because Rochester is already married to Bertha Mason, who is mentally unstable and locked away for becoming a flight risk to herself and others. When Rochester brought Jane to see who Bertha Mason truly was, Jane witnessed how, “the lunatic grappled (Mr. Rochester’s) throat viciously and laid her teeth to his cheek. They struggled. She was a big woman […] more than once did she almost throttle him” (Bronte). After her encounter with Bertha Mason, Jane leaves Thornfield and Rochester for the Moor House, where she finds her cousins, whom she never knew about. Jane lives at Moor House for a year until she receives an alluring call from Rochester and returns to Thornfield. Jane comes back to the entire estate burned down, set on fire by Bertha, who jumped to her death shortly after. Rochester became blind as a result of his attempt at saving Bertha. In the end, Jane and Rochester marry and have a son. From lighting Rochester’s bed on fire to eventually committing suicide, it is evident that Bertha Mason has serious psychiatric issues. After finishing Jane Eyre by Charlotte Bronte, an essential question is what mental disorder drove Bertha Mason to the brink of insanity.

Schizophrenia

A possible diagnosis for Bertha Mason would be schizophrenia. She displayed similar side effects and emotions to the mental disorder throughout the entirety of the book. Schizophrenia completely affects a person’s personality. The way a person thinks, feels, and behaves, almost every dynamic is altered when affected by Schizophrenia. It is described as “ a severe psychological disorder that touches every aspect of a person’s life. It is characterized by disturbances in thought and language, perception and attention […]” (Rathus 536). People with Schizophrenia develop an aberrant form of reality through hallucinations, delusions, and other symptoms. There are positive and negative symptoms that occur when one has this mental disorder. A positive symptom adds a behavior caused by the disorder, while a negative symptom takes away a behavior. “The positive symptoms of schizophrenia may include delusions, hallucinations, and disorganized speech, thoughts, beliefs, movements, and behaviors” (Izenberg 298). A few negative symptoms that would take away from the behaviors would be reduced speaking and general happiness in everyday life, loss of interest in social activities, and lack of personal hygiene. Delusions are a common attribute that occurs in most people who are diagnosed with schizophrenia. They are false beliefs or actions that are not actually occurring in reality. One would believe that they are being harmed or harassed or that someone was following them. Hallucinations also highly occur in people who have schizophrenia. A hallucination is a false perception, where a person will see, hear, smell, or feel something or someone who in reality, is not there. There are some serious cognitive symptoms that could occur in a person with schizophrenia as well. It depends on whether or not the cognitive symptoms would be subtle or severe, but they do occur. Some people could even have trouble with their memory. An example of a cognitive symptom would be the inability to understand or make decisions based on the information given to them. Another example would be that someone would have difficulty applying or using information directly after acquiring the disease. One significant part about the the mental illness, schizophrenia, is the risks along with the causes of the mental illness. “The word schizophrenia means a splitting of the mind. […] Physicians do not know the exact cause of schizophrenia” (Thompson n.p). The main cause of this disease is genetics. Schizophrenia has been proven that it does genetically run throughout families, but there are also cases where the patient did not have a family member affected with this illness. So, genetics is not the sole factor of the cause of schizophrenia. Other factors that could have a potential impact on this brain disorder would be environment and brain chemistry. Scientists came up with the theory that it is not just one gene that causes schizophrenia but several genes along with the specific interactions between those genes. With a patient’s brain chemistry, they could have an imbalance of compound reactions associated with neurotransmitters. A neurotransmitter is a chemical messenger that sends signals to other neurons. The neurotransmitters that are affected when dealing with schizophrenia are dopamine, glutamate, and a few others. There are also environmental factors that can cause the disorder as well. Some of these factors would be an exposure to specific viruses or a pregnancy or birth complication. Infants exposed to malnutrition or toxins could lead to an altered brain development. Also, the brain goes through adjustments when undergoing puberty, causing schizophrenia to begin in more drastic ways. There is no way to prevent this specific mental disorder, and since there are multiple factors for the cause of schizophrenia, scientists cannot confirm a specific cure for the mental disease. It is also known that “symptoms of schizophrenia usually start between ages 16 and 30” (National Institute of Mental Health). On the other hand, there are treatments for patients with schizophrenia. People with this mental disorder are obligated to require lifelong treatment. To manage this disorder, a person would need to use medications as well as therapy from a psychiatrist to manage the symptoms. One major medicinal treatment would be antipsychotics, which are a daily pill taken by the patient or an injection every other month. At first, the psychiatrist will try to maintain the symptoms with the lowest dose and continue increasing until the right amount is administered to lessen the symptoms. Some antidepressants or antianxiety pills will be distributed for further help for the overall end result. There are serious side effects to taking antipsychotics, therefore some patients will refuse to take the medication and will most likely receive an injection instead of a pill as treatment. After obtaining a medication that effectively works, a patient would then turn to psychosocial treatment. These treatments would include individual, social, or family therapy. These therapies help patients with completing everyday tasks, such as attending school and work. People with schizophrenia are less likely to be hospitalized or have recurring symptoms if they participate in these different therapies. There is also coordinated specialty care (CSC), that involves medication, therapy, employment, along with family and social situations that are all aimed toward lessening symptoms and increasing the condition of each patients’ lifestyle. There are support groups that help people affected by schizophrenia to maintain their self care and employment while maintaining their symptoms. Throughout the book, Jane Eyre, Bertha Mason displays very similar symptoms to schizophrenia. When Jane Eyre first encounters Bertha Mason, Jane explains her experience by saying, “Mr. Rochester flung me behind him; the lunatic (Bertha) sprung and grappled his throat viciously and laid her teeth to his cheek. They struggled. She was a big woman. […] more than once she almost throttled him” (Bronte 343). Schizophrenia is a valid mental illness that drove Bertha Mason to insanity.

Huntington’s Disease

Another possible diagnosis for Bertha Mason would be Huntington’s disease, which is the degeneration of specific brain cells in different parts of the brain. This disease is described as “A fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain. It deteriorates a person’s physical and mental abilities during their prime working years […]” (What is Huntington’s Disease). People with this mental disease deal with uncontrollable choreatic movements, violent behaviors, and dementia. Huntington’s disease is a rare neuropsychiatric condition, because it is an autosomal dominant hereditary disease. “Only about 5 out of 100,000 people develop Huntington’s disease, because it is transmitted from parent to child, only children of a parent who has the abnormal gene are at risk, and they have a 50 percent chance of developing the disease” (Izenberg 456). This disease affects everything in a person’s life, from not only speaking to swallowing/walking, but even everyday actions. There are many symptoms that can cause someone who is affected to have a very hard time getting a job or to be out in public. The main symptoms are mood swings, depression, memory, decision making, and unwanted movements. Along with the symptoms, it is shown that “most people with Huntington’s disease develop signs and symptoms in their 30’s or 40’s” (Huntington’s Disease). Although most symptoms begin to show during one’s midlife, it is also possible for them to start from anytime in childhood to old age. Once a person is diagnosed with Huntington’s disease, the disease continuously damages nerve cells in the brain that eventually lead to fatal outcomes. Some symptoms can occur earlier than other symptoms, and the mood changes are involuntary. Dystonia is known as the first unpredicted movement symptom in a patient with Huntington’s Disease. Dystonia is when one struggles with spontaneous muscle contractions that cause repeated and spiral movements. Weight loss is another major symptom that occurs throughout all stages of this illness. Along with multiple symptoms, there are a variety of treatments. Although there are no cures for Huntington’s Disease, the treatments vary depending on the specific symptoms the patient is experiencing. “There is a medicine to control the erratic movements caused by the disease. This medicine blocks the production of dopamine in the brain” (Izenberg 457). Doctors will start out with a drug called olanzapine or tetrabenazine, where they help conceal the effects of chorea. With patients who have a more threatening or violent behavior, doctors give them an atypical antipsychotic drug. With patients who experience compulsive actions and judgement, they would receive Selective serotonin reuptake inhibitors (SSRIs). SSRIs are a combination of antidepressants and anxiety medicine. Including multiple treatments that help control the effects of Huntington’s Disease, most patients will go through multiple therapy sessions such as speech therapy, occupational therapy, and nutritional support therapy. With the causes of Huntington’s Disease, men and women are equally likely to acquire the specific disruptive gene. This disease does not skip generations, so the only way to receive the gene is if one of your parents has it as well. The mutation of the gene HTT is the only way to get the mental disease, and in the end Huntington’s Disease is a severe mental illness that causes people to suffer with intense symptoms eventually, leading to death. In the book, Jane Eyre, Bertha mason expresses the same thoughts and actions as those with Huntington’s Disease. When Mr. Rochester was justifying his actions of hiding Bertha, he explained that “Bertha Mason is mad; and she came of a mad family – idiots and maniacs through three generations!” (Bronte 340). At this point in the novel, it is presented how Bertha Mason’s mental illness occurred throughout several generations of her family, which is the main cause of Huntington’s Disease. Therefore, Huntington’s Disease is a highly possible cause of Bertha Mason’s insanity.

Dissociative Identity Disorder

A third possible mental disorder that Bertha could have had is Dissociative Identity Disorder (DID). Dissociation is when a person experiences disconnection between thoughts or memories, and most people have encountered a mild type of dissociation. An example of dissociation would be daydreaming or “zoning out” while working on a project, which is considered to be a common factor. Dissociative Identity Disorder is a mental illness that is a more severe form of dissociation. Dissociative Identity Disorder is when a person cannot differ between reality and imaginary situations while experiencing multiple personalities. Spencer Rathus, a psychologist, explains that Dissociative Identity Disorder is when “two or more identities or personalities, each with distinct traits and memories, ‘occupy’ the same person” (Rathus 528). The type of symptoms a person will have is based on the specific type of Dissociative Disorder. There are three types of Dissociative Disorders:

Depersonalization-derealization disorder, Dissociative identity disorder, and Dissociative amnesia. Depersonalization-derealization disorder is when a person is having a sense of detachment from their own body, and they are experiencing unreality from their own mind. During these altered realities, people know that it is not happening, but the experience distresses them. If someone is going through an episode of Depersonalization-derealization disorder, they usually display little emotion and inertia. The second type of a Dissociation Disorder is Dissociative identity disorder. This type of disorder is when a person struggles with two or more personalities, where one cannot recall the other personality. Patients explain that they feel that they have another entity inside of them. People with Dissociative Identity Disorder have chronic memory gaps causing problems in their everyday lives. The multiple personalities in this disorder is described as “the identities of people […] can be very different from one another. They might even have different eyeglass prescriptions” (Rathus 529). The third type of a Dissociative Disorder is Dissociative Amnesia, where a person is incapable of remembering information about themselves. This disorder could not be viewed as forgetfulness. People with Dissociative Amnesia are unable to remember recent memories, going all the way to forgetting their name or childhood. All of these Dissociative Disorders have similar experiences, any patient with this disorder could have not only one but all of them. The cause of these disorders is usually due to traumatic events that were so overwhelming that the patient “blocked” their own thoughts and memory. Patients could also experience traumatic flashbacks to these events and become violent and unsafe toward others. The most common symptoms of all these disorders are amnesia (memory loss) of specific events or information about themselves, a deceived perception of reality, stress, and depression. With the likelihood of a person having this disorder, it is explained that “it’s estimated that 2% of people experience dissociative disorders, with women being more likely than men to be diagnosed. Almost half of adults in the United States experience at least one depersonalization/derealization episode in their lives, with only 2% meeting the full criteria for chronic episodes” (Multiple Personality Disorder). The treatment for this mental disorder would be a series of medications such as antidepressants as well as management of going through psychotherapies. Psychotherapy is when the patient diagnosed with the disorder will have the opportunity to talk about their condition and obtain help throughout the battle with their own mind. In Jane Eyre, Bertha Mason could potentially have Dissociative Identity Disorder with her sudden change in personalities and moods throughout the book. Mr. Rochester explained Bertha’s appearance and personality by saying, “Compare these clear eyes with the red balls yonder––this face with that mask––this form with that bulk […]” (Bronte 343). He describes how Bertha is constantly changing with her feelings and state of mind. Dissociative Identity Disorder could be a valid mental illness that led Bertha Mason to insanity.

Final thoughts

All three of these life-altering psychological disorders consist of their own horrendous effects on a person’s thoughts and actions. Between hallucinating with Schizophrenia, experiencing multiple personalities with Dissociative Identity Disorder, and involuntarily moving/thinking with Huntington’s Disease, all of these mental illnesses could qualify as a valid diagnosis for Bertha Mason. She has shown at least one symptom of each of these disorders, but the one disease she mostly resembled throughout the book is Huntington’s Disease. Not only has Bertha displayed the symptoms of Huntington’s Disease, but it was stated in the book that generations of her family members had the illness. She began developing signs of the disease around her midlife. I believe Huntington’s Disease is the most accurate mental illness for Bertha Mason, and if she were to receive the treatments that we have today, she would have been able to maintain her symptoms and live life easier compared to hers throughout the novel.

Introduction of Huntington’s disease

Huntington’s disease (HD) is a severe neurodegenerative disorder that is inherited in an autosomal dominant manner. HD progresses in mid-life showing motor and cognitive function impairments, and psychiatric deficiencies. It is caused by a mutation of the Huntingtin gene creating a CAG-elongation at the amino-terminus of the Huntingtin protein (HTT)1. Having more repeats has been previously associated with the earlier onset of the disease2. The mutated protein forms toxic aggregates in the brain, causing neural death and volume reduction in areas such as the striatum, and undermining the white matter (WM) integrity and normal brain connectivity3. Although the genetic background of the disorder is well known, the underlying mechanisms are not yet understood. Non-invasive imaging techniques like magnetic resonance imaging (MRI) have led to insights into the fundamental mechanisms of the disease and the structural changes in the brain through the progression of HD (Figure 1). In this review the current structural imaging literature will be assessed in the investigation of neuronal changes associated with HD progression, focusing on volumetric measures and diffusion imaging features.

Figure 1: The use case of applying structural imaging in Huntington’s disease to inform the treatment process. Extracted features from different imaging modalities can be used to track the progression of the disease or to predict later onset. Images adapted from Paulsen(2010) and Ruocco et al.,(2006) 4,5.

Principals of structural MRI techniques

MRI is based on the wide distribution and unique properties of the hydrogen protons in the body. Protons spinning on their axis create a small magnetic field, consequently, they can be all aligned by applying a strong magnetic field. Then a second magnetic field pulse can disturb this alignment and tip the protons into a higher energy state, decreasing the longitudinal magnetization and turning the net magnetization vector to the transverse plane. During the relaxation period, the protons return to their original state while releasing energy, which can be detected by the device. Tissues differ in relaxation time, creating the contrast to visualize different compositions and structures6.

Diffusion tensor imaging (DTI) techniques are based on water movements within tissue structures and can be used to investigate the fiber integrity of white matter. Water is able to move in any direction when free. However, when water is present in a fibre, the diffusion is anisotropic and will happen faster when aligned with the underlying fibre organizations. This difference in water movement can be measured by MR as the protons are de-phased between the two pulses in freely moving water, therefore weakening the signal. However, when there is a restriction in water movement, water molecules experience similar local magnetic fields and the protons will spin together, increasing the signal. After obtaining a sufficient number of diffusion gradient directions, the tensors can be computed for each voxel with appropriate eigenvectors and eigenvalues indicating the orientation of elements such as axons. Estimated tensors can be further used to calculate the fractional anisotropy (FA) index that represents how diffusion is directionally constrained in a voxel. Additional outcome measures that directly quantify diffusivities such as mean, radial and axial diffusivity (MD,RD,AD) are often used to describe differences in structural integrity7.

Structural MRI in HD

The most robust pathological change in HD patients are selective neural loss in areas such as the striatum8. The progressive loss can start 15 years earlier than the onset of the disease9. The number of the CAG repeats have been associated with the severity of striatal loss10. Large-scale longitudinal studies such as PREDICT-HD11 and TRACK-HD12 identified the striatal volume and the rate of atrophy as predictors for transfer into late stage HD. Some cross-sectional studies do not agree with TRACK-HD in whether the putamen or caudate changes are more prominent in terms of longitudinal alteration13. These contradictions could originate from different methods being used for outlining the two components of the striatum. As the striatum is important in executing cognitive functions that are usually impaired in HD, the robust volume loss in this area can be used as an effective biomarker13. Significant changes in this area are correlated with other cognitive14 and motor impairment measures14,15. There are some controversies in the literature on whether the rate of change in striatal volumes is consistent throughout the progression of the disease. TRACK-HD reported progressively increasing atrophy rates while other studies present a constant rate after the commencement of atrophy13. This difference could originate from not controlling for age, and differences in methods assessing the rate of change. Some other subcortical structures such as the thalamus, pallidum, and nucleus accumbens were undergoing atrophy during disease progression, however, with smaller effects sizes and less sensitivity16. Automated segmentation techniques might offer an alternative for a more precise outlining of these structures, as defining the outline of these can be challenging. Cortical thinning happens early during the disease and seems to be progressing from posterior to anterior regions of the brain and it is correlated with other clinical measures17. However, the effect sizes are still small compared to the striatum18. An additional important structural change is the degradation in WM around areas affected by the disease. Longitudinal change around striatum19, frontal lobe13 and corpus callosum20 can be followed through disease progression and these changes are associated with deteriorating cognitive measures21. Furthermore, these alterations are strong in predicting future progression of the disorder13. Structural MRI can provide a reliable monitor for longitudinal changes even within short periods of time and can be considered as an outcome measure for clinical trials in disease-modifying treatment studies in the future. The most significant differences have been reported from WM13 and striatum12 which can provide strong effect sizes.

Use of DTI in HD

The previously described findings rely on volumetric changes of brain structures, however, these do not consider microstructural differences. Grey and white matter integrity changes have been mostly quantified by DTI-based metrics to provide a complement to volumetric changes. DTI outcome measures can be used to monitor additional differences between patients and healthy individuals. Moreover, changes in these measures are expected to happen earlier than volume loss, therefore are important in predicting disease advancement. FA can suggest loss of directionality of water flow, possibly due to structural changes, like axonal loss. RD can give a measure of myelin breakdown while AD can represent the changes due to Wallerian degradation. An overall reduction in FA and increase in MD is therefore expected during disease progression. In the striatum of HD patients, an unexpectedly increased FA was reported, that could originate from selective loss of some neuronal connections, making this subcortical structure permanently more organised22. There was a significant increase of MD in the thalamus and putamen that was probably related to prior striatal injuries, as they are part of the same cortico-striatal circuit23. Areas outside this circuit such as corpus callosum that is many form from pyramidal projection also show independent atrophy24. Earlier studies found that in pre-stage patients there was an increase in AD and RD while there is a decrease in FA in corpus callosum25. This supports the idea that both demyelination and secondary effects of grey matter (GM) loss could lead to WM disruptions. In later studies, it was confirmed that changes in AD are mainly present in later stages of the disease26. There have been some controversies on whether WM atrophy is a prominent feature in early stages or just a secondary effect of GM loss. However, it is becoming more evident that there is considerable WM atrophy in multiple areas in both pre and late-stage HD. Combining DTI with quantitative magnetization transfer technique revealed that myelin might play an important role in this process27, while another type of MRI metric (NODDI)28 showed that axonal reduction may underly this pathology. As the tensor measures of DTI are an average for all microstructures within a region, it does not account for individual components. In addition, the outcome measures of DTI might mean a combination of different underlying causes and not just a single aspect. For example, an increase of RD can be interpreted as the loss of myelin in the system, but not exclusively, as axonal loss or crossing of fibers can also contribute to changes in this measure. DTI measures are related to different clinical measures, however, their future use as potential biomarkers is constrained by producing smaller effect sizes when compared to MRI volumetric analysis18.

Conclusions and future directions

In this review, the role of structural MRI was addressed in the investigation of Huntington’s disease. Volumetric changes through the progression of the disorder were most evident in the striatum and white matter, which can be used as future biomarkers in clinical trials to verify the efficacy of disease-modifying treatments, which have the prospect to be faster and more reliable than cognitive measures. When investigating further microstructural changes, white matter atrophy was confirmed as an early contributor to HD and not just a consequence of grey matter loss. Furthermore, abnormal myelin processes might mediate the effect of WM changes in HD. There have been a lot of longitudinal studies conducted in HD, however, the findings are sometimes not consistent, which could be due to different ways of measurement and data analysis methods used. Defining a standard image processing method is essential to unify these longitudinal findings. Furthermore, using a combination of imaging modalities or other clinical measures can become a powerful tool to justify the treatment potency of future drugs.

References

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27. Zhang, J., Gregory, S., Scahill, R. I., Durr, A., Thomas, D. L., Lehericy, S., … & TrackOn‐HD investigators. (2018). In vivo characterization of white matter pathology in premanifest Huntington’s disease. Annals of neurology, 84(4), 497-504.

Huntington’s disease is an inherited brain disorder that is caused when specific cells in the brain die. This leads to loss of cognitive function, loss of walking, eating and swallowing and eventually death. Symptoms typically start between 30-50-year old Huntington’s disease is extremely rare and affects one in every 10,000 people. Huntington’s disease is caused by a mutation of the HTT gene, everyone has a copy of the HTT gene but only those with the mutation may have the possibility of getting Huntington’s disease. The mutation is an increase in a small segment of DNA called CAG. Normally, individuals have approximately 17 CAG but people who have 36 CAG repeats or more are more likely to are considered mutation-positive and will develop Huntington’s disease later in their lifetime. Huntington’s disease is often described as a family disease, children whose parents are mutation-positive have a 50 percent chance of developing the disease when they are adults as seen in diagram 1. There is no cure for Huntington’s disease but predictive genetic testing which is a simple blood test allows individuals to see whether they have the genetic mutation which causes the disease and allows people to be prepared for life in the future especially as Huntington’s disease occurs during when someone is 30-50 Prospective parents consider prenatal testing when one parent has been diagnosed with Huntington’s disease or has been found to carry the gene. Prenatal testing can show whether the child will inherit the defective gene. To test the foetus, DNA is extracted from foetal cells via CVS (chorionic villi sampling) or amniocentesis which is seen in diagram 3

(CVS) is a prenatal test that is used to detect birth defects, genetic diseases, and other problems during pregnancy. During the test, a small sample of cells (called chorionic villi) is taken from the placenta where it attaches to the wall of the uterus. Chorionic villi are tiny parts of the placenta that are formed from the fertilized egg, so they have the same genes as the baby, and this allows doctors to see whether the child has the mutation in the huntingtin gene.

Amniocentesis is a prenatal test in which a small amount of amniotic fluid is removed from the sac surrounding the foetus for testing. The sample of amniotic fluid (less than one ounce) is removed through a fine needle inserted into the uterus through the abdomen, under ultrasound guidance. The fluid is then sent to a laboratory for analysis.

The genetic test for HD investigates the number of CAG triplet repeats in a huntingtin gene. The polymerase chain reaction, or PCR, is used to isolate DNA and make many copies of it. It is needed in order to make lots of copies of the huntingtin gene, allowing scientists to examine it more closely. PCR produces millions of DNA copies in a short amount of time and includes a few steps as follows. Firstly, the DNA sample is heated to nearly 100o C. DNA is normally double-stranded in a helix formation, but the heat causes the strands of DNA to separate into single strands. This process is called denaturation. Then, the sample is cooled a little. Now, primers which are a single-stranded nucleic acid utilized by living organisms in DNA synthesis can bind to each DNA strand. These are small molecules serving as the starting material for a reaction called polymerization. The goal of this reaction is to create more DNA. An enzyme called DNA polymerase makes new DNA strands by adding nucleotides, the structural unit of DNA, to the primer on each strand. It’s like adding building blocks to a pre-existing block tower. As more nucleotides are added, the strand is extended, and eventually, a new copy of the gene is made.

After creating millions of copies of the huntingtin gene using PCR, we are now ready to separate DNA fragments, in order to inspect them more closely. This can be done using a technique called gel electrophoresis which is seen in diagram 2. The principle is simple: DNA fragments are separated based on their size because smaller fragments can travel through the gel faster than larger ones. First, restriction enzymes attach themselves to DNA and cut it into small fragments. Then, the DNA pieces are placed in small wells in a gel floating horizontally in a buffer solution. This solution is located between two electrodes, one positive and the other negative. Once an electric current is passed through the gel, the fragments of DNA begin to move. DNA is negatively charged, so it is attracted to the positive electrode. The smaller fragments move faster than the larger ones, so they move across a greater distance towards the positive electrode.

Now that the fragments of DNA have been separated, the technicians are ready to inspect each DNA fragment. They do this to evaluate the number of CAG repeats in the huntingtin gene. Individuals who do not have HD usually have 28 or fewer repeats. Individuals with HD usually have 40 or more repeats.

Researchers from University College London (UCL) and University College London Hospitals (UCLH) have devised a simple blood test that can identify early physiological changes caused by Huntington’s disease. The test locates the two biomarkers, the neurofilament light protein associated with nerve damage and the disease-causing mutant huntingtin (mHTT) protein One of the most challenging issues for all HD symptomatic and at-risk persons is the profound denial of the presence of HD in the family and discrimination and shunning of the affected individuals from their own family and from the society. People with Huntington’s disease may also be refused life insurance and other forms of insurance, this means that families financially may be in poorer position as the person affected Huntington’s disease will not be covered by any form of insurance. These tests may also emotionally affect parents if they’re child has the mutation as they believe they have harmed their child.

However, these tests allow families to be proactive in preparing for the future and can offer peace of mind for those who parents had Huntington’s disease, but they themselves don’t. These tests also enable those with the mutation to begin gene therapy which has a higher success rate if started sooner.

Individuals in a survey conducted were overwhelmingly in support for the individual to have the decision to have genetic testing even if they were a child as it was the child’s life. On the other hand, in the survey those that opposed allowing the child the choice said that as they would not be able to understand the consequences of their choice, so an adult should make help them make that decision.

In another question in the survey “is it ethical to manage a disease which an individual is susceptible to if they aren’t aware that they are susceptible” Responses were fairly balanced out some were of the view that if a person does not know and are happy, testing which could remove the happiness should not be attempted, others were of the opinion that testing should be conducted so that the individual would have a greater chance of survival as the chance of gene therapy being successful depends on the time it is started.

Rationale

“Congenital diseases are disorders that are present before or at birth.” (spine-health, 2019) “Huntington’s disease is a hereditary disease that is more common in European descent.” (ghr, 2019) It will usually affect hosts at the ages between 30-40, but there are cases of juvenile Huntington’s disease and late-onset. ‘Huntington’s disease causes the breakdown of nerve cells in the brain’ (mayoclinic, 2019)

“A Pedigree is a diagram that depicts the biological relationships between an organism and its ancestors.” (biologydictionary, 2019) A pedigree is important to locate hereditary diseases and traits. Pedigrees help deciphers whether the trait or disease is dominant or recessive. This means that you can find the probability of a disease or trait in offspring. To trace a dominant disease, you would see if it is authoritative compared to the other possibility, that would normally be seen in the first generation in a pedigree. Huntington’s disease is a dominant gene and can usually be traced through a pedigree. There can be inconsistent information in a pedigree, a host could die before they have had any symptoms or the disease. This can make tracking the disease harder and that’s why pedigrees are so helpful in the case of Huntington’s disease. They can trace the generations to see the probability that their offspring could have the disease.

Huntington’s disease is not common in Asian countries compared to European. In European countries, 5-7 in 100,000 people will have HD, this is the same as countries of European descent like the USA. Asian countries are less likely to have HD with 1 in 100,000 people will have HD. This refines the disease to one heritage which helps with predicting Huntington’s disease in a pedigree, therefore someone with no European descent is less likely to have HD, this means that a pedigree is more likely to predict whether someone has HD from looking at their ethnical background and their parents. Thus, a pedigree and European descent are essential in predicting Huntington’s disease. Therefore, this essay purposes the following question:

Can Huntington’s disease be predicted through pedigrees and European descent?

Background

Huntington’s disease is a rare progressive neurogenerative disease that will typically manifest at the age of 30-45. Huntington’s causes the loss of motor control leading to jerky movements, altered personality and psychiatric symptoms, and a decline in congenital function. Most HD patients have already had children before the symptoms have become noticeable. There is a 50% chance to pass on the gene to offspring, normally in large families, there will be HD in every generation. Researchers have realized that the juvenile form of HD relates to anticipation. This is when a phenotype becomes more severe from one generation to the next. Anticipation occurs when the gene is inherited from the father. (Chia, 2019)

In Juvenile HD the patient will be 30-50% more likely that a seizure could occur. With juvenile Huntington’s disease, the individual will usually die between 10 to 15 years after signs and symptoms first occur. The DNA segment is CAG trinucleotide repeat, this segment is a series of three DNA building blocks cytosine, adenine and guanine. The increase of the CAG segment leads to long versions of the huntingtin protein. This protein is then cut into smaller, toxic pieces that bind together and bunch in neurons, disrupting the normal function of these cells. The dysfunction and death of neurons in areas of the brain underlie the symptoms of Huntington’s disease. Individuals with 27 to 35 CAG repeats in the HTT gene don’t develop HD, but their children are at risk of developing the disorder. As the gene is passed down in generations the size of the CAG trinucleotide repeat should lengthen into the range associated with HD. (ghr, 2019)

With Huntington’s disease, there are four stages of the disease and its effects, the first is the early stage where the person can function fully both at work and at home. The second is early intermediate stage, the person can still work but at a reduced capacity. The third stage is the late intermediate stage, they can no longer manage work are household responsibilities, they would also be no longer able to handle financial affairs. Then it’s the early advanced stage, the person is no longer independent with daily activities. The last stage is the advanced stage, they will require complete support in daily activities. The direct cause of death from HD is never Huntington’s disease, instead, are effects of Huntington’s disease. The causes of death can range from pneumonia to heart failure, 7% of all patient deaths are suicide. The treatments found for HD still only alleviate the symptoms, through pharmaceutical and non-pharmaceutical treatment. Huntingtin the protein itself is found or “expressed everywhere throughout the body with the highest concentration in the brain. The protein should be a necessity to humans due to an experiment where it was lethal to mouse embryos when the gene was subtracted. The most affected area if the brain is striatum, this area controls planning and controlling movement. As HD progresses it starts to affect the cortex, this deteriorates the cognitive thinking. As Huntington’s disease progresses is slowly deteriorates the whole brain. (EHDN, 2019)

Evidence

Figure 1: Pedigree of an American Huntington’s disease family.

Figure 1: Pedigree of an American Huntington’s disease family. This Pedigree shows an American family whose mother/grandmother had HD, All the offspring of Generation I had HD, the second generation all together had 11 HD offspring out of 13. This just shows how deadly the disease is. This was an American family meaning they most likely had a European background; therefore knowing your heritage would be so important for a patient to know before having children

Figure 2: Length of the HTT CAG repeat

CAG repeat length Disease-causing? Consequences for offspring? Name

Below 27 No None Normal repeat length

27 – 35 No Repeats of 27 and more can be unstable and might increase when passed on to offspring Intermediate repeat length

36 – 39 Maybe Yes, offspring have a 50% probability of inheriting the expanded gene Reduced penetrance repeat length

40 and above Yes Yes, offspring have a 50% probability of inheriting the expanded gene Fully penetrant repeat length

Figure 2: Length of the HTT CAG repeat, this table shows how the CAG is linked to the severity of the disease. When the repeat length is below 27 repeats there should be no problem causing or offspring having the disease. Then once it is above 27 there is a possibility of offspring carrying the disease, but they are still not at risk. Once you get to the reduced penetrance repeat length is where you and your offspring will possibly have HD. Once the amount of CAG in your body is over 40 you will have the disease, but their offspring will still have a 50% chance of inheriting HD.

Figure 3: What determines the age at symptom onset?

Figure 3: What determines the age at symptom onset? This table shows how the amount of CAG directly relates to the age in which the onset will occur. As you can see when the amount of CAG repeat increases above 40, juvenile Huntington’s disease starts increasing. This shows reducing the CAG would directly help the quality and amount of life the patient would have. This means that a pedigree that would also add the amount of CAG repeats would help determine the quality of life for the offspring.

Evaluation

Nature.com is a reliable source according to https://mediabiasfactcheck.com/nature/, and it has a reliable author. The main problem is that it is 11 years old, I have not found sources that disagree with the cite. The information given is very useful since I now have a pedigree base on the first known case of Huntington’s disease. The author is Heidi Chial, PhD and she has written many articles for nature.com.

Edhn.com, the cite is a secondary source that is relaying background information. This site is very useful and is corroborated by (ghr, 2019). The author is unknown but the website itself is an organization for Huntington’s disease. It seems like a reliable source with useful information surrounding Huntington’s disease. This website is an organization that covers European Huntington’s disease, which means that it is focused on this field of work and should be one of the most reliable sources that I can use.

Ghr.nlm is a government site and is apart of the U.S national library of medicine, the source was reviewed in 2013 and then published in 2019. The source is corroborated by (EHDN, 2019). The author is unknown, but it is a gov website, so I believe that it is still valuable and reliable.

Conclusion

And in conclusion, the claim was proven, but it could be added to. Huntington’s disease can be predicted with the use of pedigrees and knowing if the individual has European descent. What could be extended to the statement that would help predict the severity of the disease that the offspring, would be knowing how many CAG repeats there are in the previous generations to predict the offspring’s quality of life. This would help contain the disease and prevent CAG repeats above 40 if controlled and studied adequately. Overall the claim was proven and justified due to the sources and evidence provided.

Bibliography

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4. EHDN, 2019. About Huntington’s Disease. [Online] Available at: http://www.ehdn.org/about-hd/ghr, 2019. Huntington disease. [Online] Available at: https://ghr.nlm.nih.gov/condition/huntington-disease [Accessed 17 September 2019].
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Human Genetics and Genomics- Nonallele-specific Silencing of Mutant and Wild-type Huntingtin Demonstrates Therapeutic Efficacy in Huntington’s Disease Mice

Huntington`s Disease (HD) is an autosomal dominant neurodegenerative disease affecting 4-to-7 per 100,000 individuals. It is classed as a trinucleotide repeat disorder (Marcy et al, 1993) due to the fact that it results from an expanded CAG repeat which leads to a polyglutamine strand of variable length at the N-terminus (Walker, 2007). The normal number of CAG repeats is 10-35 times, however, in HD this repeat will occur 36 times or more and as CAG codes for glutamine, HD is classified as a polyglutamine disease. The huntingtin gene which regulates brain-derived neurotrophic factor (BDNF) that promotes the survival of neurons in the brain is affected (Zuccato et al, 2010). In Huntington`s Disease, mutated protein aggregates within the neuronal cells of the caudate and putamen of the basal ganglia causing neuronal cell death. The pathology of HD will show severe atrophy of the caudate nucleus and putamen. Cell death might be related to excitotoxicity which is the excessive signaling of these neurons, leading to high intracellular calcium (Raymond, 2003). The symptoms involve the central nervous system which will have an effect on movement (chorea and athetosis), cognitive disturbance, and mood. The loss of small neurons will also cause the expansion of the lateral ventricles and this can lead to psychological problems such as dementia, personality changes and depression.

Brain regions affected by HD have decreased GABA and acetylcholine but increased dopamine levels which helps explain why neuroleptics, which are dopamine receptor antagonists and tetrabenazine which depletes dopamine are used to treat chorea in people with HD but have no effect on overall survival. The average age of onset is around 40 years old (Vonsattel et al, 1985) but could be earlier depending on the number of repeats. Death happens within 10-20 years of diagnosis often by aspirational pneumonia on account of dis-coordinated swallowing or suicide.

The idea of using mice to silence mutant htt and wild type htt through RNA interference has shown therapeutic benefit in HD mice, mainly in silencing the wild type htt. Mouse HD genes are 81% in similarity to that of the human HD gene when expressed at DNA level (Liou, 2010). Knock in mice models have more precise portrayal of the disease`s genotype as scientists are able to replace specific gene regions of the HD gene with human copies. In 1996 the first transgenic mouse models (R6/1 and R6/2) were developed (Mangiarini et al., 1996) by inserting a part of the htt gene from a juvenile HD patient into the mouse genome. The purpose of these mice was to be able to study and understand repeat expansion which leads to Huntington`s Disease. However these models lacked the full length of mutant htt (mainly the R6/2) and the rapid progression of disease was extreme. They also had excessive weight loss and early death at usually 12-14 weeks (Crook and Housman, 2015). Due to this, other mouse models were developed such as the N171-82Q-17. These mice express the human htt cDNA which encodes glutamine and the first 171 amino acids bearing 82 CAG repeats (Schilling et al., 1999).

The aim of this study was to investigate whether therapeutic benefit is attainable via nonallelle-specific silencing of mutant and wild type htt in HD-N171-82Q mice (Boudreau et al., 2009). Previous studies of utilising RNAi induced by short hairpin RNAs (shRNAs) to reduce expression of mutant htt have shown that there is a possibility of improving abnormalities relating to HD disease in a mouse model (S.Q Harper et al, 2005). Pfister et al (2009) also suggested that targeting SNPs to degrade mutant htt while presenting the wild type htt is a promising approach. However, the number of SNP candidates is very limited in comparison to that of nonallele-specific strategy as there are countless sequences that could be targeted (Valerie et al., 2014). Although this study aims to find therapeutic benefit through nonallele-specific silencing of both the mutant and wild type huntingtin gene which codes for the huntingtin protein, it has been noted that the effects of nonallelle-specific silencing of the mutant htt still remains unknown. Allele specific targeting of mutant htt may be ideal considering that the wild type htt plays an important role in the development of neuronal nerve cells and other cellular processes (Zuccato et al., 2003).

During the study the mutant mice were injected with formulation buffer (FB), AAV1-hrGFP or AAV1-mi2.4 and the wild type mice were injected with only the formulation buffer into the striatum. Adeno-associated 2/1 viral vectors were used (AAV1-hrGFP, AAV1-mi2.4, AAV1-sh2.4 and AAV1-sh2.8). Using AAV is beneficial because they integrate into the active gene in the mice. Also, there is a lack of pathogenicity. ShRNA targets exons in HD mRNA and shRNA 2.4 and shRNA 2.8 have been known to reduce the expression of endogenous htt protein in mice C2C12 cells (McBride et al., 2008). Although this study aims to find the benefit of nonallele-specific silencing of the mutant and wild type htt, the use of AAV1 delivered shRNA in order to decrease striatal expression of the mutant htt allele has shown to improve motor and neuropathological defects in HD mouse models (Harper et al., 2005), for that reason, this suggests that it might be more beneficial for the suppression to be allele specific because reduction of wild type htt might not be well tolerated in the brain.

Immunohistochemical analysis (IHC) was used to analyse striatal neurons after they had been stained using goat anti-rabbit IgG secondary antibody. IHC is a procedure that is used for protein expression analysis. During this study, IHC was used to assess neurotoxicity by looking at DARPP-32 and Iba1. The researchers found that the mice that had been treated with AAV1-sh2.4 showed a loss of DARPP-32 which plays an important role in the regulation of dopamine-ion channels. There was also an increase in the activation of microglia which responds to neuronal damage. Mice that were injected with AAV1-mi2.4 and the buffer solution had an opposite reaction. In Huntington`s Disease the striatum is usually the most severely affected region, therefore the analysis of the striatal neurons helped to conclude that neuronal loss contributes to motor impairment but not chorea (Guo et al., 2012) as the mutant mice injected with the AAV1-mi2.4 managed to perform better in the rotarod test. The benefits of using immunohistochemical analysis are that it is relatively inexpensive, the results can be generated quite quickly as it is a rapid automated system and there is good cell morphology preservation as the aim of this technique is to use the least amount of antibody in order to cause the least damage to cells. The limitations are that it is hard to quantitate, success depends on the antibody that is used and the interpretation of the results could be subjective.

Another method that was used to analyse microglial activation is real time PCR (QPCR). This was used for analysis of CD11b mRNA and the results showed that there was a fivefold increase in sh2.4 HD-N171-82Q mice. An increased expression of CD11b represents neurodegenerative inflammation (Roy et al., 2006). These results show that mi2.4 has an improved safety in comparison to sh2.4 in HD-N171-82Q mice. Although this can be used in order to develop a much safer vector, the use of artificial miRNAs in mouse models with neurodegenerative disorders for therapeutic efficacy has not yet been published. QPCR is highly sensitive so it allows the detection of low copy targets and it has a wide dynamic range as 1-1011 of gene copies can be detected within a single run. It is also highly quantitative and accurate which means that the absolute copy number and gene expression can be measured accurately in comparison to traditional PCR. Moreover, the closed tube format it uses eliminates risk of cross contamination which is why results are measured accurately. It is also fast as no agarose gel is needed and safe because ethidium bromide is not used to stain DNA gels. The disadvantages of QPCR are that it is quite costly and might be complex so setting up requires high technical skill.

Northern blot analysis was also used to assess htt-specific antisense RNA levels in AAV1-RNAi treated striata after the striata was separated from tissue punches and then stained with ethidium bromide. Antisense RNA binds to mRNA to prevent its translation and if there is any neuronal damage, there will be an accumulation of it. Benefits of using northern blot analysis are that it has a high specificity so false positive results are reduced, it is less time consuming and requires no protection against radiation and the membranes can be stored and re-probed for years later after blotting. However, it has low sensitivity in comparison to other methods such as real time PCR.

The capacity of mi2.4 to effectively silence both mutant and wild-type mouse htt alleles was assessed by using western blot analysis. This method detects specific proteins in a sample and during this study it was used to assess the human protein, myc, and mouse htt (mHtt) proteins. In order to be able to assess this, myc-tagged human HD-N171-82Q htt fragment cells were overexpressed in C2C12, also, RNAi (mi2.4) expression plasmids were co-transfected and a reduction in the human mutant and endogenous wild-type htt produced by C2C12 cells was recorded. Previous studies have shown that in separate experimental systems, mi2.4 is able to silence both the mutant and wild type htt, the results from this western blot have highlighted that it is possible to simultaneously silence both the alleles in HD-N171-82Q mice models. Advantages of using western blot analysis are that it has a high sensitivity and specificity as it can detect as little as ng of protein in a sample and will only detect the protein of interest. However, it is time consuming and has a high demand in terms of experience.

Another method used in this study was microarray analyses to look for transcriptional changes between AAV1-hrGFP treated group and AAV1-RNAi groups. They therefore evaluated the transcriptional profile changes resulting from RNAi-mediated silencing of striatal htt, with the purposes of wanting to gain additional insight into the functions of wild-type htt and to further evaluate the safety of suppressing wild-type htt in adult mouse striatum. This procedure revealed htt as the most downregulated gene meaning that htt-related cellular pathways are disrupted after specific RNAi treatment. The benefits of using microarray is that it makes it possible to examine the expression of thousands of genes simultaneously, however, hybridisation is potentially non-specific. The method relies on existing knowledge about the genome sequence and may be expensive as it has a need for highly trained personnel. In order to be able to perform the microarray, a Tukey-Kramer test was completed first in order to cut down the number of genes that were expressed from 761 to 473. This test is used to compare the mean values of the experimental group (RNAi) against the control group (hrGFP). A p value of 0.05 was considered to be significant and a low p value means a higher chance of the hypothesis being true. The hypothesis of the study being that nonallelle-specific silencing of mutant and wild-type htt provides therapeutic benefit in HD mice. This test reduces the chances of type 1 errors being made, however, it is not designed to text complex comparisons.

The HD-N171-82Q mice were also subjected to a rotarod performance test which evaluates motor coordination and balance. Mice were tested at 10, 14 and 18 weeks and killed at 20 weeks for histological analyses. Mutant mice injected with FB, AAV1-hrGFP or AAV1-mi2.4 performed better than the wild type injected with FB. However, this test has no negative impact on motor behaviour and animals that have poor coordination will fall off at the start making it partially subjective.

Summary of results

When the mice were killed at 20 weeks of age in order to perform histological analyses and QPCR analyses in order to evaluate long-term suppression of mutant human and wild-type mouse htt transcripts, the researchers found that HD-N171-82Q mice treated with AAV1-mi2.4 showed significant reductions (~75%) in human and mouse htt mRNA levels, relative to control-treated mice (P < 0.01). These results, together with data from the rotarod analyses demonstrate that nonallele-specific silencing of mutant and wild-type htt provides therapeutic benefit in HD-N171-82Q mice.

The methods employed in this study were appropriate and helped to answer the research question, however some of them, such as the use of vectors would not have been strong enough to answer the question without relating to findings of previous studies as the results from that showed that it might not be safe to use shRNA compared to mi2.4.

Impact of findings

There are no current treatments for neurodegeneration but only medication to manage the symptoms. The findings of this study have an impact as they show that it is achievable to be able to reduce mutant genes in genetic disorders and hopefully lead to the treatment of them. The researchers found that the mice were able to tolerate a reduction in both the mutant and wild type htt. The mammalian brain is able to tolerate an up to 75% reduction in wild type htt mRNA in the striatum for several months. This research can be useful towards the development of treatment for other trinucleotide disorders such as myotonic dystrophy and spinocerebellar ataxia type 7. Recently, there have been studies into the nonallele-specific silencing of ataxin 7. There is evidence that nonallele specific silencing of ataxin-7 by RNAi is well tolerated in a SCA7 mouse model (Ramachandran et al., 2014).

Some stem cell research on HD mouse models has also shown that it might be possible to take stem cells from an individual with Huntington’s disease, correct the HD mutation and implant it back into the person`s brain. An alternative to this would be to mobilise the neural stem cells that are already in the brain and revive with a specific growth factor delivered to the brain.

References

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12. Ramachandran, P., Boudreau, R., Schaefer, K., La Spada, A. and Davidson, B. (2014). Nonallele Specific Silencing of Ataxin-7 Improves Disease Phenotypes in a Mouse Model of SCA7. Molecular Therapy, 22(9), pp.1635-1642.
13. Raymond, L. (2003). Excitotoxicity in Huntington disease. Clinical Neuroscience Research, 3(3), pp.121-128.
14. Roy, A., Fung, Y., Liu, X. and Pahan, K. (2006). Up-regulation of Microglial CD11b Expression by Nitric Oxide. Journal of Biological Chemistry, 281(21), pp.14971-14980.
15. Swanson, P. (2015). Immunohistochemistry as a Surrogate for Molecular Testing. Applied Immunohistochemistry & Molecular Morphology, 23(2), pp.81-96.
16. onsatell, J., Myers, H., Stevens, T., Ferrante, R., Bird, E. and Richardson, E. (1985). Neuropathological classification of Huntington’s disease. pp.559-77.
17. Wallace, L., Moreo, A., Clark, K. and Harper, S. (2013). Dose-dependent Toxicity of Humanized Renilla reniformis GFP (hrGFP) Limits Its Utility as a Reporter Gene in Mouse Muscle. Molecular Therapy – Nucleic Acids, 2, p.e86.

Narrative

In my early 40s I began to have more difficulty concentrating, and I remember feeling unusually forgetful. For a while, I ignored these symptoms until I started to uncontrollably twitch and make fidgety motions. When the chorea started, it was clear to my doctor that I was dealing with something more than just forgetfulness. The fact that my mom also suffered from the disease confirmed the doctor’s predictions, and that is when I was diagnosed with Huntington’s Disease. From then on things only got worse, my symptoms of chorea began to occur more frequently, primarily in my hands, feet, and face, causing involuntary body movements, and making it very hard to go about daily life. Now, it is even difficult for me to remember specific conversations, TV shows or books. My disease affects my ability to plan, make decisions and process complex topics. I have trouble navigating, even to places I have been many times, although I can retain memories and continue to do things I have been for a long time. I get easily agitated, irritated and aggressive over little things that I can’t control. All these symptoms induce anxiety and depression and I often go into periods where I am constantly frustrated and down, but I don’t know why. I have recently noticed that my voice has become hoarse, slurred, and I either speak too quickly or too slowly. While all these symptoms make life much harder to enjoy, the worse part of having Huntington’s disease is knowing that it doesn’t just affect me, but potentially my children and our entire family for years to come. I am 55 and I have lived with Huntington’s Disease for just over 10 years, and I cherish every moment I have left with my family and friends. (Living with Huntington’s 2013)

Background Information

Huntington’s disease was discovered in 1872 by George Huntington, a 22-year-old American doctor. He published a paper called On Chorea which lead the disease to be first recognized as an inherited disorder known as Huntington’s Chorea. In the 1980s and strong push to find the gene at fault began. Researchers built long and detailed pedigrees and using blood samples from large families with HD discovered its location, on chromosome 4. In 1993, the mutation was identified. This allowed HD families to be now tested to find out if they carried the mutation before the symptoms began to develop. (Kaplan 2019) Huntington’s Disease has affected many well-known individuals including; Woody Guthrie, Trey Gray and Charles Sabine. Probably the most famous person to suffer from Huntington’s Disease was Woody Guthrie, an icon in the folk music world, who was diagnosed with HD in 1952. Sadly, at the time little about the disease was known so his illness was essentially left untreated. Woody died at age 55, in 1967, only 15 years after he was diagnosed. His death helped increase public awareness for Huntington’s and lead to the development of the Huntington’s Disease Society of America (HDSA). For a long time, even after George Huntington discovered the disease, it was poorly understood. People believed the twitches characterized by HD were possessed by devils. Furthermore, people with the HD gene were dying before the symptoms could even develop, making it very hard for research to be done. So, when the gene was finally discovered in 1993, it was a breakthrough in the history of HD. (Zachary 2019)

Huntington’s Disease causes movement, cognitive and psychiatric disorders. Symptoms of Huntington’s vary greatly from person to person. Oftentimes symptoms increase in harshness or frequency as the disease progresses, and one disorder tends to be more dominant than the other. Specific symptoms that affect movement include; involuntary jerking (chorea), muscle rigidity or contracture (dystonia), slow eye movements, impaired posture, balance, and difficulty speaking or swallowing. (Mayo 2018) These symptoms cause both involuntary movements to be altered, and impairments to voluntary movements, making daily life very difficult. Huntington’s also causes cognitive issues like, difficulty organizing and prioritizing, tendency to get stuck on a thought, acting without thinking, lack of awareness, and difficultly obtaining new information. (Huntington’s Disease Genetics 2019) Finally, symptoms of psychiatric disorders also appear causing irritability, apathy, social withdrawal, insomnia, fatigue and suicidal thoughts. Symptoms of juvenile HD are mostly like regular Huntington’s but there are some differences including; stiffness of the legs, clumsiness, poor school performance, speech problems and behavioral disturbances. Seizures also occur in 25-30% of cases in adolescents, this is almost never seen in adults with HD. (Huntington’s Disease, 2019)

Huntington’s Disease affects one in every 10,000 people and around 30,000 people in the United States. While 150,000 or more people are at risk of developing the disorder due to inheritance from their parents. The condition is inevitably fatal, with an average life expectancy of 20 years after the first symptoms are identified. HD is found most commonly in Western Countries, affecting around 3 to 7 per 100,000 people with European descent. The disorder is less common in populations including people of Japanese, Chinese and African ancestry. (Huntington’s Disease Alzheimer’s Association, 2019) In certain populations and regions you are at a greater risk of developing the disease. For example, there is an unusually high concentration of people with HD in the Lake Maracaibo region of Venezuela, where the prevalence averages to around 700 affected individuals per 100,000 people. Similarly, in Australia over 1,800 people have HD and approximately 9,000 are at risk. Huntington’s Disease is inherited in an autosomal dominate fashion. So, the probability of each offspring inheriting the affected gene is 50%. Huntington’s is independent of gender, and the trait doesn’t skip generations due to its dominance. There is a wide variation of occurrence based on age, but the average onset is 40 years old. However, symptoms can manifest as early as age 2 or as late as 80. (What is Huntington’s Disease? 2015)

Scientific Information

a) Genetic Cause

Huntington’s Disease is caused by a mutation in the HTT gene found on the short arm of chromosomes 4. The HTT gene gives instructions for making the protein huntingtin. The HTT mutation involves a DNA segment that all HTT genes contain, known as CAG trinucleotide repeat, which encodes the huntingtin protein. Huntingtin is important in the proper functioning of nerve cells in the brain. It is crucial for proper cell division and apoptosis to occur, and it interacts with many other proteins in the brain making it also involved in cell transport, signaling, and intra-cellular transportation. It is found in many of the body tissues, but the highest level of activity is carried out in the brain. The CAG trinucleotide repeat segment is made up of a series of three nucleotides, cytosine, adenine, and guanine. In normal humans, the segment is repeated between 10 to 35 times within the gene, whereas for people with Huntington’s, the gene is repeated 36 to more than 120 times. The codon CAG codes for the amino acid glutamine. During transcription, the CAG repeats create a polyglutamate section within the polypeptide. The non-mutated allele would then fold into its 3D shape and form the normal huntingtin protein that interacts with others to support healthy brain cells. The mutated allele however, folds in a shape that alters the tertiary structure of the huntingtin protein and causes neurons in the brain to malfunction and die. The extra-long polyglutamate chains break of very easily and because glutamine is a charged molecule the excess fragments that are broken off causes proteins to link and clump together altering their normal protein shape as well. These resulting masses are called protein aggregates, and this is why Huntington’s is so deadly as not only does it cause an alteration in the huntingtin protein but others around it too. The death and dysfunctions of [image: Image result for pedigree of huntington’s disease]these neurons are what cause the symptoms of Huntington’s. Huntington’s Disease is inherited in an autosomal dominant fashion. This means that a person only needs to inherit one copy of the mutated allele from either of their parents to get the disease. Most people with HD are heterozygotes because the disease is so rare and the probably of both of your parents having Huntington’s is very slim. In the pedigree, it is shown that the only way for offspring to not inherit the disease is having a homozygous recessive genotype and, in that case, you will not pass the disease to subsequent generations. If you are homozygous dominant or heterozygous you will eventually develop the disease. Furthermore, the HD gene is located on the short arm of chromosomes 4, meaning it is autosomal or not found on the sex chromosomes.

b) Biochemical Result

Huntingtin is the protein that is created by the CAG trinucleotide repeat, found on chromosome 4. All HTT genes have CAG repeats however, the longer the repeat the more likely you are to develop the disease and have an earlier onset. The more CAG codons there are, the more glutamine produced. Glutamine is a vital protein used for synthesizing proteins however too much glutamine makes the huntingtin polypeptide sticky. The proteins, such as huntingtin and others that are critical to brain cell health all get caught up in aggregates due to this stickiness, making them unable to carry out their functions. The protein aggregates also become toxic to the brain cells which results in the loss of brain tissue. Huntingtin is present in cells throughout the body, however, HD selectively kills nerve cells. This suggests that the huntingtin protein regularly interacts with proteins found only in the brain and that the altered form of huntingtin disrupts the interaction causing nerve cell death. The proteins that huntingtin is discovered to mostly interact with is the huntingtin’s interactor protein (HIP-1) and huntingtin’s associated protein (HAP-1). The number of CAG trinucleotide repeats determine how much or how little huntingtin interacts with these surrounding proteins. As the amount of CAG repeats increase, huntingtin binds to HIP-1 and HAP-1 less. Scientists have discovered that although these two proteins interact overall less, the mutated huntingtin protein and HAP-1 bind more tightly than the normal huntingtin protein does. The interaction between these two proteins, is believed to contribute to the degeneration of the nerve cells. These interactions cause the nerve cells of people with HD to become more sensitive to glutamate, an amino acid precursor. This sensitivity leads to the activation of proteins called caspases that chop huntingtin into small fragments. The fragments are now small enough to slip into the nucleus of the nerve cell and interfere with normal production of proteins. The interference causes cellular stress which could lead to more huntingtin polypeptides being broken into fragments. This cycle continues are eventually leads to nerve cell death. Cells in the basal ganglia, the part of the brain that is responsible for coordinating movement, as well as the cortex, which control memory and thoughts, are most affected by HD. This causes the symptoms of chorea, emotional disturbance and cognitive decline. However, when the patients are examined after death, no area of the brain is left completely unaffected. Currently, there are no treatment options that will prevent or stop Huntington’s from progressing but there are medications that can keep patients’ symptoms under control. First there are medications that suppress the involuntary movement component of HD such as Tetrabenazine or Antipsychotic drugs (Haloperidol, Chlorpromazine, Risperdal, Seroquel). There are also medications to treat psychiatric disorders including, Antidepressants and Mood-stabilizing drugs (Valproate, Carbamazepine, Lamictal). Lastly, most patients are involved into multiple kinds of therapies in addition to their medications like, psychotherapy, speech therapy, physical therapy and occupational therapy.

c) Resources for Patients and their Families

While scientists are still searching for a cure for Huntington’s Disease, it is very important patients and families know exactly what they are dealing with, so they can plan for now and the future. Below is a list of helpful resources to inform those affected that will hopefully answer some common questions as well.

About Huntington’s Disease https://www.hopkinsmedicine.org/psychiatry/specialty_areas/huntingtons_disease/patient_family_resources/education_whatis.html

Glossary of Frequently Used Terms https://www.hopkinsmedicine.org/psychiatry/specialty_areas/huntingtons_disease/patient_family_resources/HD_terms.html

Common Misconceptions and Myth About HD https://www.hopkinsmedicine.org/psychiatry/specialty_areas/huntingtons_disease/patient_family_resources/myths_about_HD.html

Publications, Links, and Support Groups https://www.hopkinsmedicine.org/psychiatry/specialty_areas/huntingtons_disease/patient_family_resources/resources.html

References

1. Living with Huntington’s Disease. Huntington’s Disease News. [accessed 2019 Feb 27]. https://huntingtonsdiseasenews.com/living-with-huntingtons-disease/
2. Kaplan Lewis. Huntington’s New South Wales. What Is The History Of Huntington’s Disease (HD)? | Huntington’s NSW. [accessed 2019 Feb 27]. https://www.huntingtonsnsw.org.au/information/hd-facts/history
3. Zachary H. Celebrities With Huntingtons Disease: Woody Guthrie, Trey Gray. Health Care Zone. [accessed 2019 Feb 27]. https://healthcarenewsblog.com/celebrities-with-huntingtons-disease/
4. Huntington’s disease. Mayo Clinic. 2018 May 16 [accessed 2019 Feb 27]. https://www.mayoclinic.org/diseases-conditions/huntingtons-disease/symptoms-causes/syc-20356117
5. Huntington disease – Genetics Home Reference – NIH. U.S. National Library of Medicine. [accessed 2019 Feb 27]. https://ghr.nlm.nih.gov/condition/huntington-disease#statistics
6. Huntington’s disease. Wikipedia. 2019 Feb 23 [accessed 2019 Feb 27]. https://en.m.wikipedia.org/wiki/Huntington’s_disease
7. Huntington’s Disease. Alzheimer’s Association. [accessed 2019 Feb 27]. https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/huntington-s-disease
8. What is Huntington’s disease? Stories. 2015 Jun 19 [accessed 2019 Feb 27]. https://www.yourgenome.org/facts/what-is-huntingtons-disease
9. https://pdfs.semanticscholar.org/2519/ec210be655b1d801cb40d700ca350dc6910c.pdf
10. https://hopes.stanford.edu/the-basic-neurobiology-of-huntingtons-disease-text-and-audio/
11. https://www.ncbi.nlm.nih.gov/pubmed/6446256
12. https://www.britannica.com/science/Huntington-disease#ref950749
13. https://ghr.nlm.nih.gov/condition/huntington-disease#genes

There are many diseases out in the world that are affecting people’s lives in different ways. They can either be an infectious or a non-infectious disease. A non- infectious disease would be Huntington’s disease which is inherited. It causes a severe breakdown of nerve cells of the brain. The parts of the brain that get damage are the basal ganglia, cerebral cortex the frontal and temporal lobes, ventricles, and caudate nuclei. This disease is most frequently found in people with European ancestry and it’s is less common in people with Japanese, Chinese, and African ancestry. About 3 out of 7 per 100,000 people that have European genes are affected by Huntington’s disease according to U.S. National Library of Medicine. It doesn’t matter whether a patient is a women or a man because anyone can get HD. A person can experience symptoms at the age of 30 to 50 years of age and they can also come at the early age of 20 which is referred to juvenile HD. According to statistics more than 30,000 Americans have Huntington’s disease. The reason that this disease is developed in a human is the mutation in the gene of a protein named huntingtin which causes cytosine, adenine, and guanine building blocks of DNA to replicate a more times than it should. A child with a parent that has HD has a fifty fifty, possibility of inheriting the disease. Now a person who does not inherit HD can not get the disease and can’t pass it onto future generations.

George Huntington, American physician from Long Island, New York was the one to contribute to the explanation of HD which was named after him in 1872. Huntington wrote a paper called ‘On Chorea’ which was later published in the Medical and Surgical Reporter of Philadelphia and became known for Huntington’s Chorea. Huntington’ Chorea evolved through the years and is even known today as huntington’s Disease. In the year of 1933 a research group found the gene of HD, because of this discovery it is possible to diagnose a person through the use of their blood and tissue samples.

Huntington’s disease occurs from the mutation in the gene that is located on chromosome 4. Every person has this gene and has the CAG repeat sequence. When someone has HD, their CAG sequence has a high number of repeats which is a result of protein that has a long polyglutamine sequence. The regular huntingtin gene contains 17 to 20 repetitions of the code of its total of 3,100. The number of repeats that adults with HD have is more than 40 and for people who have juvenile HD usually have more than 60 CAG repeats. Depending if one has a big number of triplet repeats the more it is likely to develop HD at an early stage of life. A father passing the gene to his child might extend the gene even more, starting the disease at an early age. For those who contain 27 to 35 repeats don’t develop Huntington’s disease but there is a slight possibility that their children will get the disorder.

The symptoms of this disease varies for each person, but HD does cause psychiatric, cognitive, and movement problems. Depression is an example of a psychiatric effect that Huntington’s disease causes. It occurs because of the injury the brain goes through and changes in the functions of the brain. Other psychiatric disorders are obsessive compulsive disorder, mania, and bipolar disorder. Some signs include feeling irritable, sadness, social withdraw, insomnia, fatigue, and frequent thoughts of suicide. For cognitive disorders people may experience difficulty organizing or focusing on tasks, people may tend to get stuck on a thought or on an action. When someone is talking they may forget what they just said and not be able to come up with a response as fast as a person who doesn’t have HD can. People also are not aware of their own behavior and are slow at processing thoughts and have difficulty learning new information. Huntington’s disease effects ones movement ability which can be involuntary movement problems and the damage in voluntary movements. This includes involuntary jerking or writhing movements, muscle problems like rigidity, slow eye movements, difficulty with posture and balance, and having a hard time with speech and swallowing. Once a person starts having symptoms of Huntington’s disease the duration can be from ten to thirty years. According to the Huntington’s Disease Society of America, “Huntington’s Disease manifests as a triad of motor, cognitive, and psychiatric symptoms which begin insidiously and progress over many years, until the death of the individual. The average length of survival after clinical diagnosis is typically 10-20 years, but some people have lived thirty or forty years. Late stage HD may last up to a decade or more”. Voluntary movements are really impactful on an individual’s ability to work, act, and communicate.

The symptoms for younger people who have Juvenile Huntington’s disease are a little different than those of adults. Juvenile HD is not as common as adult HD itself. People have behavioral changes like losing academics or physical skills, a decrease in school performance, and behavioral problems. They also suffer in physical changes that include contracted muscles that affect their walking ability, changes in motor skills like their handwriting, seizures, and involuntary shaking. Weight loss is another factor that is affected because of HD. When a young person has to go through these symptoms they may experience anger, sadness, and fear, leading to aggressiveness. Children who inherit Juvenile Huntington’s disease get their sequence repeats from their fathers however they can inherit it from their mothers even though it is rare. The life span for individuals with Juvenile HD is no more than 10 to 15 years after they begin experiencing symptoms. This affects young person daily life from attending school to having a job and even their chance of creating a family in fear of passing the gene of HD on to them.

There are five stages to Huntington’s disease progression. The first stage is considered the early stage, from when it starts it can last up to about eight years. During this stage the person has been diagnosed with HD but can function at home and in the workplace. They still have independence and can do activities own their own like managing their finances, home responsibilities, eating on their own, getting dressed, bathing, and so much more other things. Patients usually don’t experience movement problems but can experience cognitive symptoms as well as psychiatric symptoms. The second stage is the early intermediate stage. It can last up to three to thirteen years from the first day of HD onset. The individual can still function at their workplace but not to the same ability they first began with when they did not have HD. They are somewhat able to do daily life activities but have some difficulties which requires them to have some help from others. However at this stage some may be incapable to work and need a lot of assistance in one certain activity but are fully capable to complete other activities. Involuntary movement in the body which is called Chorea becomes present in this stage. In the third stage the, late intermediate stage can last up to five and sixteen years. An individual can’t maintain house responsibilities or work any longer. They will also need significant help for finances, responsibilities in their home and activities they have in their daily lives. Their thinking ability weakens and some psychiatric symptoms become more prominent like anxiety, irritation, and they become more impulsive. Dementia is also is a disorder they can get this far into the disease. Not only does the psychiatric worsen but so does cognitive symptoms. The second to last stage is called the early advanced stage which lasts from nine to twenty-one years. They are no longer independent and can still stay living in their homes with the help of family members or with professional help. Facilities home can provide them better assistance in their needs and daily activities. They will require a lot help in all their activities and be aware of what they have to do. The last stage, the fifth stage, is called the advanced stage. The duration for this stage is eleven to twenty six years. They need a 100% help from a nurse and Chorea gets toned down. Although Chorea lessens Parkinsonism intensifies which causes slowness,unusual posture, stiffness, and grinding of the teeth. There is a more probability of accidents like falling and as it states in Huntington’s Disease News “Speech can become difficult at this stage and the patient may go through periods of confusion and screaming. The ability to swallow also can worsen, and there can be extreme fluctuations in blood pressure and temperature”.

People with Huntington’s disease die fifteen to twenty years after being diagnosed and they die because of a complication of this disease. These life threatening complications are pneumonia and heart disease. Huntington’s disease patients have a bigger chance of choking causing respiratory problems, they can get gastrointestinal problems like cancer in the pancreas. As stated in the excerpt titled ‘Complications of Huntington’s Disease’ “As a result of these movements, the epiglottis a flap that acts as a valve in our throat, prevents food from entering the airway. People with HD often lack this coordination, and food will accidentally enter the respiratory tract, leading to choking. Moreover, when food particles manage to get into the trachea (the “wind pipe” leading to the lungs), instead of the esophagus (the “food pipe” leading to the stomach), the lungs can become infected and cause what is known as aspiration pneumonia”. As stated this is one complication that leads to the death of a person with Huntington’s disease. One can prevent this from happening by adjusting the diet of the patient to a make sure they have a more appropriate intake of the right food. A study that took place in the years of 1952 until 1979 in Victoria, Australia showed that 51% of patients that had HD, died from getting pneumonia.

There is no cure for this that can backtrack or slow down the symptoms to this disease, however there is medication that helps with symptoms. Some of these medications are Tetrabenazine which is accepted by the Food and Drug Administration, treats involuntary jerking movements or chorea. Side effects do come with this medication and they are feeling sad, losing interest in relationships with others, either sleeping more or less than one should, feeling angry, and weight loss. With these side effects the patient should contact a doctor. Medication that controls movements and hallucinations are clonazepam, haloperidol, and clozapine. Depression is one of the symptoms that Huntington’s disease cause, so to ease that there is fluoxetine (Prozac), sertraline (Zoloft), nortriptyline (Pamelor). Many patients with HD experience mood phases and to lessen that they can take mood- stabilizing drugs.

To help a patients speaking ability there is a choice of doing speech therapy as well as other types of therapy to help with their different necessities. Psychotherapy helps the individual to be able to control their aggressive behavior and they are demonstrated strategies to communicate with others. Speech therapy helps better their speech and exercises the muscles that have to do with the mouth and throat. For physical therapy the therapist helps the patient gain strength in their muscles which improves their ability to walk and their balance. They also provide them with techniques on posture and how to properly use a walker or a wheelchair. Lastly occupational therapy can help the patient with HD, their family or caregivers. They teach them about equipment they can use to help assist the patient.

There are six different types of ways a person with HD can get tested to see if they carry the gene for it. The first one is the neurological examination were a neurologist asks a series of questions and does tests to be able to examine their abilities. They test their movements, their senses, and their feelings. Another test is the neuropsychological testing that has to do with the patients memory. Mentality, and reasoning. The next one will be the psychiatric evaluation which is in relation with behavior, emotions, and their thinking. Brain imaging and function is another form of testing that show the structure of the brain and how it is functioning. It can be an MRI or a CT scan. They will show how the brain has changed and how it has been affected by Huntington’s disease. There is genetic counseling to test out their genetics if they have the defective gene.

Lastly there is predictive genetic testing for those whose family members have had this disease but they themselves don’t show any signs, symptoms of having HD. Some people prefer to do this type of testing so they know what is to come and know whether they have the disease so they are able to decide if they want to have children and start a family knowing the risks there could be.

For families and patients there are organizations that are nonprofit that equip caregivers with information and services. There are also organizations that provide programs and care for individuals with Huntington’s disease.

To recap all this information Huntington’s disease is caused by an abnormal repeat of a gene that makes protein which helps neurons in particular parts of the brain. The protein from the repeated gene causes the diminishing of the nerve cells rather than creating them. They then become less over a period of time. Each area of the brain have to do with thinking, movements, mental health, and learning. There are many changes that the body experiences during different stages of this disease. Some people are affected differently and have different symptoms than others but there is some medication to help subdue the difficulties they pass having Huntington’s disease.

A person can start experiencing symptoms at an early age as well as at an old age. Women and men have the same probability of inheriting HD, also people who have European ancestry. There is five stages that each patient goes through while living with this disease. The person that has Huntington’s disease has the dominant gene. People who inherit the repeated gene are likely to start experiencing symptoms at a later stage in their lives. Some want to get tested so they can know what is to come and start preparing for their medical necessities. There are voluntary movements and involuntary movements that are caused because of HD. According to Huntington’s Disease Facts and Statistics by Nadia Khan “Huntington’s disease occurs in three out of every 100,000”. It is a genetic disease so the parent has to pass it on to their children in order for them to inherit HD. Huntington’s disease is found on chromosome 4.

Huntington’s disease causes the brain to lessen in its weight. Once a person has had HD for a lot of years the brain could lose thirty percent of all of its weight. According to statistics an adult brain is most likely to be three pounds. Over the years the brain may weigh up to only one pound which is not a good thing.

The gene of Huntington’s disease gives directions to make protein to which is called huntingtin. Huntington’s disease affects many parts of the body and some can lead to other disorders. These disorders can be depression when an individual finds out that they in fact have this disease. Another would be obsessive- compulsive disorder and being bipolar. Emotions change and so does their behavior towards others who might try to help.

As mentioned previously younger people can get HD but it’s not known for a lot of people to get it at a young age. It could sometimes be misunderstood by others that the way they behave and the symptoms they have is just regular teenage behavior. There is a chance that they go through extreme weight loss from the lack of wanting to eat food.

There is a slight difference in adult huntington’s disease and juvenile huntington’s disease. For example in teenagers it can affect their school work and their attitude towards school leading them to do bad and to not have interest in it. They can get affected in their movements, writing, thinking, have many moods, and can even get seizures. The disease doesn’t get any better after it is diagnosed making the patient suffer and have difficulty in activities they were able to do before the disease progressively worsened. One way that could help a person with Huntington’s disease is through therapy which has many other choices that deal with different topics. They include speech therapy, physical therapy, and occupational therapy, and lastly psychotherapy.

There are some ways that someone with Huntington’s disease can prevent their kids from getting the disease. People who are fearful on passing the gene because of previous members who have had the disease can do genetic testing and try to do family planning options.

For a couple who doesn’t want to pass the gene on to their newborn they can chose to do a vitro fertilization which is when eggs are discarded from the ovaries then it is fertilized with the sperm the father produces. They then test the embryos to see which has inherited the Huntington repeated gene and to check which don’t have it to chose those to insert in the female’s uterus.

Huntington’s disease has five stages. The first stage is the early stage and the patient is not really affected or experiencing any of the symptoms. They go throughout their day doing their daily activities, going to work, doing their finances. The second stage is the earl intermediate stage were they can work in the workplace but at a slower rate and can do parts of daily activities but might need assistance in performing certain things. The third is the late intermediate stage were the person can’t work or do household chores. They will need assistance in their daily activities. Their thinking slows down and their behavior towards others gets bad. The fourth stage is the early advanced stage where the patient requires a lot of help from a nurse to do activities but they will be conscious of what they need to get done. The last step wis the advanced stage where they can’t practically do anything by themselves and swallowing becomes hard for them .Huntington’s’ disease has no cure but there is medication to help with some of the symptoms. It affects an individual in their abilities to perform different tasks. It’s the breakdown of nerve cells which affects how the brain functions.